124 results on '"Alkadhi KA"'
Search Results
2. Synaptic Plasticity and Cognitive Ability in Experimental Adult-Onset Hypothyroidism.
- Author
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Alkadhi KA
- Subjects
- Animals, Humans, Neuronal Plasticity, Long-Term Potentiation physiology, Cognition, Hippocampus, Hypothyroidism
- Abstract
Adult-onset hypothyroidism impairs normal brain function. Research on animal models of hypothyroidism has revealed critical information on how deficiency of thyroid hormones impacts the electrophysiological and molecular functions of the brain, which leads to the well known cognitive impairment in untreated hypothyroid patients. Currently, such information can only be obtained from experiments on animal models of hypothyroidism. This review summarizes important research findings that pertain to understanding the clinical cognitive consequences of hypothyroidism, which will provide a better guiding path for therapy of hypothyroidism. SIGNIFICANCE STATEMENT: Cognitive impairment occurs during adult-onset hypothyroidism in both humans and animal models. Findings from animal studies validate clinical findings showing impaired long-term potentiation, decreased CaMKII, and increased calcineurin. Such findings can only be gleaned from animal experiments to show how hypothyroidism produces clinical symptoms., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2024
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3. Understanding stress: Insights from rodent models.
- Author
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Atrooz F, Alkadhi KA, and Salim S
- Abstract
Through incorporating both physical and psychological forms of stressors, a variety of rodent models have provided important insights into the understanding of stress physiology. Rodent models also have provided significant information with regards to the mechanistic basis of the pathophysiology of stress-related disorders such as anxiety disorders, depressive illnesses, cognitive impairment and post-traumatic stress disorder. Additionally, rodent models of stress have served as valuable tools in the area of drug screening and drug development for treatment of stress-induced conditions. Although rodent models do not accurately reproduce the biochemical or physiological parameters of stress response and cannot fully mimic the natural progression of human disorders, yet, animal research has provided answers to many important scientific questions. In this review article, important studies utilizing a variety of stress models are described in terms of their design and apparatus, with specific focus on their capabilities to generate reliable behavioral and biochemical read-out. The review focusses on the utility of rodent models by discussing examples in the literature that offer important mechanistic insights into physiologically relevant questions. The review highlights the utility of rodent models of stress as important tools for advancing the mission of scientific research and inquiry., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2021
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4. NMDA receptor-independent LTP in mammalian nervous system.
- Author
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Alkadhi KA
- Subjects
- Animals, Calcium metabolism, Glutamates, Hippocampus metabolism, Humans, Receptors, N-Methyl-D-Aspartate metabolism, Synapses metabolism, Long-Term Potentiation
- Abstract
Long-term potentiation (LTP) of synaptic transmission is a form of activity-dependent synaptic plasticity that exists at most synapses in the nervous system. In the central nervous system (CNS), LTP has been recorded at numerous synapses and is a prime candidate mechanism associating activity-dependent plasticity with learning and memory. LTP involves long-lasting increase in synaptic strength with various underlying mechanisms. In the CNS, the predominant type of LTP is believed to be dependent on activation of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR), which is highly calcium-permeable. However, various forms of NMDAR-independent LTP have been identified in diverse areas of the nervous system. The NMDAR-independent LTP may require activation of glutamate metabotropic receptors (mGluR) or ionotropic receptors other than NMDAR such as nicotinic acetylcholine receptor (α7-nAChR), serotonin 5-HT3 receptor or calcium-permeable AMPA receptor (CP-AMPAR). In this review, NMDAR-independent LTP of various areas of the central and peripheral nervous systems are discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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5. Comparison of Effects of Spatial and Non-Spatial Memory Acquisition on the CaMKII Pathway During Hypothyroidism and Nicotine Treatment.
- Author
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Alkadhi KA and Alzoubi KH
- Subjects
- Animals, Calcineurin metabolism, Calmodulin metabolism, Hippocampus drug effects, Hippocampus metabolism, Hippocampus pathology, Hippocampus physiopathology, Male, Morris Water Maze Test, Protein Kinase C metabolism, Rats, Wistar, Task Performance and Analysis, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Hypothyroidism metabolism, Hypothyroidism physiopathology, Nicotine pharmacology, Signal Transduction drug effects, Spatial Memory drug effects
- Abstract
Molecular, cellular, and behavioral studies have shown that hypothyroidism impairs hippocampus-dependent learning and memory in adult rats. In these studies, spatial learning and memory were tested in the radial arm water maze (RAWM), which involved locating a hidden platform. In the present study, we investigated the effects of nicotine and hypothyroidism on the CaMKII pathway during learning and memory processes in both spatial and non-spatial memory forms. We used nicotine as a neuroprotective agent. Hypothyroidism was induced by thyroidectomy in adult rats. Rats were trained on the hidden platform (the RAWM for spatial learning and memory) and compared with age-matched rats that were trained on a clearly visible platform system (2 cm above water with no radial arms for non-spatial learning and memory). Nicotine (1 mg/kg twice/day) was administered subcutaneously for 4 weeks. Immediately after training, the protein levels of memory-related signaling molecules were determined in hippocampal area CA1. Western blot analysis revealed a significant increase in calcineurin levels and decreases in P-CaMKII, PKCγ, and calmodulin protein levels in area CA1 of the hippocampi of hypothyroid rats trained on both the visible and hidden platforms. Nicotine treatment normalizes these levels in hypothyroid rats trained on both the visible and hidden platforms. The results suggest that chronic nicotine treatment prevents hypothyroidism-induced suppression of the CaMKII pathway after spatial and non-spatial learning and memory.
- Published
- 2020
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6. Cellular and Molecular Differences Between Area CA1 and the Dentate Gyrus of the Hippocampus.
- Author
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Alkadhi KA
- Subjects
- Aging physiology, Amyloid beta-Peptides metabolism, Animals, Calcium metabolism, Humans, Neuronal Plasticity, CA1 Region, Hippocampal metabolism, Dentate Gyrus metabolism
- Abstract
A distinct feature of the hippocampus of the brain is its unidirectional tri-synaptic pathway originating from the entorhinal cortex and projecting to the dentate gyrus (DG) then to area CA3 and subsequently, area CA1 of the Ammon's horn. Each of these areas of the hippocampus has its own cellular structure and distinctive function. The principal neurons in these areas are granule cells in the DG and pyramidal cells in the Ammon's horn's CA1 and CA3 areas with a vast network of interneurons. This review discusses the fundamental differences between the CA1 and DG areas regarding cell morphology, synaptic plasticity, signaling molecules, ability for neurogenesis, vulnerability to various insults and pathologies, and response to pharmacological agents.
- Published
- 2019
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7. Effect of Exercise and Aβ Protein Infusion on Long-Term Memory-Related Signaling Molecules in Hippocampal Areas.
- Author
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Alkadhi KA and Dao AT
- Subjects
- Animals, Brain-Derived Neurotrophic Factor metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Hippocampus drug effects, Infusion Pumps, Male, Memory, Long-Term drug effects, Physical Conditioning, Animal methods, Random Allocation, Rats, Amyloid beta-Peptides administration & dosage, Hippocampus metabolism, Memory, Long-Term physiology, Physical Conditioning, Animal physiology, Rats, Wistar
- Abstract
Alzheimer's disease (AD) results from over-production and aggregation of β-amyloid (Aβ) oligopeptides in the brain. The benefits of regular physical exercise are now recognized in a variety of disorders including AD. In order to understand the effect of exercise at the molecular level, we studied the impact of exercise on long-term memory-related signaling molecules in an AD rat model. The rat model of AD (AD rat) was produced by 14-day osmotic pump infusion of i.c.v. 250 pmol/day Aβ
1-42 . The effects of 4 weeks of regular rodent treadmill exercise on the protein levels of CREB, CaMKVI, and MAPK-ERK1/2 in this model were determined by immunoblot analysis in the CA1 and dentate gyrus (DG) areas of the hippocampus, which is among the first brain structures impacted by AD. Aβ infusion caused marked reductions in the basal protein levels of CaMKVI and phosphorylated CREB without significantly affecting total CREB levels in both CA1 and DG areas. As predicted, our exercise regimen totally prevented these effects in the brains of exercised AD rats. Surprisingly, however, neither Aβ infusion nor exercise had any significant effect on the levels of phosphorylated or total ERK in the CA1 and DG areas. Additionally, exercise did not increase any of these molecules in healthy normal rats, which indicated a protective effect of exercise. These findings suggest that CaMKIV is likely a major kinase for phosphorylation of CREB. Therefore, regular exercise is highly effective in preventing the effects of AD even at the molecular level in both areas of the hippocampus. Considering the well-known resistance of the DG area to insults relative to area CA1, the present findings revealed similar molecular vulnerability of the two areas to AD pathology.- Published
- 2019
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8. Neuroprotective Effects of Nicotine on Hippocampal Long-Term Potentiation in Brain Disorders.
- Author
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Alkadhi KA
- Subjects
- Animals, Humans, Brain Diseases physiopathology, Hippocampus drug effects, Hippocampus physiopathology, Long-Term Potentiation drug effects, Neuroprotective Agents pharmacology, Nicotine pharmacology
- Abstract
Long-term potentiation (LTP) is commonly considered the cellular correlate of learning and memory. In learning and memory impairments, LTP is invariably diminished in the hippocampus, the brain region responsible for memory formation. LTP is measured electrophysiologically in various areas of the hippocampus. Two mechanistically distinct phases of LTP have been identified: early phase LTP, related to short-term memory; and late-phase LTP, related to long-term memory. These two forms can be severely reduced in a variety of conditions but can be rescued by treatment with nicotine. This report reviews the literature on the beneficial effect of nicotine on LTP in conditions that compromise learning and memory., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2018
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9. Delayed effects of combined stress and Aβ infusion on L-LTP of the dentate gyrus: Prevention by nicotine.
- Author
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Alkadhi KA
- Subjects
- Animals, Infusion Pumps, Implantable, Infusions, Intraventricular, Long-Term Potentiation drug effects, Male, Rats, Rats, Wistar, Stress, Psychological metabolism, Time Factors, Amyloid beta-Peptides administration & dosage, Amyloid beta-Peptides toxicity, Long-Term Potentiation physiology, Nicotine administration & dosage, Stress, Psychological prevention & control, Stress, Psychological psychology
- Abstract
Alzheimer's Disease (AD) is a progressive dementia hallmarked by the presence in the brain of extracellular beta-amyloid (Aβ) plaques and intraneuronal fibrillary tangles. Chronic stress is associated with heightened Aβ buildup and acceleration of development of AD, however, stress alone has no significant effect on synaptic plasticity in the dentate gyrus (DG) area. Previously, we have reported that the combination of stress and AD causes more severe inhibition of synaptic plasticity of hippocampal area CA1 than chronic stress or AD alone, and that chronic nicotine treatment prevents this impairment. To investigate the effect of stress and nicotine on synaptic plasticity in the relatively injury-resistant DG area, the present experiments analyzed the effect of chronic stress and the neuroprotective effect of nicotine on LTP in the DG area of a rat model of AD. Wistar rats were chronically stressed and treated with nicotine (1 mg/kg/twice daily; s.c.) for six weeks. Then, at weeks 5-6, AD model was generated by 14-day i.c.v osmotic pump infusion of Aβ peptides (300 pmol/day) into the brains of these rats. Field potential recordings from the DG area of anesthetized rats, revealed that while chronic stress did not accentuate Aβ-induced impairments of E-LTP, it markedly augmented Aβ effect on L-LTP that was only seen 100 min after multiple high frequency stimulation. This delayed action is likely to be due to impairment of process of de novo protein synthesis required for maintenance phase of L-LTP. Chronic nicotine treatment prevented stress-enhanced suppression of synaptic plasticity., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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10. Exercise as a Positive Modulator of Brain Function.
- Author
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Alkadhi KA
- Subjects
- Animals, Humans, Neuroprotection, Oxidative Stress, Stress, Physiological, Brain physiology, Exercise physiology, Physical Conditioning, Animal
- Abstract
Various forms of exercise have been shown to prevent, restore, or ameliorate a variety of brain disorders including dementias, Parkinson's disease, chronic stress, thyroid disorders, and sleep deprivation, some of which are discussed here. In this review, the effects on brain function of various forms of exercise and exercise mimetics in humans and animal experiments are compared and discussed. Possible mechanisms of the beneficial effects of exercise including the role of neurotrophic factors and others are also discussed.
- Published
- 2018
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11. Correction to: Prevention by Regular Exercise of Acute Sleep Deprivation-Induced Impairment of Late Phase LTP and Related Signaling Molecules in the Dentate Gyrus.
- Author
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Zagaar MA, Dao AT, Alhaider IA, and Alkadhi KA
- Abstract
The original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. "Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004" should have been included on the paper.
- Published
- 2018
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12. Correction to: Moderate Treadmill Exercise Protects Synaptic Plasticity of the Dentate Gyrus and Related Signaling Cascade in a Rat Model of Alzheimer's Disease.
- Author
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Dao AT, Zagaar MA, and Alkadhi KA
- Abstract
The original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. "Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004" should have been included on the paper.
- Published
- 2018
- Full Text
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13. Exercise decreases BACE and APP levels in the hippocampus of a rat model of Alzheimer's disease.
- Author
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Alkadhi KA and Dao AT
- Subjects
- Alzheimer Disease chemically induced, Alzheimer Disease therapy, Amyloid beta-Peptides administration & dosage, Animals, Exercise Test methods, Infusions, Intraventricular, Male, Peptide Fragments administration & dosage, Physical Conditioning, Animal methods, Rats, Rats, Wistar, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Peptides toxicity, Aspartic Acid Endopeptidases metabolism, Disease Models, Animal, Peptide Fragments metabolism, Peptide Fragments toxicity, Physical Conditioning, Animal physiology
- Abstract
We investigated the effect of treadmill exercise training on the levels of Alzheimer's disease (AD)-related protein molecules in the DG and CA1 areas of a rat model of AD, i.c.v. infusion of Aβ1-42 peptide, 2weeks (250pmol/day). Aβ infusion markedly increased protein levels of amyloid precursor protein (APP), the secretase beta-site APP cleaving enzyme-1 (BACE-1) and Aβ in the CA1 and DG areas. The results also revealed that 4weeks of treadmill exercise prevented the increase in the levels of APP, BACE-1 and Aβ proteins in both hippocampal areas. Exercise, however, did not affect the levels of these proteins in normal rats. We suggest that exercise might be changing the equilibrium of APP processing pathway towards the nonpathogenic pathway most probably via increasing BDNF levels in the brain of AD model., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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14. Correction to: Comparison of the Effect of Exercise on Late-Phase LTP of the Dentate Gyrus and CA1 of Alzheimer's Disease Model.
- Author
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Dao AT, Zagaar MA, Levine AT, and Alkadhi KA
- Abstract
The original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. "Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004" should have been included on the paper.
- Published
- 2018
- Full Text
- View/download PDF
15. Comparison of the Effect of Exercise on Late-Phase LTP of the Dentate Gyrus and CA1 of Alzheimer's Disease Model.
- Author
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Dao AT, Zagaar MA, Levine AT, and Alkadhi KA
- Subjects
- Alzheimer Disease pathology, Alzheimer Disease physiopathology, Amyloid beta-Peptides toxicity, Animals, Brain-Derived Neurotrophic Factor metabolism, CA1 Region, Hippocampal pathology, Calcium-Calmodulin-Dependent Protein Kinase Type 4 metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Dentate Gyrus pathology, Disease Models, Animal, Male, Maze Learning drug effects, Memory Disorders etiology, Memory Disorders pathology, Memory Disorders physiopathology, Phosphorylation drug effects, Rats, Wistar, Alzheimer Disease complications, CA1 Region, Hippocampal physiopathology, Dentate Gyrus physiopathology, Long-Term Potentiation drug effects, Physical Conditioning, Animal
- Abstract
We investigated the neuroprotective effect of regular treadmill exercise training on long-term memory and its correlate: the late-phase long-term potentiation (L-LTP) and plasticity- and memory-related signaling molecules in the DG and CA1 areas of a rat model of Alzheimer's disease (AD) (i.c.v. infusion of Aβ
1-42 peptides, 2 weeks, 250 pmol/day). Testing in the radial arm water maze revealed severe impairment of spatial long-term memory in Aβ-infused sedentary rats but not in exercised Aβ-infused rats. The L-LTP, measured as changes in the field (f)EPSP and in the amplitude of population spike (pspike), was induced by multiple high-frequency stimulation in the CA1 and DG areas of anesthetized rats. The L-LTP of fEPSP in both areas was severely impaired in the sedentary Aβ rats but not in exercised Aβ rats. However, L-LTP of the pspike was severely suppressed in the CA1 area but not in the DG of sedentary Aβ rats. Immunoblot analysis revealed no increase in the levels of phosphorylated (p)-CREB, CaMKIV, and brain-derived neurotrophic factor (BDNF) in both CA1 and DG areas of sedentary Aβ rats during L-LTP, whereas the levels of these molecules were robustly increased in exercised Aβ rats. Impairment of synaptic function may be due to deleterious changes in the molecular signaling cascades that mediate synaptic structural and functional changes. The protective effect of regular exercise can be a promising therapeutic measure for countering or delaying the AD-like pathology.- Published
- 2016
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16. Prevention by Regular Exercise of Acute Sleep Deprivation-Induced Impairment of Late Phase LTP and Related Signaling Molecules in the Dentate Gyrus.
- Author
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Zagaar MA, Dao AT, Alhaider IA, and Alkadhi KA
- Subjects
- Animals, Brain-Derived Neurotrophic Factor metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 4 metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Male, Phosphorylation, Rats, Wistar, Dentate Gyrus metabolism, Dentate Gyrus physiopathology, Long-Term Potentiation, Physical Conditioning, Animal, Signal Transduction, Sleep Deprivation physiopathology, Sleep Deprivation prevention & control
- Abstract
The dentate gyrus (DG) and CA1 regions of the hippocampus are intimately related physically and functionally, yet they react differently to insults. The purpose of this study was to determine the protective effects of regular treadmill exercise on late phase long-term potentiation (L-LTP) and its signaling cascade in the DG region of the hippocampus of rapid eye movement (REM) sleep-deprived rats. Adult Wistar rats ran on treadmills for 4 weeks then were acutely sleep deprived for 24 h using the modified multiple platform method. After sleep deprivation, the rats were anesthetized and L-LTP was induced in the DG region. Extracellular field potentials from the DG were recorded in vivo, and levels of L-LTP-related signaling proteins were assessed both before and after L-LTP expression using immunoblot analysis. Sleep deprivation reduced the basal levels of phosphorylated cAMP response element-binding protein (P-CREB) as well as other upstream modulators including calcium/calmodulin kinase IV (CaMKIV) and brain-derived neurotrophic factor (BDNF) in the DG of the hippocampus. Regular exercise prevented impairment of the basal levels of P-CREB and total CREB as well as those of CaMKIV in sleep-deprived animals. Furthermore, regular exercise prevented sleep deprivation-induced inhibition of L-LTP and post-L-LTP downregulation of P-CREB and BDNF levels in the DG. The current findings show that our exercise regimen prevents sleep deprivation-induced deficits in L-LTP as well as the basal and poststimulation levels of key signaling molecules.
- Published
- 2016
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17. Caffeine and REM sleep deprivation: Effect on basal levels of signaling molecules in area CA1.
- Author
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Alkadhi KA and Alhaider IA
- Subjects
- Animals, Brain-Derived Neurotrophic Factor genetics, Brain-Derived Neurotrophic Factor metabolism, CA1 Region, Hippocampal metabolism, CA1 Region, Hippocampal physiology, Caffeine therapeutic use, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Central Nervous System Stimulants therapeutic use, Cyclic AMP Response Element-Binding Protein genetics, Cyclic AMP Response Element-Binding Protein metabolism, Down-Regulation, Male, Neuroprotective Agents therapeutic use, Rats, Rats, Wistar, Sleep Deprivation drug therapy, CA1 Region, Hippocampal drug effects, Caffeine pharmacology, Central Nervous System Stimulants pharmacology, Neuroprotective Agents pharmacology, Signal Transduction, Sleep Deprivation metabolism, Sleep, REM drug effects
- Abstract
We have investigated the neuroprotective effect of chronic caffeine treatment on basal levels of memory-related signaling molecules in area CA1 of sleep-deprived rats. Animals in the caffeine groups were treated with caffeine in drinking water (0.3g/l) for four weeks before they were REM sleep-deprived for 24h in the Modified Multiple Platforms paradigm. Western blot analysis of basal protein levels of plasticity- and memory-related signaling molecules in hippocampal area CA1 showed significant down regulation of the basal levels of phosphorylated- and total-CaMKII, phosphorylated- and total-CREB as well as those of BDNF and CaMKIV in sleep deprived rats. All these changes were completely prevented in rats that chronically consumed caffeine. The present findings suggest an important neuroprotective property of caffeine in sleep deprivation., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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18. Moderate Treadmill Exercise Protects Synaptic Plasticity of the Dentate Gyrus and Related Signaling Cascade in a Rat Model of Alzheimer's Disease.
- Author
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Dao AT, Zagaar MA, and Alkadhi KA
- Subjects
- Alzheimer Disease physiopathology, Amyloid beta-Peptides toxicity, Animals, Brain-Derived Neurotrophic Factor biosynthesis, Calcineurin metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Excitatory Postsynaptic Potentials physiology, Humans, Long-Term Potentiation, Male, Nerve Tissue Proteins metabolism, Peptide Fragments toxicity, Perforant Pathway physiology, Phosphorylation, Protein Processing, Post-Translational, Rats, Rats, Wistar, Running physiology, Signal Transduction physiology, Alzheimer Disease therapy, Dentate Gyrus physiopathology, Exercise Therapy, Neuronal Plasticity, Physical Conditioning, Animal physiology
- Abstract
The dentate gyrus (DG) of the hippocampus is known to be more resistant to the effects of various external factors than other hippocampal areas. This study investigated the neuroprotective effects of moderate treadmill exercise on early-phase long-term potentiation (E-LTP) and its molecular signaling pathways in the DG of amyloid β rat model of sporadic Alzheimer's disease (AD). Animals were preconditioned to run on treadmill for 4 weeks and concurrently received ICV infusion of Aβ₁₋₄₂ peptides (250 pmol/day) during the third and fourth weeks of exercise training. We utilized in vivo electrophysiological recordings to assess the effect of exercise and/or AD pathology on basal synaptic transmission and E-LTP magnitude of the perforant pathway synapses in urethane-anesthetized rats. Immunoblotting analysis was used to quantify changes in the levels of learning and memory-related key signaling molecules. The AD-impaired basal synaptic transmission and suppression of E-LTP in the DG were prevented by prior moderate treadmill exercise. In addition, exercise normalized the basal levels of memory and E-LTP-related signaling molecules including Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), calcineurin (PP2B), and brain-derived neurotrophic factor (BDNF). Exercise also prevented the reduction of phosphorylated CaMKII and aberrant increase of PP2B seen after E-LTP induction in amyloid-infused rats. Our data suggests that by restoring the balance of kinase-phosphatase, 4 weeks of moderate treadmill exercise prevents DG synaptic deficits and deleterious alterations in signaling pathways associated with AD.
- Published
- 2015
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19. Caffeine treatment prevents rapid eye movement sleep deprivation-induced impairment of late-phase long-term potentiation in the dentate gyrus.
- Author
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Alhaider IA and Alkadhi KA
- Subjects
- Animals, Brain Waves drug effects, Brain-Derived Neurotrophic Factor metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 4 metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Dentate Gyrus metabolism, Excitatory Postsynaptic Potentials drug effects, Male, Phosphorylation, Rats, Rats, Wistar, Signal Transduction drug effects, Sleep Deprivation metabolism, Caffeine administration & dosage, Dentate Gyrus drug effects, Dentate Gyrus physiopathology, Long-Term Potentiation drug effects, Sleep Deprivation physiopathology, Sleep, REM
- Abstract
The CA1 and dentate gyrus (DG) are physically and functionally closely related areas of the hippocampus, but they differ in various respects, including their reactions to different insults. The purpose of this study was to determine the protective effects of chronic caffeine treatment on late-phase long-term potentiation (L-LTP) and its signalling cascade in the DG area of the hippocampus of rapid eye movement sleep-deprived rats. Rats were chronically treated with caffeine (300 mg/L drinking water) for 4 weeks, after which they were sleep-deprived for 24 h. L-LTP was induced in in anaesthetized rats, and extracellular field potentials from the DG area were recorded in vivo. The levels of L-LTP-related signalling proteins were assessed by western blot analysis. Sleep deprivation markedly reduced L-LTP magnitude, and basal levels of total cAMP response element-binding protein (CREB), phosphorylated CREB (P-CREB), and calcium/calmodulin kinase IV (CaMKIV). Chronic caffeine treatment prevented the reductions in the basal levels of P-CREB, total CREB and CaMKIV in sleep-deprived rats. Furthermore, caffeine prevented post-L-LTP sleep deprivation-induced downregulation of P-CREB and brain-derived neurotrophic factor in the DG. The current findings show that caffeine treatment prevents acute sleep deprivation-induced deficits in brain function., (© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)
- Published
- 2015
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20. Chronic Stress Decreases Basal Levels of Memory-Related Signaling Molecules in Area CA1 of At-Risk (Subclinical) Model of Alzheimer's Disease.
- Author
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Alkadhi KA and Tran TT
- Subjects
- Animals, Brain-Derived Neurotrophic Factor metabolism, CA1 Region, Hippocampal pathology, Calcineurin metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Chronic Disease, Cyclic AMP Response Element-Binding Protein metabolism, Disease Models, Animal, Phosphorylation, Rats, Wistar, Stress, Psychological physiopathology, Alzheimer Disease metabolism, Alzheimer Disease physiopathology, CA1 Region, Hippocampal metabolism, CA1 Region, Hippocampal physiopathology, Memory, Signal Transduction, Stress, Psychological metabolism
- Abstract
An important factor that may affect the severity and time of onset of Alzheimer's disease (AD) is chronic stress. Epidemiological studies report that chronically stressed individuals are at an increased risk for developing AD. The purpose of this study was to reveal whether chronic psychosocial stress could hasten the appearance of AD symptoms including changes in basal levels of cognition-related signaling molecules in subjects who are at risk for the disease. We investigated the effect of chronic psychosocial stress on basal levels of memory-related signaling molecules in area CA1 of subclinical rat model of AD. The subclinical symptomless rat model of AD was induced by osmotic pump continuous intracerebroventricular (ICV) infusion of 160 pmol/day Aβ1-42 for 14 days. Rats were chronically stressed using the psychosocial stress intruder model. Western blot analysis of basal protein levels of important signaling molecules in hippocampal area CA1 showed no significant difference between the subclinical AD rat model and control rat. Following six weeks of psychosocial stress, molecular analysis showed that subclinical animals subjected to stress have significantly reduced basal levels of p-CaMKII and decreased p-CaMKII/t-CaMKII ratio as well as decreased basal levels of p-CREB, total CREB, and BDNF. The present results suggest that these changes in basal levels of signaling molecules may be responsible for impaired learning, memory, and LTP in this rat model, which support the proposition that chronic stress may accelerate the emergence of AD in susceptible individuals.
- Published
- 2015
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21. Chronic psychosocial stress impairs early LTP but not late LTP in the dentate gyrus of at-risk rat model of Alzheimer's disease.
- Author
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Alkadhi KA and Tran TT
- Subjects
- Amyloid beta-Peptides, Animals, CA1 Region, Hippocampal physiopathology, Calcineurin metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Catheters, Indwelling, Chronic Disease, Disease Models, Animal, Electrodes, Immunoblotting, Peptide Fragments, Rats, Wistar, Social Environment, Time Factors, Alzheimer Disease physiopathology, Dentate Gyrus physiopathology, Long-Term Potentiation physiology, Stress, Psychological physiopathology
- Abstract
The CA1 and dentate gyrus regions of the hippocampus are physically and functionally closely related but they react differently to insults. This study examined the effect of chronic psychosocial stress on the dentate gyrus of an at-risk (preclinical) rat model of Alzheimer's disease (subAβ rats). Chronic psychosocial stress was produced using a rat intruder model. The at-risk rat model of Alzheimer's disease was created by osmotic pump infusion of sub-pathological dose of Aβ (160 pmol Aβ1-42/day i.c.v) for 14 days. Electrophysiological methods were used to evoke and record early and late phase LTP in the dentate gyrus of anesthetized rats, and immunoblotting was used to measure levels of memory-related signaling molecules in the same region. Electrophysiological and molecular tests in the dentate gyrus showed that subAβ rats or stressed rats were not different from control rats. However, when the subAβ rats were chronically stressed, the combined treatments severely suppressed early phase LTP without affecting the late phase LTP of dentate gyrus. Additionally, in the chronically stressed subAβ rats the expected elevation of levels of phosphorylated CaMKII did not materialize after expression of early phase LTP suggesting impaired phosphorylation, which may explain the severely blocked early phase LTP., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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22. Chronic nicotine treatment reverses hypothyroidism-induced impairment of L-LTP induction phase: critical role of CREB.
- Author
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Alzoubi KH and Alkadhi KA
- Subjects
- Animals, Male, Rats, Rats, Wistar, Treatment Outcome, Cyclic AMP Response Element-Binding Protein physiology, Hypothyroidism drug therapy, Hypothyroidism physiopathology, Long-Term Potentiation drug effects, Long-Term Potentiation physiology, Nicotine administration & dosage
- Abstract
We have previously shown that adult onset hypothyroidism impairs late-phase long-term potentiation (L-LTP) and reduces basal protein levels of cyclic-AMP response element binding protein (CREB), mutagen-activated protein kinase (MAPKp42/44), and calcium calmodulin kinase IV (CaMKIV) in area Cornu Ammonis 1 (CA1) of the hippocampus. These changes were reversed by chronic nicotine treatment. In the present study, levels of signaling molecules important for L-LTP were determined in CA1 area of the hippocampus during the induction phase. Standard multiple high-frequency stimulation (MHFS) was used to evoke L-LTP in the CA1 area of the hippocampus of hypothyroid, nicotine-treated hypothyroid, nicotine, and sham control anaesthetized adult rats. Chronic nicotine treatment reversed hypothyroidism-induced impairment of L-LTP at the induction phase. Five minutes after MHFS, Western blotting showed an increase in the levels of P-CREB, and P-MAPKp42/44 in sham-operated control, nicotine, and nicotine-treated hypothyroid animals, but not in hypothyroid animals. The protein levels of total CREB, total MAPK p42/44, BDNF, and CaMKIV were not altered in all groups 5 min after MHFS. Therefore, normalized phosphorylation of essential kinases such as P-CREB and P-MAPK p42/44 in the CA1 area of nicotine-treated hypothyroid animals plays a crucial role in nicotine-induced rescue of L-LTP induction during hypothyroidism.
- Published
- 2014
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23. Regular exercise prevents non-cognitive disturbances in a rat model of Alzheimer's disease.
- Author
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Dao AT, Zagaar MA, Salim S, Eriksen JL, and Alkadhi KA
- Subjects
- Alzheimer Disease chemically induced, Alzheimer Disease metabolism, Animals, Anxiety chemically induced, Anxiety metabolism, Anxiety prevention & control, Behavior, Animal physiology, CA1 Region, Hippocampal pathology, Calcineurin metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Disease Models, Animal, Male, Physical Conditioning, Animal methods, Random Allocation, Rats, Rats, Wistar, Synaptic Transmission physiology, Alzheimer Disease prevention & control, CA1 Region, Hippocampal metabolism, Motor Activity physiology
- Abstract
Previously, we reported that in a rat model of sporadic Alzheimer's disease (AD) generated by exogenous administration of Aβ₁₋₄₂ (250 pmol/d for 2 wk) via mini-osmotic pump, the animals exhibited learning and memory impairment, which could be attributed to the deleterious alterations in the levels of cognition-related signalling molecules. We showed that 4 wk of treadmill exercise totally prevented these impairments. Here, we evaluated the effect of exercise on non-cognitive function and basal synaptic transmission in the Cornu Ammonis 1 (CA1) area using the same AD model. Our results indicated that the anxiety behaviour of Aβ-treated rats was prevented by 4 wk of treadmill exercise. Exercised/Aβ-infused rats spent a longer time in the centre area of the open field (OF), elevated plus maze (EPM) paradigms and the light area of the light-dark (LD) box, which were similar to those of control and exercise rats. Furthermore, under basal conditions the aberrant up-regulation of calcineurin (PP2B) and reduction of phosphorylated Ca²⁺/calmodulin dependent protein kinase II (p-CaMKII) levels induced by AD-like pathology were normalised by the exercise regimen. We conclude that regular exercise may exert beneficial effects on both cognitive and non-cognitive functions in this AD model.
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- 2014
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24. Levothyroxin replacement therapy restores hypothyroidism induced impairment of L-LTP induction: critical role of CREB.
- Author
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Alzoubi KH and Alkadhi KA
- Subjects
- Animals, Blotting, Western, CA1 Region, Hippocampal drug effects, Disease Models, Animal, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, Hypothyroidism complications, Male, Phosphorylation, Rats, Rats, Wistar, Signal Transduction drug effects, Signal Transduction physiology, Thyroidectomy, CA1 Region, Hippocampal metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Hypothyroidism metabolism, Long-Term Potentiation drug effects, Thyroxine pharmacology
- Abstract
Cyclic-AMP response element binding protein (CREB) is a transcription factor crucial for late phase long-term potentiation (L-LTP) induction and maintenance. Upon multiple high frequency stimulation (MHFS), large Ca(2+) influx activates adenylyl cyclase. This, in turn, activates PKA, which by itself or through MAPK p42/p44 can activate (phosphorylate) CREB. Upon phosphorylation, P-CREB activates multiple genes essential for L-LTP generation. Calcium calmodulin kinase IV (CaMKIV) is also activated by calcium and can directly activate CREB. We have shown previously that hypothyroidism impairs L-LTP and reduces the basal protein levels of CREB, MAPK p42/p44, and CaMKIV in area CA1 of the hippocampus. In the present study, levels of these signaling molecules were determined in area CA1 during the induction and maintenance phases of L-LTP. Standard MHFS was used to evoke L-LTP in the CA1 area of hypothyroid, levothyroxin treated hypothyroid and sham control anesthetized adult rats. Chronic levothyroxin treatment reversed hypothyroidism-induced L-LTP impairment. Five minutes after MHFS, western blotting showed an increase in the levels of P-CREB, and P-MAPK p42/p44 in sham-operated control, and levothyroxin treated hypothyroid animals, but not in hypothyroid animals. The protein levels of total CREB, total MAPK p42/p44, BDNF and CaMKIV were not altered in all groups five minutes after MHFS. Four hours after MHFS, the levels of P-CREB, and P-MAPK p42/p44 remained unchanged in hypothyroid animals, while they were elevated in sham-operated control, and levothyroxin treated hypothyroid animals. We conclude that respective normalized phosphorylation of essential kinases such as P-CREB and P-MAPK p42/p44 is correlated with restoration of normal L-LTP induction and maintenance in the CA1 area of levothyroxin-treated hypothyroid animals., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2014
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25. Diabetes impairs synaptic plasticity in the superior cervical ganglion: possible role for BDNF and oxidative stress.
- Author
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Alzoubi KH, Khabour OF, Alhaidar IA, Aleisa AM, and Alkadhi KA
- Subjects
- Action Potentials, Animals, Diabetes Mellitus, Experimental physiopathology, Glutathione metabolism, Male, Rats, Rats, Wistar, Superior Cervical Ganglion physiopathology, Brain-Derived Neurotrophic Factor metabolism, Diabetes Mellitus, Experimental metabolism, Long-Term Potentiation, Oxidative Stress, Superior Cervical Ganglion metabolism
- Abstract
The majority of diabetics develop serious disorders of the autonomic nervous system; however, there is no clear understanding on the causes of these complications. In this study, we examined the effect of streptozocin (STZ)-induced diabetes on activity-dependent synaptic plasticity, associated levels of brain-derived neurotrophic factor (BDNF) and antioxidant biomarkers in the rat sympathetic superior cervical ganglion. Diabetes (STZ-induced) was achieved by a single intraperitoneal injection of streptozocin (55 mg/kg).Compound action potentials were recorded from isolated ganglia before (basal) and after repetitive stimulation, or trains of paired pulses to express ganglionic long-term potentiation (gLTP) or long-term depression (gLTD). The input/output curves of ganglia from STZ-treated animals showed a marked rightward shift along most stimulus intensities, compared to those of ganglia from control animals, indicating impaired basal synaptic transmission in ganglia from STZ-induced diabetic animals. Repetitive stimulation induced robust gLTP and gLTD in ganglia isolated from control animals; the same protocols failed to induce gLTP or gLTD in ganglia from STZ-induced diabetic animals, indicating impairment of activity-dependent synaptic plasticity in these animals. Molecular analysis revealed significant reduction in the levels of BDNF and the ratio of glutathione/oxidized glutathione. Additionally, the activity of glutathione peroxidase, glutathione reductase, catalase, and the levels of thiobarbituric acid-reactive substances were increased in ganglia from STZ-treated animals. In conclusion, impaired basal synaptic transmission and synaptic plasticity are associated with reduced BDNF and altered oxidative stress biomarkers in the sympathetic ganglia from STZ-induced diabetic animals, suggesting a possible correlation of these factors with the manifestations of STZ-induced diabetes in the peripheral nervous system.
- Published
- 2013
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26. Grape powder intake prevents ovariectomy-induced anxiety-like behavior, memory impairment and high blood pressure in female Wistar rats.
- Author
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Patki G, Allam FH, Atrooz F, Dao AT, Solanki N, Chugh G, Asghar M, Jafri F, Bohat R, Alkadhi KA, and Salim S
- Subjects
- Animals, Anxiety etiology, Anxiety metabolism, Blood Pressure drug effects, Female, Gene Expression drug effects, Hippocampus drug effects, Hippocampus metabolism, Hippocampus pathology, Hypertension etiology, Hypertension metabolism, Lactoylglutathione Lyase genetics, Lactoylglutathione Lyase metabolism, Long-Term Potentiation drug effects, Maze Learning drug effects, Memory Disorders etiology, Memory Disorders metabolism, Ovariectomy adverse effects, Powders, Rats, Rats, Wistar, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Anxiety prevention & control, Estrogens deficiency, Hypertension prevention & control, Memory Disorders prevention & control, Plant Extracts pharmacology, Vitis chemistry
- Abstract
Diminished estrogen influence at menopause is reported to be associated with cognitive decline, heightened anxiety and hypertension. While estrogen therapy is often prescribed to overcome these behavioral and physiological deficits, antioxidants which have been shown beneficial are gaining nutritional intervention and popularity. Therefore, in the present study, utilizing the antioxidant properties of grapes, we have examined effect of 3 weeks of grape powder (GP; 15 g/L dissolved in tap water) treatment on anxiety-like behavior, learning-memory impairment and high blood pressure in ovariectomized (OVX) rats. Four groups of female Wistar rats were used; sham control, sham-GP treated, OVX and OVX+GP treated. We observed a significant increase in systolic and diastolic blood pressure in OVX rats as compared to sham-controls. Furthermore, ovariectomy increased anxiety-like behavior and caused learning and memory impairment in rats as compared to sham-controls. Interestingly, providing grape powder treated water to OVX rats restored both systolic and diastolic blood pressure, decreased anxiety-like behavior and improved memory function. Moreover, OVX rats exhibited an impaired long term potentiation which was restored with grape powder treatment. Furthermore, ovariectomy increased oxidative stress in the brain, serum and urine, selectively decreasing antioxidant enzyme, glyoxalase-1 protein expression in the hippocampus but not in the cortex and amygdala of OVX rats, while grape powder treatment reversed these effects. Other antioxidant enzyme levels, including manganese superoxide dismutase (SOD) and Cu/Zn SOD remained unchanged. We suggest that grape powder by regulating oxidative stress mechanisms exerts its protective effect on blood pressure, learning-memory and anxiety-like behavior. Our study is the first to examine behavioral, biochemical, physiological and electrophysiological outcome of estrogen depletion in rats and to test protective role of grape powder, all in the same study.
- Published
- 2013
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27. Treadmill exercise prevents learning and memory impairment in Alzheimer's disease-like pathology.
- Author
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Dao AT, Zagaar MA, Levine AT, Salim S, Eriksen JL, and Alkadhi KA
- Subjects
- Alzheimer Disease chemically induced, Alzheimer Disease pathology, Amyloid beta-Peptides toxicity, Analysis of Variance, Animals, Brain-Derived Neurotrophic Factor metabolism, CA1 Region, Hippocampal pathology, Calcineurin metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Disease Models, Animal, Drug Delivery Systems, Electric Stimulation, Exercise Test, Long-Term Potentiation drug effects, Male, Maze Learning drug effects, Memory, Short-Term drug effects, Peptide Fragments toxicity, Rats, Rats, Wistar, Up-Regulation drug effects, Alzheimer Disease complications, Alzheimer Disease rehabilitation, Learning Disabilities prevention & control, Memory Disorders prevention & control, Physical Conditioning, Animal methods
- Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive memory loss. In contrast, accumulating evidence suggests a neuroprotective role of regular exercise in aging associated memory impairment. In this study, we investigated the ability of regular exercise to prevent impairments of short-term memory (STM) and early long-term potentiation (E-LTP) in area CA1 of the hippocampus in a rat model of AD (i.c.v. infusion of 250 pmol/day Aβ1-42 peptides). We utilized behavioral assessment, in vivo electrophysiological recording, and immunoblotting in 4 groups of adult Wistar rats: control, treadmill exercise (Ex), β-amyloid-infused (Aβ), and amyloid-infused/treadmill exercised (Ex/Aβ). Our findings indicated that Aβ rats made significantly more errors in the radial arm water maze (RAWM) compared to all other groups and exhibited suppressed E-LTP in area CA1, which correlated with deleterious alterations in the levels of memory and E-LTP-related signaling molecules including calcineurin (PP2B), brain derivedneurotrophic factor (BDNF) and phosphorylated CaMKII (p-CaMKII). Compared to controls, Ex and Ex/Aβ rats showed a similar behavioral performance and a normal E-LTP with no detrimental changes in the levels of PP2B, BDNF, and p- CaMKII. We conclude that treadmill exercise maybe able to prevent cognitive impairment associated with AD pathology.
- Published
- 2013
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28. Role of α7- and α4β2-nAChRs in the neuroprotective effect of nicotine in stress-induced impairment of hippocampus-dependent memory.
- Author
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Alzoubi KH, Srivareerat M, Tran TT, and Alkadhi KA
- Subjects
- Aconitine analogs & derivatives, Analysis of Variance, Animals, Dihydro-beta-Erythroidine pharmacology, Disease Models, Animal, Drug Delivery Systems, Hippocampus drug effects, Male, Maze Learning drug effects, Memory Disorders etiology, Nicotinic Antagonists pharmacology, Rats, Rats, Wistar, Stress, Psychological complications, Time Factors, Hippocampus physiology, Memory Disorders drug therapy, Neuroprotective Agents therapeutic use, Nicotine therapeutic use, Receptors, Nicotinic metabolism, alpha7 Nicotinic Acetylcholine Receptor metabolism
- Abstract
We have previously shown that nicotine prevents stress-induced memory impairment. In this study, we have investigated the role of α7- and α4β2-nicotinic acetylcholine receptors (nAChRs) in the protective effect of nicotine during chronic stress conditions. Chronic psychosocial stress was induced using a form of rat intruder model. During stress, specific antagonist for either α7-nAChRs [methyllycaconitine (MLA)] or α4β2-nAChRs [dihydro-β-erythroidine (DHβE)] was infused into the hippocampus using a 4-wk osmotic pump at a rate of 82 μg/side.d and 41 μg/side.d, respectively. Three weeks after the start of infusion, all rats were subjected to a series of cognitive tests in the radial arm water maze (RAWM) for six consecutive days or until the animal reached days to criterion (DTC) in the fourth acquisition trial and in all memory tests. DTC is defined as the number of days the animal takes to make no more than one error in three consecutive days. In the short-term memory test, MLA-infused stressed/nicotine-treated rats made similar errors to those of stress and significantly more errors compared to those of stress/nicotine, nicotine or control groups. This finding was supported by the DTC values for the short memory tests. Thus, MLA treatment blocked the neuroprotective effect of nicotine during chronic stress. In contrast, DHβE infusion did not affect the RAWM performance of stress/nicotine animals. These results strongly suggest the involvement of α7-nAChRs, but not α4β2-nAChRs, in the neuroprotective effect of chronic nicotine treatment during chronic stress conditions.
- Published
- 2013
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29. Grape powder supplementation prevents oxidative stress-induced anxiety-like behavior, memory impairment, and high blood pressure in rats.
- Author
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Allam F, Dao AT, Chugh G, Bohat R, Jafri F, Patki G, Mowrey C, Asghar M, Alkadhi KA, and Salim S
- Subjects
- Animals, Anxiety etiology, Behavior, Animal, Brain Chemistry, Brain-Derived Neurotrophic Factor analysis, Buthionine Sulfoximine administration & dosage, Calcium-Calmodulin-Dependent Protein Kinase Type 4 analysis, Cyclic AMP Response Element-Binding Protein analysis, Dietary Supplements, Disease Models, Animal, Extracellular Signal-Regulated MAP Kinases metabolism, Food, Preserved, Freeze Drying, Glutathione Reductase analysis, Hypertension etiology, Lactoylglutathione Lyase analysis, Male, Memory Disorders etiology, Polyphenols administration & dosage, Rats, Rats, Sprague-Dawley, Anxiety prevention & control, Fruit chemistry, Hypertension prevention & control, Memory Disorders prevention & control, Oxidative Stress physiology, Vitis chemistry
- Abstract
We examined whether or not grape powder treatment ameliorates oxidative stress-induced anxiety-like behavior, memory impairment, and hypertension in rats. Oxidative stress in Sprague-Dawley rats was produced by using L-buthionine-(S,R)-sulfoximine (BSO). Four groups of rats were used: 1) control (C; injected with vehicle and provided with tap water), 2) grape powder-treated (GP; injected with vehicle and provided for 3 wk with 15 g/L grape powder dissolved in tap water), 3) BSO-treated [injected with BSO (300 mg/kg body weight), i.p. for 7 d and provided with tap water], and 4) BSO plus grape powder-treated (GP+BSO; injected with BSO and provided with grape powder-treated tap water). Anxiety-like behavior was significantly greater in BSO rats compared with C or GP rats (P < 0.05). Grape powder attenuated BSO-induced anxiety-like behavior in GP+BSO rats. BSO rats made significantly more errors in both short- and long-term memory tests compared with C or GP rats (P < 0.05), which was prevented in GP+BSO rats. Systolic and diastolic blood pressure was significantly greater in BSO rats compared with C or GP rats (P < 0.05), whereas grape powder prevented high blood pressure in GP+BSO rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK-1/2) was activated (P < 0.05), whereas levels of glyoxalase-1 (GLO-1), glutathione reductase-1 (GSR-1), calcium/calmodulin-dependent protein kinase type IV (CAMK-IV), cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) were significantly less (P < 0.05) in BSO but not in GP+BSO rats compared with C or GP rats. We suggest that by regulating brain ERK-1/2, GLO-1, GSR-1, CAMK-IV, CREB, and BDNF levels, grape powder prevents oxidative stress-induced anxiety, memory impairment, and hypertension in rats.
- Published
- 2013
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30. Caffeine prevents cognitive impairment induced by chronic psychosocial stress and/or high fat-high carbohydrate diet.
- Author
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Alzoubi KH, Abdul-Razzak KK, Khabour OF, Al-Tuweiq GM, Alzubi MA, and Alkadhi KA
- Subjects
- Analysis of Variance, Animals, Body Weight drug effects, Disease Models, Animal, Male, Maze Learning drug effects, Memory drug effects, Rats, Rats, Wistar, Time Factors, Caffeine therapeutic use, Central Nervous System Stimulants therapeutic use, Cognition Disorders etiology, Cognition Disorders prevention & control, Diet, High-Fat adverse effects, Stress, Psychological complications
- Abstract
Caffeine alleviates cognitive impairment associated with a variety of health conditions. In this study, we examined the effect of caffeine treatment on chronic stress- and/or high fat-high carbohydrate Western diet (WD)-induced impairment of learning and memory in rats. Chronic psychosocial stress, WD and caffeine (0.3 g/L in drinking water) were simultaneously administered for 3 months to adult male Wistar rats. At the conclusion of the 3 months, and while the previous treatments continued, rats were tested in the radial arm water maze (RAWM) for learning, short-term and long-term memory. This procedure was applied on a daily basis to all animals for 5 consecutive days or until the animal reaches days to criterion (DTC) in the 12th learning trial and memory tests. DTC is the number of days that the animal takes to make zero error in two consecutive days. Chronic stress and/or WD groups caused impaired learning, which was prevented by chronic caffeine administration. In the memory tests, chronic caffeine administration also prevented memory impairment during chronic stress conditions and/or WD. Furthermore, DTC value for caffeine treated stress, WD, and stress/WD groups indicated that caffeine normalizes memory impairment in these groups. These results showed that chronic caffeine administration prevented stress and/or WD-induced impairment of spatial learning and memory., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
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31. Chronic caffeine treatment prevents stress-induced LTP impairment: the critical role of phosphorylated CaMKII and BDNF.
- Author
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Alzoubi KH, Srivareerat M, Aleisa AM, and Alkadhi KA
- Subjects
- Animals, CA1 Region, Hippocampal physiology, Calcineurin metabolism, Electric Stimulation, Male, Neurons physiology, Phosphorylation, Rats, Rats, Wistar, Signal Transduction, Brain-Derived Neurotrophic Factor metabolism, Caffeine pharmacology, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Central Nervous System Stimulants pharmacology, Long-Term Potentiation drug effects, Stress, Psychological physiopathology
- Abstract
Caffeine has been reported to enhance cognition in animal and humans. Additionally, caffeine alleviates cognitive impairment associated with a number of disorders including Alzheimer's disease. The lipophilic nature of caffeine allows for rapid absorption into the bloodstream where it freely crosses the blood-brain barrier. Caffeine promotes dendritic spine growth in cultured hippocampal neurons, which suggests a neuroprotective effect. We examined the effect of chronic caffeine treatment on stress-induced suppression of long-term potentiation (LTP) and impairment of molecules of its signaling cascade. Rats were subjected to daily stress using the psychosocial stress paradigm (intruder model), in vivo recordings from area CA1 of the hippocampus of adult rat, and immunoblot analysis of essential signaling molecules. Caffeine prevented stress-induced LTP impairment. Western blot analysis showed reduction of the basal levels of the phosphorylated calcium calmodulin kinase II (P-CAMKII), total CaMKII, and brain-derived neurotrophic factor (BDNF) in area CA1 of stressed rats. These reductions were prevented by chronic caffeine treatment (0.33 mg/L in drinking water). In addition, caffeine prevented the upregulation of calcineurin levels in stressed rats. High-frequency stimulation (HFS) normally increased P-CaMKII, total CaMKII, and calcineurin levels in control as well as in caffeine-treated stressed rats. However, in stressed rats, the same HFS induced increases in the levels of total CaMKII and calcineurin, but not those of P-CaMKII. The levels of signaling molecules may not reflect activities of these molecules. It appears that the neuroprotective effect of caffeine involves preservation of the levels of essential kinases and phosphatases in stressed rats. This may include preservation of basal levels of BDNF by chronic caffeine treatment in stressed animals. These findings highlight the critical role of P-CaMKII and BDNF in caffeine-induced prevention of stress-induced LTP impairment.
- Published
- 2013
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32. Elevation of BACE in an Aβ rat model of Alzheimer's disease: exacerbation by chronic stress and prevention by nicotine.
- Author
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Alkadhi KA, Alzoubi KH, Srivareerat M, and Tran TT
- Subjects
- Alzheimer Disease etiology, Amyloid beta-Protein Precursor metabolism, Animals, Chronic Disease, Disease Models, Animal, Male, Nicotine pharmacology, Rats, Rats, Wistar, Stress, Psychological complications, Stress, Psychological prevention & control, Alzheimer Disease enzymology, Alzheimer Disease prevention & control, Amyloid Precursor Protein Secretases metabolism, Aspartic Acid Endopeptidases metabolism, Nicotine therapeutic use, Stress, Psychological enzymology
- Abstract
In Alzheimer's disease (AD), progressive accumulation of β-amyloid (Aβ) peptides impairs nicotinic acetylcholine receptor (nAChR) function by a mechanism that may involve α7 and α4β2-nAChR subtypes. Additionally, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), the rate-limiting enzyme in the pathogenic Aβ production pathway, is expressed at high levels in hippocampal and cortical regions of AD brains. We measured hippocampal area CA1 protein levels of BACE and α7- and α4β2-nAChR subunits using an Aβ rat model of AD (14-d osmotic pump i.c.v. infusion of 300 pmol/d Aβ peptides) in the presence and absence of chronic stress and/or chronic nicotine treatment. There was a significant increase in the levels of BACE in Aβ-infused rats, which were markedly intensified by chronic (4-6 wk) stress, but were normalized in Aβ rats chronically treated with nicotine (1 mg/kg b.i.d.). The levels of the three subunits α7, α4 and β2 were significantly decreased in Aβ rats, but these were also normalized in Aβ rats chronically treated with nicotine. Chronic stress did not further aggravate the reduction of nAChRs in Aβ-infused rats. The increased BACE levels and decreased nAChR levels, which are established hallmarks of AD, provide additional support for the validity of the Aβ i.c.v.-infused rat as a model of AD.
- Published
- 2012
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33. Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stress-induced amnesia.
- Author
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Zoladz PR, Park CR, Halonen JD, Salim S, Alzoubi KH, Srivareerat M, Fleshner M, Alkadhi KA, and Diamond DM
- Subjects
- Amnesia etiology, Animals, Brain-Derived Neurotrophic Factor metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Male, Phosphorylation physiology, Rats, Rats, Sprague-Dawley, Stress, Psychological complications, Amnesia metabolism, Amygdala metabolism, Hippocampus metabolism, Maze Learning physiology, Predatory Behavior physiology, Prefrontal Cortex metabolism, Stress, Psychological metabolism
- Abstract
We have studied the effects of spatial learning and predator stress-induced amnesia on the expression of calcium/calmodulin-dependent protein kinase II (CaMKII), brain-derived neurotrophic factor (BDNF) and calcineurin in the hippocampus, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adult male rats were given a single training session in the radial-arm water maze (RAWM) composed of 12 trials followed by a 30-min delay period, during which rats were either returned to their home cages or given inescapable exposure to a cat. Immediately following the 30-min delay period, the rats were given a single test trial in the RAWM to assess their memory for the hidden platform location. Under control (no stress) conditions, rats exhibited intact spatial memory and an increase in phosphorylated CaMKII (p-CaMKII), total CaMKII, and BDNF in dorsal CA1. Under stress conditions, rats exhibited impaired spatial memory and a suppression of all measured markers of molecular plasticity in dorsal CA1. The molecular profiles observed in the BLA, mPFC, and ventral CA1 were markedly different from those observed in dorsal CA1. Stress exposure increased p-CaMKII in the BLA, decreased p-CaMKII in the mPFC, and had no effect on any of the markers of molecular plasticity in ventral CA1. These findings provide novel observations regarding rapidly induced changes in the expression of molecular plasticity in response to spatial learning, predator exposure, and stress-induced amnesia in brainregions involved in different aspects of memory processing., (Copyright © 2011 Wiley Periodicals, Inc.)
- Published
- 2012
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34. Chronic psychosocial stress exposes Alzheimer's disease phenotype in a novel at-risk model.
- Author
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Alkadhi KA
- Subjects
- Alzheimer Disease psychology, Animals, Chronic Disease, Humans, Maze Learning, Neuronal Plasticity, Phenotype, Rats, Alzheimer Disease complications, Disease Models, Animal, Disease Susceptibility, Stress, Psychological complications
- Abstract
Because of the extensive individual variations in the time of onset and severity of the prevalent sporadic form of Alzheimer's disease (AD), a patient-related external factor must be assumed to play a significant role in the development of the disease. Since stress is increasingly recognized as an external factor in the development of AD, a number of labs, including this lab, have shown that chronic stress or corticosterone administration worsens the AD phenotype in both transgenic and non-transgenic models of the disease. Recently we develop a novel at-risk model that correlates with seemingly normal individuals who are predisposed to develop AD. This review is a summarized recount of the findings we have reported on the effect of chronic psychosocial stress in this at-risk model of AD. Behavioral (learning and memory tests), electrophysiological and molecular findings indicated that even mild chronic psychosocial stress clearly transforms this seemingly normal rat model to a full-fledge AD phenotype.
- Published
- 2012
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35. Chronic stress and Alzheimer's disease-like pathogenesis in a rat model: prevention by nicotine.
- Author
-
Alkadhi KA
- Abstract
Environmental factors including chronic stress may play a critical role in the manifestation of Alzheimer's disease (AD).This review summarizes our studies of the aggravation of the impaired cognitive ability and its cellular and molecular correlates by chronic psychosocial stress and prevention by nicotine in an Aβ rat model of AD. We utilized three approaches: learning and memory tests in the radial arm water maze, electrophysiological recordings of the cellular correlates of memory, long-term potentiation (LTP) and long-term depression (LTD), in anesthetized rats, and immunoblot analysis of synaptic plasticity- and cognition-related signaling molecules. The Aβ rat model, representing the sporadic form of established AD, was induced by continuous i.c.v. infusion of a pathogenic dose of Aβ peptides via a 14- day osmotic pump. In this AD model, chronic stress intensified cognitive deficits, accentuated the disruption of signaling molecules levels and produced greater depression of LTP than what was seen with Aβ infusion alone. Chronic treatment with nicotine was highly efficient in preventing the effects of Aβ infusion and the exacerbating impact of chronic stress. Possible mechanisms for the effect of chronic stress are discussed.
- Published
- 2011
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36. Chronic psychosocial stress exacerbates impairment of synaptic plasticity in β-amyloid rat model of Alzheimer's disease: prevention by nicotine.
- Author
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Alkadhi KA, Alzoubi KH, Srivareerat M, and Tran TT
- Subjects
- Alzheimer Disease chemically induced, Amyloid beta-Peptides toxicity, Animals, Blotting, Western, Disease Models, Animal, Male, Rats, Rats, Wistar, Alzheimer Disease physiopathology, Alzheimer Disease psychology, Neuronal Plasticity drug effects, Nicotine pharmacology, Nicotinic Agonists pharmacology, Stress, Psychological complications
- Abstract
Alzheimer's disease (AD) is a degenerative disorder that leads to progressive, irreversible cognitive decline. It develops as a result of over-production and aggregation of β-amyloid (Aβ) peptides in the brain. We have recently shown that stress exacerbates, while nicotine prevents long-term memory impairment induced by β-Amyloid. In this study, we evaluated the effect of chronic psychosocial stress on synaptic plasticity (Late-phase long-term potentiation; L-LTP, and long-term depression; LTD) in the β-Amyloid rat model of AD, and the positive impact of chronic nicotine treatment. Chronic psychosocial stress was induced by an intruder method. The Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ1-40/Aβ1-42. The rats were treated with nicotine (2 mg/kg/day) for 6 weeks. In vivo electrophysiological recordings of L-LTP, and LTD in hippocampal area CA1 showed that chronic stress by itself did not affect L-LTP. However, it markedly aggravated the impairment of this response as well as LTD in Aβ- treated rats. The effects of Aβ and the combination of stress and Aβ were totally prevented by chronic nicotine treatment. Immunoblot analysis revealed that stress and/or Aβ significantly increased the basal levels of calcineurin and prevented the expected L-LTP-induced increase in CREB phosphorylation, and CaMKIV levels. These effects were not seen in Aβ- infused rats chronically treated with nicotine. The changes in synaptic plasticity-related molecules may explain the effects of stress and/or chronic nicotine on L-LTP in Aβ animals.
- Published
- 2011
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37. Chronic psychosocial stress enhances long-term depression in a subthreshold amyloid-beta rat model of Alzheimer's disease.
- Author
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Tran TT, Srivareerat M, Alhaider IA, and Alkadhi KA
- Subjects
- Alzheimer Disease chemically induced, Alzheimer Disease pathology, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides administration & dosage, Animals, Aspartic Acid Endopeptidases metabolism, Blotting, Western, Brain-Derived Neurotrophic Factor metabolism, CA1 Region, Hippocampal metabolism, Calcineurin blood, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Chronic Disease, Depression genetics, Depression physiopathology, Electrophysiological Phenomena, Hippocampus pathology, Infusion Pumps, Implantable, Male, Peptide Fragments administration & dosage, Rats, Rats, Wistar, Risk, Stress, Psychological genetics, Stress, Psychological physiopathology, Synaptic Transmission, Alzheimer Disease psychology, Amyloid beta-Peptides pharmacology, Depression psychology, Peptide Fragments pharmacology, Social Environment, Stress, Psychological psychology
- Abstract
In addition to genetic aspects, environmental factors such as stress may also play a critical role in the etiology of the late onset, sporadic Alzheimer's disease (AD). The present study examined the effect of chronic psychosocial stress in a sub-threshold Aβ (subAβ) rat model of AD on long-term depression by two techniques: electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of memory- and AD-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD, which was intended to represent outwardly normal individuals with a pre-disposition to AD, was induced by continuous infusion of 160 pmol/day Aβ₁₋₄₂ via a 14-day i.c.v. osmotic pump. Results from electrophysiological recordings showed that long-term depression evoked in stress/subAβ animals was significantly enhanced compared with that in animals exposed to stress or subAβ infusion alone. Molecular analysis of various signaling molecules 1 h after induction of long-term depression revealed an increase in the levels of calcineurin and phosphorylated CaMKII in groups exposed to stress compared with other groups. The levels of the brain-derived neurotrophic factor (BDNF) were significantly decreased in stress/subAβ animals but not in stress or subAβ animals. In addition, the levels of beta-site amyloid precursor protein cleaving enzyme were markedly increased in stress/subAβ. These findings suggest that chronic stress may accelerate the impairment of synaptic plasticity and consequently cognition in individuals 'at-risk' for AD., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)
- Published
- 2011
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38. Acute nicotine treatment prevents REM sleep deprivation-induced learning and memory impairment in rat.
- Author
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Aleisa AM, Helal G, Alhaider IA, Alzoubi KH, Srivareerat M, Tran TT, Al-Rejaie SS, and Alkadhi KA
- Subjects
- Animals, Male, Maze Learning drug effects, Memory Disorders drug therapy, Rats, Rats, Wistar, Sleep Deprivation physiopathology, Sleep, REM, Space Perception drug effects, Stress, Psychological, CA1 Region, Hippocampal drug effects, Dentate Gyrus drug effects, Long-Term Potentiation drug effects, Memory, Short-Term drug effects, Nicotine administration & dosage, Nicotine therapeutic use
- Abstract
Rapid eye movement (REM) sleep deprivation (SD) is implicated in impairment of spatial learning and memory and hippocampal long-term potentiation (LTP). An increase in nicotine consumption among habitual smokers and initiation of tobacco use by nonsmokers was observed during SD. Although nicotine treatment was reported to attenuate the impairment of learning and memory and LTP associated with several mental disorders, the effect of nicotine on SD-induced learning and memory impairment has not been studied. Modified multiple platform paradigm was used to induce SD for 24 or 48 h during which rats were injected with saline or nicotine (1 mg kg(-1) s.c.) twice a day. In the radial arm water maze (RAWM) task, 24- or 48-h SD significantly impaired learning and short-term memory. In addition, extracellular recordings from CA1 and dentate gyrus (DG) regions of the hippocampus in urethane anesthetized rats showed a significant impairment of LTP after 24- and 48-h SD. Treatment of normal rats with nicotine for 24 or 48 h did not enhance spatial learning and memory or affect magnitude of LTP in the CA1 and DG regions. However, concurrent, acute treatment of rats with nicotine significantly attenuated SD-induced impairment of learning and STM and prevented SD-induced impairment of LTP in the CA1 and DG regions. These results show that acute nicotine treatment prevented the deleterious effect of sleep loss on cognitive abilities and synaptic plasticity., (Copyright © 2010 Wiley-Liss, Inc.)
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- 2011
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39. Post-learning REM sleep deprivation impairs long-term memory: reversal by acute nicotine treatment.
- Author
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Aleisa AM, Alzoubi KH, and Alkadhi KA
- Subjects
- Animals, Male, Memory Disorders etiology, Memory, Long-Term physiology, Rats, Rats, Wistar, Memory Disorders drug therapy, Memory, Long-Term drug effects, Nicotine pharmacology, Sleep Deprivation complications
- Abstract
Rapid eye movement sleep deprivation (REM-SD) is associated with spatial learning and memory impairment. During REM-SD, an increase in nicotine consumption among habitual smokers and initiation of tobacco use by non-smokers have been reported. We have shown recently that nicotine treatment prevented learning and memory impairments associated with REM-SD. We now report the interactive effects of post-learning REM-SD and/or nicotine. The animals were first trained on the radial arm water maze (RAWM) task, then they were REM-sleep deprived using the modified multiple platform paradigm for 24h. During REM-SD period, the rats were injected with saline or nicotine (1mg/kg s.c. every 12h: a total of 3 injections). The animals were tested for long-term memory in the RAWM at the end of the REM-SD period. The 24h post-learning REM-SD significantly impaired long-term memory. However, nicotine treatment reversed the post-learning REM-SD-induced impairment of long-term memory. On the other hand, post-learning treatment of normal rats with nicotine for 24h enhanced long-term memory. These results indicate that post-learning acute nicotine treatment prevented the deleterious effect of REM-SD on cognitive abilities., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2011
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40. Chronic psychosocial stress accelerates impairment of long-term memory and late-phase long-term potentiation in an at-risk model of Alzheimer's disease.
- Author
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Tran TT, Srivareerat M, and Alkadhi KA
- Subjects
- Alzheimer Disease metabolism, Amyloid beta-Peptides administration & dosage, Amyloid beta-Peptides physiology, Animals, Chronic Disease, Cognition Disorders etiology, Cognition Disorders psychology, Male, Rats, Rats, Wistar, Risk Factors, Stress, Psychological metabolism, Time Factors, Alzheimer Disease etiology, Alzheimer Disease psychology, Disease Models, Animal, Long-Term Potentiation physiology, Memory, Long-Term physiology, Stress, Psychological etiology, Stress, Psychological psychology
- Abstract
Although it is generally agreed that Aβ contributes to the pathogenesis of AD, its precise role in AD and the reason for the varying intensity and time of onset of the disease have not been elucidated. In addition to genetic factors, environmental issues such as stress may also play a critical role in the etiology of AD. This study examined the effect of chronic psychosocial stress in an at-risk (treatment with a subpathogenic dose of Aβ; "subAβ") rat model of AD on long-term memory by three techniques: memory tests in the radial arm water maze, electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of learning- and long-term memory-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD was induced by continuous infusion of 160 pmol/day Aβ(1-42) via a 14-day i.c.v. osmotic pump. All tests showed that subAβ rats were not different from control rats. Result from behavioral tests and electrophysiological recordings showed that infusion of subAβ in chronically stressed rats (stress/subAβ group) caused significant impairment of cognitive functions and late-phase long-term potentiation (L-LTP). Molecular analysis of various signaling molecules after expression of L-LTP, revealed an increase in the levels of p-CREB in control, stress, and subAβ rats, but not in the stress/subAβ rats. These findings suggest that the chronic stress-induced molecular alteration may accelerate the impairment of cognition and synaptic plasticity in individuals "at-risk" for AD., (Copyright © 2010 Wiley-Liss, Inc.)
- Published
- 2011
- Full Text
- View/download PDF
41. Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease.
- Author
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Srivareerat M, Tran TT, Salim S, Aleisa AM, and Alkadhi KA
- Subjects
- Amyloid Precursor Protein Secretases metabolism, Animals, Aspartic Acid Endopeptidases metabolism, Brain-Derived Neurotrophic Factor biosynthesis, CA1 Region, Hippocampal drug effects, Disease Models, Animal, Learning drug effects, Male, Maze Learning drug effects, Rats, Rats, Wistar, Receptors, Nicotinic drug effects, Synaptic Transmission drug effects, Up-Regulation, Alzheimer Disease drug therapy, Amyloid beta-Peptides metabolism, Ganglionic Stimulants therapeutic use, Long-Term Potentiation drug effects, Memory Disorders drug therapy, Memory, Short-Term drug effects, Nicotine therapeutic use
- Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (Aβ) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of Aβ peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve α(7)- and α(4)β(2)-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of Aβ-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ(1-40)/Aβ(1-42) or Aβ(40-1) (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on Aβ-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), Aβ and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of Aβ(1-40) and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aβ-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aβ-induced reduction of α(7)- and α(4)-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF)., (Copyright © 2009 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
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42. Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine.
- Author
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Alhaider IA, Aleisa AM, Tran TT, and Alkadhi KA
- Subjects
- Animals, Cyclic AMP Response Element-Binding Protein genetics, Hippocampus drug effects, Hippocampus metabolism, Humans, Long-Term Potentiation drug effects, Long-Term Potentiation physiology, Male, Memory Disorders etiology, Phosphorylation, Rats, Rats, Wistar, Sleep Deprivation complications, Brain drug effects, Brain metabolism, Brain-Derived Neurotrophic Factor metabolism, Caffeine pharmacology, Cyclic AMP Response Element-Binding Protein metabolism, Memory drug effects, Sleep Deprivation physiopathology
- Abstract
It is well known that caffeine and sleep deprivation have opposing effects on learning and memory; therefore, this study was undertaken to determine the effects of chronic (4wks) caffeine treatment (0.3g/l in drinking water) on long-term memory deficit associated with 24h sleep deprivation. Animals were sleep deprived using the modified multiple platform method. The results showed that chronic caffeine treatment prevented the impairment of long-term memory as measured by performance in the radial arm water maze task and normalized L-LTP in area CA1 of the hippocampi of sleep-deprived anesthetized rats. Sleep deprivation prevents the high frequency stimulation-induced increases in the levels of phosphorylated-cAMP response element binding protein (P-CREB) and brain-derived neurotrophic factor (BDNF) seen during the expression of late phase long-term potentiation (L-LTP). However, chronic caffeine treatment prevented the effect of sleep-deprivation on the stimulated levels of P-CREB and BDNF. The results suggest that chronic caffeine treatment may protect the sleep-deprived brain probably by preserving the levels of P-CREB and BDNF., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
43. Intensification of long-term memory deficit by chronic stress and prevention by nicotine in a rat model of Alzheimer's disease.
- Author
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Alkadhi KA, Srivareerat M, and Tran TT
- Subjects
- Amyloid metabolism, Amyloid pharmacology, Animals, Brain-Derived Neurotrophic Factor metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 4 metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Ganglionic Stimulants pharmacology, Ganglionic Stimulants therapeutic use, Learning drug effects, Learning physiology, Male, Memory Disorders drug therapy, Memory Disorders physiopathology, Memory, Long-Term physiology, Neuropsychological Tests, Nicotine pharmacology, Rats, Rats, Wistar, Stress, Physiological drug effects, Stress, Physiological physiology, Alzheimer Disease drug therapy, Alzheimer Disease physiopathology, Memory, Long-Term drug effects, Nicotine therapeutic use
- Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cholinergic dysfunction and deposition of beta-amyloid (Aβ) in regions of the brain associated with learning and memory. The sporadic nature and late onset of most AD cases suggests that aside from biological determinants, environmental factors such as stress may also play a role in the progression of the disease. Behavioral and molecular studies were utilized to evaluate the effects of chronic nicotine treatment in the prevention of impairment of long-term memory. The rat model of AD was induced by i.c.v. osmotic pump infusion of Aβ peptides. Chronic psychosocial stress and chronic nicotine treatment were instituted for 6weeks. Spatial memory testing in the Radial Arm Water Maze revealed that, although stress, by itself, did not affect long-term memory, the combination of chronic stress and Aβ infusion impaired long-term memory significantly more than Aβ peptides infusion alone. Chronic nicotine treatment completely prevented Aβ- and stress/Aβ combination-induced memory impairment. Furthermore, molecular findings in hippocampal CA1 region of stress/Aβ rats indicated marked reduction in the protein levels of phosphorylated cAMP response element binding (p-CREB) and calcium-calmodulin-dependent protein kinase IV (CaMKIV), with significant increases in the levels of brain-derived neurotrophic factor (BDNF). These disturbances in signaling pathways, which may be the underlying mechanisms of impairment of long-term memory in these rats, were totally prevented by chronic nicotine treatment., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
44. In vivo expression of ganglionic long-term potentiation in superior cervical ganglia from hypertensive aged rats.
- Author
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Alzoubi KH, Aleisa AM, and Alkadhi KA
- Subjects
- Aging metabolism, Animals, Blood Pressure physiology, Blotting, Western, Calcineurin metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Electric Stimulation, Electrophysiology, Hypertension metabolism, Long-Term Potentiation drug effects, Male, Ondansetron pharmacology, Phosphorylation physiology, Rats, Receptors, Serotonin, 5-HT3 metabolism, Serotonin Antagonists pharmacology, Signal Transduction physiology, Superior Cervical Ganglion drug effects, Superior Cervical Ganglion metabolism, Aging physiology, Hypertension physiopathology, Long-Term Potentiation physiology, Superior Cervical Ganglion physiopathology
- Abstract
Sustained increase in central sympathetic outflow to ganglia may provide the repeated high frequency presynaptic activity required for induction of long-term potentiation in sympathetic ganglia (gLTP), which is known to be involved in the manifestation of a neurogenic form of hypertension, namely stress-hypertension. Aging is often viewed as a progressive decline in physiological competence with a corresponding impaired ability to adapt to stressful stimuli. Old animals have exaggerated sympathetic activity as well as increased morbidity and mortality during prolonged exposure to stressful stimuli. Using the superior cervical ganglion (SCG) as a model for sympathetic ganglia, electrophysiological and biochemical evidence show that mildly hypertensive aged rats (22-month old) have expressed gLTP in vivo. This is suggested by a number of lines of evidence. Firstly, a shift in input/output (I/O) curve of ganglia from aged rats to the left side of I/O curve of ganglia from 6-month old (adult) rats indicating expression of gLTP. Secondly, failure of in vitro high frequency stimulation to induce gLTP in ganglia isolated from aged rats, which indicates occlusion due to saturation, which, in turn, suggests in vivo expression of gLTP in these ganglia. Thirdly, in vitro inhibition of basal ganglionic transmission by blockers of gLTP (5-HT(3) antagonists) is observed in ganglia isolated from aged rats, but not in those from adult rats. Finally, immunoblot analysis revealed that protein levels of signaling molecules such as calcium-calmodulin kinase II (CaMKII; phosphorylated and total), which normally increase during expression of LTP, are elevated in ganglia isolated from aged rats compared to those from adult ones. Protein levels of calcineurin, which dephosphorylates P-CaMKII, were reduced in ganglia isolated from aged rats, probably as a support mechanism to allow prolonged phosphorylation of CaMKII. Our findings suggest in vivo expression of gLTP in sympathetic ganglia of aged animals, which may contribute to the moderate hypertension often seen in aged subjects., ((c) 2008 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
45. Caffeine prevents sleep loss-induced deficits in long-term potentiation and related signaling molecules in the dentate gyrus.
- Author
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Alhaider IA, Aleisa AM, Tran TT, and Alkadhi KA
- Subjects
- Administration, Oral, Animals, Brain-Derived Neurotrophic Factor metabolism, Caffeine administration & dosage, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Central Nervous System Stimulants administration & dosage, Dentate Gyrus physiopathology, In Vitro Techniques, Male, Phosphorylation, Random Allocation, Rats, Rats, Wistar, Sleep Deprivation physiopathology, Synapses drug effects, Synapses physiology, Time Factors, Caffeine pharmacology, Central Nervous System Stimulants pharmacology, Dentate Gyrus drug effects, Long-Term Potentiation drug effects, Sleep Deprivation drug therapy
- Abstract
We have previously reported that caffeine prevented sleep deprivation-induced impairment of long-term potentiation (LTP) of area CA1 as well as hippocampus-dependent learning and memory performance in the radial arm water maze. In this report we examined the impact of long-term (4-week) caffeine consumption (0.3 g/L in drinking water) on synaptic plasticity (Alhaider et al., 2010) deficit in the dentate gyrus (DG) area of acutely sleep-deprived rats. The sleep deprivation and caffeine/sleep deprivation groups were sleep-deprived for 24 h by using the columns-in-water technique. We tested the effect of caffeine and/or sleep deprivation on LTP and measured the basal levels as well as stimulated levels of LTP-related molecules in the DG. The results showed that chronic caffeine administration prevented the impairment of early-phase LTP (E-LTP) in the DG of sleep-deprived rats. Additionally, chronic caffeine treatment prevented the sleep deprivation-associated decreases in the basal levels of the phosphorylated calcium/calmodulin-dependent protein kinase II (P-CaMKII) and brain derived neurotrophic factor (BDNF) as well as in the stimulated levels of P-CaMKII in the DG area. The results suggest that chronic use of caffeine prevented anomalous changes in the basal levels of P-CaMKII and BDNF associated with sleep deprivation and as a result contributes to the revival of LTP in the DG region.
- Published
- 2010
- Full Text
- View/download PDF
46. Chronic psychosocial stress triggers cognitive impairment in a novel at-risk model of Alzheimer's disease.
- Author
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Tran TT, Srivareerat M, and Alkadhi KA
- Subjects
- Alzheimer Disease complications, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Peptides toxicity, Animals, Behavior, Animal physiology, Brain drug effects, Brain metabolism, Calcineurin metabolism, Calcium metabolism, Calcium Signaling physiology, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Chronic Disease, Cognition Disorders complications, Cognition Disorders metabolism, Disease Models, Animal, Long-Term Potentiation physiology, Maze Learning physiology, Neuronal Plasticity physiology, Peptide Fragments metabolism, Peptide Fragments toxicity, Rats, Rats, Wistar, Social Behavior, Stress, Psychological complications, Stress, Psychological metabolism, Alzheimer Disease physiopathology, Brain physiopathology, Cognition Disorders physiopathology, Stress, Psychological physiopathology
- Abstract
Although it is generally accepted that Abeta contributes to the pathogenesis of Alzheimer's disease (AD), other factors that impact the severity and time of onset of the disease are not well known. Aside from genetic factors, environmental factors such as stress may also play a critical role in the manifestation of AD. The present study examined the effect of chronic psychosocial stress in an at-risk, subthreshold Abeta (subAbeta) rat model of AD by three approaches: learning and memory tests in the radial arm water maze, electrophysiological recordings of long-term potentiation (LTP) in anesthetized rats, and immunoblot analysis of learning- and memory-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAbeta rat model of AD was induced by continuous i.c.v. infusion of 160 pmol/day Abeta(1-42) via a 14-day osmotic pump. Behavioral tests and electrophysiological recordings showed that subAbeta rats were not significantly different from control rats. However, chronically stressed subAbeta rats showed more significant impairment of cognitive functions and early-phase LTP (E-LTP) than that caused by stress alone. Molecular analysis of essential signaling molecules after induction of E-LTP revealed an increase in the levels of p-CaMKII in control as well as subAbeta infused rats, but not in stressed or stressed at-risk rats. In addition, compared to unstimulated control, the levels of both total CaMKII and calcineurin were increased in all stimulated animals groups after HFS. These findings suggest that the stress-induced alterations may accelerate the impairment of cognition and synaptic plasticity in individuals "at-risk" for AD., (2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
47. Adverse effect of combination of chronic psychosocial stress and high fat diet on hippocampus-dependent memory in rats.
- Author
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Alzoubi KH, Abdul-Razzak KK, Khabour OF, Al-Tuweiq GM, Alzubi MA, and Alkadhi KA
- Subjects
- Analysis of Variance, Animals, Male, Maze Learning physiology, Memory Disorders physiopathology, Memory, Short-Term physiology, Rats, Rats, Wistar, Social Behavior, Space Perception, Time Factors, Weight Gain, Diet, Dietary Fats administration & dosage, Hippocampus physiopathology, Memory physiology, Memory Disorders etiology, Stress, Psychological physiopathology
- Abstract
The combined effects of high fat diet (HFD) and chronic stress on the hippocampus-dependent spatial learning and memory were studied in rats using the radial arm water maze (RAWM). Chronic psychosocial stress and/or HFD were simultaneously administered for 3 months to young adult male Wister rats. In the RAWM, rats were subjected to 12 learning trials as well as short-term and long-term memory tests. This procedure was applied on a daily basis until the animal reaches days to criterion (DTC) in the 12th learning trial and in memory tests. DTC is the number of days that the animal takes to make zero error in two consecutive days. Groups were compared based on the number of errors per trial or test as well as on the DTC. Chronic stress, HFD and chronic stress/HFD animal groups showed impaired learning as indicated by committing significantly (P<0.05) more errors than untreated control group in trials 6 through 9 of day 4. In memory tests, chronic stress, HFD and chronic stress/HFD groups showed significantly impaired performance compared to control group. Additionally, the stress/HFD was the only group that showed significantly impaired performance in memory tests on the 5th training day, suggesting more severe memory impairment in that group. Furthermore, DTC value for above groups indicated that chronic stress or HFD, alone, resulted in a mild impairment of spatial memory, but the combination of chronic stress and HFD resulted in a more severe and long-lasting memory impairment. The data indicated that the combination of stress and HFD produced more deleterious effects on hippocampal cognitive function than either chronic stress or HFD alone.
- Published
- 2009
- Full Text
- View/download PDF
48. Chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in beta-amyloid rat model of Alzheimer's disease.
- Author
-
Srivareerat M, Tran TT, Alzoubi KH, and Alkadhi KA
- Subjects
- Alzheimer Disease chemically induced, Amyloid beta-Peptides administration & dosage, Analysis of Variance, Animals, Behavior, Animal, Biophysics, Calcineurin metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Disease Models, Animal, Down-Regulation drug effects, Down-Regulation physiology, Electric Stimulation, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, Long-Term Potentiation drug effects, Male, Maze Learning physiology, Patch-Clamp Techniques, Peptide Fragments administration & dosage, Rats, Rats, Wistar, Stress, Psychological etiology, Alzheimer Disease complications, Cognition Disorders etiology, Cognition Disorders pathology, Hippocampus physiopathology, Long-Term Potentiation physiology, Stress, Psychological complications
- Abstract
Background: Alzheimer's disease (AD) is a degenerative disorder that leads to progressive cognitive decline. Alzheimer's disease develops as a result of over-production and aggregation of beta-amyloid (Abeta) peptides in the brain. The reason for variation in the gravity of symptoms among AD patients is unknown and might result from patient-related factors including lifestyle. Individuals suffering from chronic stress are at an increased risk for developing AD. This study investigated the effect of chronic psychosocial stress in Abeta rat model of AD., Methods: Psychosocial stress was induced with a rat intruder model. The rat model of AD was induced by 14-day osmotic pump infusion of a mixture of 300 pmol/day Abeta(1-40)/Abeta(1-42). The effect of chronic stress on the severity of Abeta-induced spatial learning and memory impairment was tested by three approaches: behavioral testing in the radial arm water maze, in vivo electrophysiological recording in anesthetized rat, and immunoblot analysis to determine protein levels of learning- and memory-related molecules., Results: A marked impairment of learning and memory developed when stress was combined with Abeta, more so than that caused by Abeta alone. Additionally, there was a significantly greater impairment of early-phase long-term potentiation (E-LTP) in chronically stressed/Abeta-treated rats than in either the stressed or Abeta-treated rats. This might be a manifestation of the reduction in protein levels of calcium/calmodulin-dependent protein kinase II (CaMKII) and the abnormal increase in calcineurin levels., Conclusions: Chronic stress significantly intensified Abeta-induced deficits of short-term memory and E-LTP by a mechanism involving decreased CaMKII activation along with increased calcineurin levels.
- Published
- 2009
- Full Text
- View/download PDF
49. Calmodulin and guanylyl cyclase inhibitors block the in vivo expression of gLTP in sympathetic ganglia from chronically stressed rats.
- Author
-
Alzoubi KH and Alkadhi KA
- Subjects
- Aminoquinolines pharmacology, Animals, Calmodulin antagonists & inhibitors, Disease Models, Animal, Electric Stimulation methods, Guanylate Cyclase antagonists & inhibitors, Long-Term Potentiation physiology, Male, Rats, Rats, Wistar, Superior Cervical Ganglion physiopathology, Enzyme Inhibitors pharmacology, Imidazoles pharmacology, Long-Term Potentiation drug effects, Stress, Psychological pathology, Sulfonamides pharmacology, Superior Cervical Ganglion drug effects
- Abstract
Previous work from this laboratory indicated that superior cervical ganglia from rats exposed to chronic psychosocial stress expressed ganglionic long-term potentiation (gLTP) in vivo. In the present study, we report additional pharmacological evidence indicating involvement of calmodulin and guanylyl cyclase in gLTP, and supporting the in vivo gLTP expression in ganglia from chronically stressed rats. Pretreatment with the calmodulin inhibitors W-7 (5 microM) or calmidazolium (5 microM) or with guanylyl cyclase inhibitor LY-83583 (5 microM) completely blocked HFS (20 Hz/20s)-induced gLTP in superior cervical ganglia isolated from normal rats. Along with that, inhibition of apparent basal ganglionic transmission by W-7 (5 microM), calmidazolium (5 microM) or LY-83583 (5 microM) is observed in ganglia isolated from chronically stressed rats, but not in those from control rats, indicating in vivo expression of gLTP in ganglia isolated from stressed rats. The present results confirm the involvement of both calmodulin and GC activities in gLTP, and indicate that ganglia from stressed rats may have expressed gLTP in vivo, which is known to precipitate hypertension in these animals.
- Published
- 2009
- Full Text
- View/download PDF
50. Levothyroxin restores hypothyroidism-induced impairment of hippocampus-dependent learning and memory: Behavioral, electrophysiological, and molecular studies.
- Author
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Alzoubi KH, Gerges NZ, Aleisa AM, and Alkadhi KA
- Subjects
- Animals, Cyclic AMP Response Element-Binding Protein drug effects, Cyclic AMP Response Element-Binding Protein metabolism, Hippocampus metabolism, Hippocampus physiopathology, Hypothyroidism metabolism, Learning drug effects, Learning physiology, Long-Term Potentiation drug effects, Long-Term Potentiation physiology, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System physiology, Male, Maze Learning drug effects, Maze Learning physiology, Memory drug effects, Memory physiology, Memory Disorders metabolism, Rats, Rats, Wistar, Thyroxine therapeutic use, Treatment Outcome, Hippocampus drug effects, Hypothyroidism complications, Hypothyroidism drug therapy, Memory Disorders drug therapy, Memory Disorders etiology, Thyroxine pharmacology
- Abstract
Hypothyroidism induces cognitive impairment in experimental animals and patients. Clinical reports are conflicting about the ability of thyroid hormone replacement therapy to fully restore the hypothyroidism-induced learning and memory impairment. In this study, we investigated the effects of L-thyroxin (thyroxin) treatment on hippocampus-dependent learning and memory in thyroidectomized adult rats. In the radial arm water maze (RAWM) task, thyroxin treated thyroidectomized animals made significantly fewer errors than the untreated hypothyroid animals in Trial 3 of the acquisition phase, short-term memory and long-term memory tests. In addition, the number of errors made by the thyroxin treated thyroidectomized animals was not different from that of the control group. Furthermore, the days-to-criterion (DTC) values for thyroxin treated thyroidectomized animals were not different from those of the control group but significantly lower than those of the untreated hypothyroid animals. In anesthetized rats, extracellular recording from hippocampal area CA1 of hypothyroid rats shows that thyroxin treatment restores impaired Late-phase long-term potentiation (L-LTP). Immunoblot analysis of signaling molecules, including cyclic-AMP response element binding protein (CREB), mitogen-activated protein kinases (MAPKp44/42; ERK1/2), in area CA1 revealed that thyroxin treatment reversed hypothyroidism-induced reduction of signaling molecules essential for learning and memory, and L-LTP. This study shows that thyroxin treatment reverses hypothyroidism-induced impairment of hippocampus-dependent cognition, and L-LTP, probably by restoring the levels of signaling molecule important for these processes., (Copyright 2008 Wiley-Liss, Inc.)
- Published
- 2009
- Full Text
- View/download PDF
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