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Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. However, current animal models have not been successful in replicating the pathology and disabilities seen in SAH patients, especially the long‐term neurocognitive deficits that affect the survivor's quality of life. Therefore, there is an unmet need to develop experimental models that reliably replicate the long‐term clinical ramifications of SAH – especially in mice where genetic manipulations are straightforward and readily available. To address this need, a standardized mouse SAH model is developed that reproducibly produced significant and trackable long‐term cognitive deficits. SAH is induced by performing double blood injections into the prechiasmatic cistern – a simple modification to the well‐characterized single prechiasmatic injection mouse model of SAH. Following SAH, mice recapitulated key characteristics of SAH patients, including cerebral edema measured by MRI ‐ an indicator of early brain injury (EBI), neuroinflammation, apoptosis, and long‐term cognitive impairment. This newly developed SAH mouse model is considered an ideal paradigm for investigating the complex SAH pathophysiology and identifying novel druggable therapeutic targets for treating SAH severity and SAH‐associated long‐term neurocognitive deficits in patients. [ABSTRACT FROM AUTHOR]

Background: An active lifestyle is associated with improved cognitive functions in aged people and may prevent or slow down the progression of various neurodegenerative diseases including Alzheimer's disease (AD). To investigate these protective effects, male APPNL-G-F mice were exposed to long-term voluntary exercise. Methods: Three-month-old AD mice were housed in a cage supplemented with a running wheel for 9 months for long-term exercise. At the age of 12 months, behavioral tests were completed for all groups. After completing behavioral testing, their brains were assessed for amyloid pathology, microgliosis, and cholinergic cells. Results: The results showed that APPNL-G-F mice allowed to voluntarily exercise showed an improvement in cognitive functions. Furthermore, long-term exercise also improved anxiety in APPNL-G-F mice as assessed by measuring thigmotaxis in the Morris water task. We also found reductions in amyloid load and microgliosis, and a preservation of cholinergic cells in the brain of APPNL-G-F mice allowed to exercise in their home cages. These profound reductions in brain pathology associated with AD are likely responsible for the observed improvement of learning and memory functions following extensive and regular exercise. Conclusion: These findings suggest the potential of physical exercise to mitigate the cognitive deficits in AD. [ABSTRACT FROM AUTHOR]

Previous reports indicate a potential role for signal transducer and activator of transcription 3 (STAT3) in amyloid-β (Aβ) processing and neuritic plaque pathogenesis. In the present study, the impact of STAT3 inhibition on cognition, cerebrovascular function, amyloid pathology, oxidative stress, and neuroinflammation was studied using in vitro and in vivo models of Alzheimer's disease (AD)-related pathology. For in vitro experiments, human brain vascular smooth muscle cells (HBVSMC) and human brain microvascular endothelial cells (HBMEC) were used, and these cultured cells were exposed to Aβ peptides followed by measurement of activated forms of STAT3 expression and reactive oxygen species (ROS) generation. Further, 6 months old 5XFAD/APOE4 (5XE4) mice and age-matched negative littermates were used for in vivo experiments. These mice were treated with STAT3 specific inhibitor, LLL-12 for 2 months followed by neurobehavioral and histopathological assessment. In vitro experiments showed exposure of cerebrovascular cells to Aβ peptides upregulated activated forms of STAT3 and produced STAT3-mediated vascular oxidative stress. 5XE4 mice treated with the STAT3-specific inhibitor (LLL-12) improved cognitive functions and functional connectivity and augmented cerebral blood flow. These functional improvements were associated with a reduction in neuritic plaques, cerebral amyloid angiopathy (CAA), oxidative stress, and neuroinflammation. Reduction in amyloid precursor protein (APP) processing and attenuation of oxidative modification of lipoprotein receptor related protein-1 (LRP-1) were identified as potential underlying mechanisms. These results demonstrate the broad impact of STAT3 on cognitive functions, parenchymal and vascular amyloid pathology and highlight the therapeutic potential of STAT3 specific inhibition for treatment of AD and CAA. [ABSTRACT FROM AUTHOR]

Concerns are growing that exposure to environmental pollutants, such as traffic noise, might cause cognitive impairments and predispose individuals toward the development of Alzheimer's disease (AD) dementia. In this study in a knock‐in mouse model of AD, we investigated how chronic traffic noise exposure (CTNE) impacts cognitive performance and amyloid‐beta (Aβ) pathology. A group of APPNL‐G‐F/NL‐G‐F mice was exposed to CTNE (70 dBA, 8 hr/day for 1 month) and compared with nonexposed counterparts. Following CTNE, an increase in hypothalamic–pituitary–adrenal (HPA) axis responsivity was observed by corticosterone assay of the blood. One month after CTNE, the CTNE group demonstrated impairments in cognitive and motor functions, and indications of anxiety‐like behavior, relative to the control animals. The noise‐exposed group also showed elevated Aβ aggregation, as inferred by a greater number of plaques and larger average plaque size in various regions of the brain, including regions involved in stress regulation. The results support that noise‐associated dysregulation of the neuroendocrine system as a potential risk factor for developing cognitive impairment and Aβ pathology, which should be further investigated in human studies. [ABSTRACT FROM AUTHOR]

Abstract Saito et al developed a novel amyloid precursor protein (APP) knock-in mouse model (APPNL-G-F) for Alzheimer's disease (AD) to overcome the problem of overexpression of APP in available transgenic mouse models. However, this new mouse model for AD is not fully characterized age-dependently with respect to behavioral and biochemical changes. Therefore, in the present study, we performed an age-dependent behavioral and biochemical characterization of this newly developed mouse model. Here, we used 3-, 6-, 9-, and 12-month-old APPNL-G-F and C57BL/6J mice. We used a separate cohort of animals at each age point. Morris water maze, object recognition, and fear-conditioning tests were used for the assessment of learning and memory functions and open-field test to measure the general locomotor activity of mice. After each testing point, we perfused the mice and collected the brain for immunostaining. We performed the immunostaining for amyloid burden (4G8), glial fibrillary acidic protein, choline acetyltransferase, and tyrosine hydroxylase. The results of the present study indicate that APPNL-G-F mice showed age-dependent memory impairments with maximum impairment at the age of 12 months. These mice showed memory impairment in Morris water maze and fear conditioning tests when they were 6 months old, whereas, in object recognition test, memory deficit was found in 9-month-old mice. APPNL-G-F mice age dependently showed an increase in amyloid load in different brain regions. However, no amyloid pathology was found in 3-month-old APPNL-G-F mice. Choline acetyltransferase neurons in medial septum-diagonal band complex and tyrosine hydroxylase neurons in locus coeruleus were decreased significantly in APPNL-G-F mice. This mouse model also indicated an age-dependent increase in glial fibrillary acidic protein load. It can be concluded from the results that the APPNL-G-F mouse model may be used to explore the Aβ hypothesis, molecular, and cellular mechanisms involved in AD pathology and to screen the therapeutic potential compounds for the treatment of AD. Highlights • Age dependent behavioral and biochemical changes of APPNL−G-F mice were evaluated. • APPNL−G-F showed age dependent memory deficit in various behavioral tests. • These mice showed an increase in amyloid and GFAP load in various brain regions. • Cholinergic and norepinephrine dysfunctions were also observed in this mouse model. [ABSTRACT FROM AUTHOR]

Most studies investigating hippocampal‐dependent learning and memory in mouse models of disease use the standard version of the Morris water task (MWT), in which a place is learned over several days. While useful in determining if there are learning and memory deficits, often it is not clear if memory acquisition, consolidation, or retrieval is affected. For rats, we developed a variant of the task in which we added a single‐massed training session to a new location after the standard distributed version of the MWT. Using this version of the task, competition between these two spatial representations can then be assessed in a probe trial. We have found in rat models of Alzheimer's disease that this paradigm can detect subtle impairments that are often missed in the standard version of the MWT. To the best of our knowledge, MWT paradigm with a single‐massed training session have never been used for mice. We sought to validate this paradigm for the use of assessing mouse models of disease. In the first two experiments, control mice did not have a preference for the new platform location, but instead with extensive training in the massed session displayed a preference for both the old and new locations. In the third experiment, a novel mouse model of Alzheimer's disease was impaired in the standard version of the MWT, but not in the massed training phase of this paradigm. Importantly, these data demonstrate that our paradigm is more informative in characterizing spatial learning and memory in mouse models of disease. [ABSTRACT FROM AUTHOR]

In the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer's disease pathology. [ABSTRACT FROM AUTHOR]

Maternal stress is a common adversity during pregnancy. Gestational corticosterone alternations are thought to contribute to the etiology of postpartum behavioral disturbances. However, the impact of stress during pregnancy, in particular noise exposure, on gestational corticosterone fluctuations and spatial cognition in postpartum mice has not been fully understood yet. We hypothesized that noise exposure during pregnancy negatively affects gestational corticosterone levels and postpartum memory function in the dams similar to the physical stressors. Pregnant C57BL/6 mice were randomly assigned to either one of two stress conditions or a control condition. The noise stress (NS) was induced by presenting a loud intermittent 3000 Hz frequency on gestational days (GDs) 12, 14, and 16 for 24 hours, whereas the physical stress (PS) consisted of restraint and exposure to an elevated platform on GDs 12–16. Plasma corticosterone level was collected on GDs 11 and 17, and Morris water task (MWT) was carried out 30 days after parturition. Compared to the control group, the level of corticosterone in the stressed groups was significantly increased on GD17 relative to GD11. Significantly longer swim time and lower swim speed were observed in both stressed groups relative to the control group. Probe time was significantly shorter in the NS group than the other groups. The delta corticosterone level was significantly correlated with the swim time as well as the probe time in the three groups. Given the results, the adverse effects of gestational noise exposure on the hypothalamic pituitary-adrenal (HPA) axis activation and postpartum spatial learning and memory function were as large as/ or a bit stronger than the physical stresses. The findings suggest the significance of conservation against loud noise exposure in daily living, as well as need to further notice to the different aspects of gestational stress in mothers’ behavior like offspring. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD. [ABSTRACT FROM AUTHOR]

Rationale: Clitoria ternatea, commonly known as Aparajita, is used as Medhya rasayana in Ayurveda. The role of C. ternatea in experimental models of cognitive impairment is yet to be explored. Objectives: The present study was designed to study the effect of aqueous and hydroalcoholic extracts of C. ternatea on biochemical and behavioral parameters related to cognitive impairment in in vitro and in vivo studies. Methods: In vitro free radical scavenging and enzyme-inhibitory (cholinesterase, glycogen synthase kinase-3-β, rho kinase, prolyl endopeptidase, catechol- O-methyl transferase, and lipoxygenase) activities of aqueous and hydroalcoholic extracts of C. ternatea plant were evaluated. Based on in vitro results, hydroalcoholic extract of C. ternatea (100, 300, and 500 mg/kg, p.o.) was selected for evaluation in intracerebroventricularly injected streptozotocin (STZ)-induced cognitive impairment in male Wistar rats. Behavioral assessment was performed at baseline and on the 14th, 21st, and 28th days after STZ injection using elevated plus maze, passive avoidance, Morris water maze, and photoactometer. Oxidative stress parameters (malondialdehyde, reduced glutathione, nitric oxide levels, and superoxide dismutase activity), cholinesterase activity, and rho kinase (ROCK II) expression were studied in cerebral cortex and hippocampus of rats' brain at the end of the study. Results: The hydroalcoholic extract possessed significantly more in vitro antioxidant and enzyme-inhibitory activities as compared to aqueous extract. The hydroalcoholic extract of C. ternatea prevented STZ-induced cognitive impairment dose dependently by reducing oxidative stress, cholinesterase activity, and ROCK II expression. Conclusion: In vitro and in vivo results suggest the potential of hydroalcoholic extract of C. ternatea for treatment of cognitive deficit in neurological disorders. [ABSTRACT FROM AUTHOR]

Anacyclus pyrethrum ( A. pyrethrum) has been reported to exhibit anticonvulsant activity. In the present study, the effect of hydro-alcoholic extract of A. pyrethrum root (HEAP) on pentylenetetrazole (PTZ) induced kindling, spatial memory, oxidative stress and rho kinase (ROCK II) was assessed. Male albino mice (25-30 g) were used in the study. PTZ (35 mg/kg, i.p. on alternate days) was injected to induce kindling and PTZ (70 mg/kg, i.p) challenge was given 7 days post-kindling. HEAP was administered orally daily in the doses of 100, 250 and 500 mg/kg along with PTZ injections during the kindling process and continued till PTZ challenge post kindling. Spatial memory was assessed using Morris water maze test. Oxidative stress parameters [malondialdehyde (MDA) and reduced glutathione (GSH)] and ROCK II expression were estimated in whole brain at the end of the study. Pre-treatment with HEAP (250 and 500 mg/kg) showed significant increase in the myoclonic jerk latency and delay in the development of kindling. A significant decrease in mortality was observed at higher doses of HEAP (250 and 500 mg/kg). Pre-treatment with HEAP significantly increased the number of platform crossings and decreased the escape latency, as opposed to the PTZ group, thus showing protection against memory deficit. HEAP pre-treatment also attenuated the oxidative stress induced by PTZ kindling. PTZ induced kindling increased the ROCK II expression whereas, HEAP pre-treatment attenuated the increase in ROCK II expression. To conclude, HEAP pre-treatment showed antiepileptic effect and also showed protection against cognitive impairment by decreasing oxidative stress and ROCK II expression in PTZ kindled mice. [ABSTRACT FROM AUTHOR]

The long term effect of single (day 1) and twice (day 1 and 3) injections of intracerebroventricular (ICV) streptozotocin (STZ) at the doses of 1 and 3 mg/kg on the cognitive functions of male Wistar rats was evaluated. Elevated plus maze, passive avoidance, and Morris water maze tests were used to assess the cognitive functions. A significant cognitive deficit was found at the 2nd week onwards, which persisted up to the 14th week with single and twice ICV-STZ (3 mg/kg) injections, whereas no cognitive impairment was found in ICV-STZ (1 mg/kg) treated groups after 8-10 weeks. [ABSTRACT FROM AUTHOR]

Abstract: Evolvulus alsinoides, also known as Shankpushapi, is a commonly used traditional medicine for enhancing memory. We evaluated the in vitro free radical scavenging and enzymes [acetylcholinesterase, butyrylcholinestrase, glycogen synthase kinase-3-β (GSK-3-β), rho kinase (ROCK II), prolyl endopeptidase (PEP), catechol-O-methyl transferase (COMT) and lipoxygenase (LOX)] inhibitory activities of aqueous and hydro-alcoholic extracts of E. alsinoides. Hydro-alcoholic extract of E. alsinoides demonstrated more free radical scavenging activity as compared to aqueous extract. Hydro-alcoholic extract also showed higher cholinesterase, GSK-3-β, ROCK II, PEP, COMT and LOX enzyme inhibitory activities as compared to aqueous extract. Phytochemical analysis revealed more flavanoids in hydro-alcoholic extract as compared to aqueous extract but no significant difference in phenolic content of the two extracts was observed. Based on in vitro data, hydro-alcoholic extract (100, 300 and 500mg/kg, p.o.) was selected for in vivo study in intracerebroventricularly injected streptozotocin (STZ) induced cognitive impairment in male Wistar rats. Elevated plus maze, passive avoidance and Morris water maze were used for assessment of cognitive function on 14th, 21st and 28th day after STZ injection. Oxidative stress parameters (malondialdehyde, reduced glutathione, nitric oxide levels and superoxide dismutase activity), cholinergic dysfunction and rho kinase (ROCK II) expression were studied in cerebral cortex and hippocampus of rat brain at the end of the study. Hydro-alcoholic extract of E. alsinoides dose dependently prevented STZ induced cognitive impairment by reducing the oxidative stress, improving cholinergic function and preventing the increase in rho kinase expression. The results suggest an anti-Alzheimer potential of hydro-alcoholic extract of E. alsinoides. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Orchis mascula tuber is used in many polyherbal formulations as a nerve tonic in India. Aim of the study: In the present study, effect of hydroalcholic extract of O. mascula (HEOM) tuber was evaluated against seizures, seizure-induced oxidative stress and cognitive deficit in pentylenetetrazole and maximal electroshock-induced seizures in rats. Materials and methods: HEOM was administered orally 30min before induction of seizures by pentylenetetrazole (PTZ; 60mg/kg, i.p) or maximal electroshock (MES; 70mA). Elevated plus maze and passive avoidance tests were used to assess the learning and memory. Oxidative stress was studied by estimation of reduced glutathione and lipid peroxidation. Whole brain total cholinesterase activity was also evaluated. Results: HEOM produced 33.3%, 50% and 66.7% protection in PTZ model and 16.7%, 16.7% and 33.3% at 250, 500 and 1000mg/kg, respectively, in MES-induced seizures. Pre-treatment with HEOM significantly decreased the retention transfer latency in elevated plus maze test, and an increase in the retention latency in passive avoidance test was observed. Oxidative stress induced by seizures was also attenuated as indicated by significant increase in GSH and decrease in MDA levels in HEOM treated groups. PTZ and MES caused a significant decrease in AChE and BChE activities, which was prevented by HEOM. Conclusions: HEOM thus showed protection against seizures, prevented the associated memory impairment probably by modulating cholinergic status and reducing oxidative stress. [Copyright &y& Elsevier]

Summary: In Ayurveda, Anacyclus pyrethrum has been used as a brain tonic. The present study evaluates the effect of hydroalcoholic extract of A. pyrethrum (HEAP) root against seizures, seizure-induced oxidative stress and cognitive impairment in experimental models of seizures. Male Wistar rats were used in the study. HEAP was administered in doses of 50, 100, 250, 500 in pentylenetetrazole (PTZ) model and 250, 500 and 1000mg/kg in maximal electroshock (MES) model. Myoclonic jerk latency and generalized tonic clonic seizures (GTCS) were noted in PTZ whereas occurrence of tonic hind limb extension (THLE) was observed in MES seizures. Cognitive deficit was assessed using elevated plus maze and passive avoidance tests. Whole brain reduced glutathione, malondialdehyde levels and cholinesterase activity were measured. HEAP showed 50, 66.7, 83.3 and 100% protection at 50,100, 250 and 500mg/kg, respectively against GTCS in PTZ induced seizures. In MES induced seizures, HEAP produced 16.7, 33.3 and 50% protection against THLE at 250, 500 and 1000mg/kg, respectively. HEAP administration significantly prevented seizure induced oxidative stress and cognitive impairment in a dose-dependent manner. HEAP also normalized the decrease in cholinesterase activity caused by seizures. Thus, HEAP showed protective effect against seizures, seizure-induced oxidative stress and cognitive impairment in rats. [ABSTRACT FROM AUTHOR]

Abstract: The present study investigates the interaction of curcumin with four antiepileptic drugs (AEDs) in male Wistar rats. In the first protocol, seizures were induced using pentylenetetrazole (PTZ) and valproate was injected intraperitoneally (i.p.) in therapeutic and sub-therapeutic doses 30min before PTZ administration. Curcumin was co-administered with sub-therapeutic dose of valproate 60min before PTZ injection. In the second protocol, seizures were induced by maximal-electroshock. Phenytoin, phenobarbitone and carbamazepine were injected in their therapeutic and sub-therapeutic doses 120, 60 and 30min, respectively, before seizure induction. Curcumin was administered along with sub-therapeutic doses of phenytoin, phenobarbitone and carbamazepine, 60min before induction of seizures. Behavioral parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were assessed and the serum levels of the AEDs were estimated. The AEDs in their therapeutic doses produced complete protection against seizures. However, sub-therapeutic doses of these AEDs failed to completely protect against seizures. Co-administration of curcumin with sub-therapeutic dose of valproate significantly increased the latency to myoclonic jerks. The percentage protection against seizures with sub-therapeutic doses of valproate, phenytoin, phenobarbitone and carbamazepine was also enhanced by concomitant curcumin administration. Both PTZ and MES induced seizures caused significant impairment of cognitive functions. Co-administration of curcumin with these AEDs in their sub-therapeutic doses prevented the impairment of learning and memory due to seizures whereas no such improvement was observed in the groups administered the sub-therapeutic doses of the AEDs alone. Additionally, curcumin reversed the oxidative stress due to seizures. However, curcumin co-administration did not cause any significant alteration in the serum levels of the AEDs. The results thus suggest the potential of curcumin as an adjunct to these AEDs in epilepsy with the advantage of increasing the efficacy, reducing the dose and side effects of the AEDs. [Copyright &y& Elsevier]

Abstract: The anticonvulsant effect of the hydroalcoholic extract of Zizyphus jujuba (HEZJ) fruit (100, 250, 500, and 1000mg/kg, orally) was evaluated in experimental seizure models in rats. The effect of HEZJ on seizure-induced cognitive impairment, oxidative stress, and cholinesterase activity was also investigated. HEZJ (1000mg/kg) exhibited maximum protection (100%) against generalized tonic–clonic seizures in the pentylenetetrazole (PTZ) seizure model and and 66.7% protection against tonic hindlimb extension in the maximal electroshock (MES) seizure model. Significant impairment in cognitive functions was observed in both PTZ- and MES-challenged rats. Pretreatment with HEZJ resulted in significant improvement in learning and memory. HEZJ also reversed the oxidative stress induced by both PTZ and MES. The significant decrease in cholinesterase activity observed in the PTZ and MES models was significantly reversed by pretreatment with HEZJ. Thus, the present study demonstrates the anticonvulsant effect of HEZJ as well as amelioration of cognitive impairment induced by seizures in rats. [Copyright &y& Elsevier]

Abstract: Aim: Epilepsy as well as chronic use of most antiepileptic drugs predisposes to cognitive impairment. Curcumin has been reported to possess antioxidant, anticonvulsant as well as neuroprotective potential. Hence, this study was conducted to evaluate the effect of curcumin against seizures, cognitive impairment and oxidative stress in pentylenetetrazole-induced kindling in rats. Main methods: The effect of pretreatment with curcumin (100, 200 and 300mg/kg, orally) on pentylenetetrazole (PTZ)-induced kindling, kindling-induced cognitive impairment and oxidative stress was evaluated. Male Wistar rats were injected PTZ (30mg/kg, i.p.) once every alternate day (48±1h) until the development of kindling. Cognitive impairment was assessed using elevated plus maze and passive avoidance test while the oxidative stress parameters (malondialdehyde and glutathione) were estimated in the whole brain at the end of experiments. Key findings: PTZ, 30mg/kg, induced kindling in rats after 31.0±1.4days. Curcumin showed dose-dependent anti-seizure effect. Curcumin (300mg/kg) significantly increased the latency to myoclonic jerks, clonic seizures as well as generalized tonic–clonic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ kindling induced a significant oxidative stress and cognitive impairment which was reversed by pretreatment with curcumin in a dose-dependent manner. Significance: The results indicate that pretreatment with curcumin ameliorates seizures, oxidative stress and cognitive impairment in PTZ induced kindling in rats. These results thus suggest the potential of curcumin as an adjuvant in epilepsy both to prevent seizures as well as to protect against seizure induced memory impairment. [ABSTRACT FROM AUTHOR]

Abstract: The antiepileptic drugs, phenobarbitone and carbamazepine are well known to cause cognitive impairment on chronic use. The increase in free radical generation has been implicated as one of the important mechanisms of cognitive impairment by antiepileptic drugs. Curcumin has shown antioxidant, anti-inflammatory and neuro-protective properties. Therefore, the present study was carried out to investigate the effect of chronic curcumin administration on phenobarbitone- and carbamazepine-induced cognitive impairment and oxidative stress in rats. Pharmacokinetic interactions of curcumin with phenobarbitone and carbamazepine were also studied. Vehicle/drugs were administered daily for 21days to male Wistar rats. Passive avoidance paradigm and elevated plus maze test were used to assess cognitive function. At the end of study period, serum phenobarbitone and carbamazepine, whole brain malondialdehyde and reduced glutathione levels were estimated. The administration of phenobarbitone and carbamazepine for 21days caused a significant impairment of learning and memory as well as an increased oxidative stress. Concomitant curcumin administration prevented the cognitive impairment and decreased the increased oxidative stress induced by these antiepileptic drugs. Curcumin co-administration did not cause any significant alteration in the serum concentrations of both phenobarbitone as well as carbamazepine. These results show that curcumin has beneficial effect in mitigating the deterioration of cognitive functions and oxidative damage in rats treated with phenobarbitone and carbamazepine without significantly altering their serum concentrations. The findings suggest that curcumin can be considered as a potential safe and effective adjuvant to phenobarbitone and carbamazepine therapy in preventing cognitive impairment associated with these drugs. [ABSTRACT FROM AUTHOR]

Abstract: The present study investigates the effect of chronic curcumin administration on phenytoin-induced cognitive impairment and oxidative stress in rats. Male Wistar rats were administered drugs/vehicle for 21 days. Learning and memory was evaluated using the passive avoidance paradigm and the elevated plus maze. On day 21, serum phenytoin concentrations and whole brain malondialdehyde (MDA) and glutathione (GSH) levels were estimated. Phenytoin (75 mg/kg, i.p.) produced significant deficits in learning/memory as indicated by the significant increase in retention transfer latency in elevated plus maze test and a significant decrease in retention latency in the passive avoidance paradigm. Chronic administration of phenytoin also produced significant elevations in brain MDA and reduction of brain GSH levels. Curcumin (100, 200 and 300 mg/kg, orally), when administered with phenytoin, significantly prevented phenytoin-induced cognitive impairment and oxidative stress in a dose-dependent manner. There were no significant differences in the serum levels of phenytoin in any of the treatment groups. This study demonstrates that curcumin is effective in preventing phenytoin-induced cognitive impairment and oxidative stress in rats without altering the serum phenytoin levels. This suggests the potential of adjuvant curcumin therapy in ameliorating cognitive impairment caused by chronic phenytoin therapy. [Copyright &y& Elsevier]

Cognitive impairment, associated with ageing, stress, hypertension and various neurodegenerative disorders including Parkinson's disease and epilepsy, is a major health issue. The present review focuses on Alzheimer's disease (AD), since it is the most important cause of cognitive impairment. It is characterized by progressive memory loss, language deficits, depression, agitation, mood disturbances and psychosis. Although the hallmarks of AD are cholinergic dysfunction, β-amyloid plaques and neurofibrillary tangle formation, it is also associated with derangement of other neurotransmitters, elevated levels of advanced glycation end products, oxidative damage, neuroinflammation, genetic and environmental factors. On one hand, this complex etiopathology makes a response to commonly used drugs such as donepezil, rivastigmine, galantamine and memantine less predictable and often unsatisfactory. On the other hand, it supports the use of herbal medicines due to their nonspecific antioxidant and anti-inflammatory activity and specific cholinesterase inhibitory activity. The popularity of herbal medicines is also increasing due to their perceived effectiveness, safety and affordability. In the present article, the experimental and clinical evidence have been reviewed for various Indian herbal medicines such as Centella asiatica, Bacopa monnieri, Curcuma longa, Clitoria ternatea, Withania somnifera, Celastrus paniculatus, Evolvulus alsinoides, Desmodium gangeticum, Eclipta alba, Moringa oleifera and Convolvulus pluricaulis, which have shown potential in cognitive impairment. Some commonly available herbal formulations for memory impairment in India have also been reviewed. [ABSTRACT FROM AUTHOR]

A correction notice is presented for the article "Clitoria Ternatea Ameliorated the Intracerebroventricularly Injected Streptozotocin Induced Cognitive Impairment in Rats: Behavioral and Biochemical Evidence" by Jogender Mehla, Monika Pahuja, Pooja Gupta et al., which was published online on September 24, 2014.

The functional importance of many non-coding RNAs (ncRNAs) generated by repetitive elements and their connection with pathologic processes remains elusive. B2 RNAs, a class of ncRNAs of the B2 family of SINE repeats, mediate through their processing the transcriptional activation of various genes in response to stress. Here, we show that this response is dysfunctional during amyloid beta toxicity and pathology in the mouse hippocampus due to increased levels of B2 RNA processing, leading to constitutively elevated B2 RNA target gene expression and high Trp53 levels. Evidence indicates that Hsf1, a master regulator of stress response, mediates B2 RNA processing in hippocampal cells and is activated during amyloid toxicity, accelerating the processing of SINE RNAs and gene hyper-activation. Our study reveals that in mouse, SINE RNAs constitute a novel pathway deregulated in amyloid beta pathology, with potential implications for similar cases in the human brain, such as Alzheimer's disease (AD). [ABSTRACT FROM AUTHOR]

Environmental distresses occurring during the sensitive periods of early life may exacerbate the vulnerability to develop physical and mental diseases in old age. Studies have shown the impact of prenatal stress (PS) on the endocrine development and reprogramming of hypothalamic-pituitary-adrenal axis functions in association with cognitive development and susceptibility to neuropsychiatric diseases. Long-term exposure to glucocorticoids can damage the brain and intensify the progression of Alzheimer's disease (AD)-like neuropathological changes, especially in females. There is, however, less information as to the link between PS and the risk of developing AD pathology throughout the lifespan. In the present study, male and female APP NL-G-F/NL-G-F offspring of dams exposed to gestational noise stress were compared with the control offspring in corticosterone alternations, cognitive and motor performances, and the onset age and development of amyloid beta (Aβ) plaques across age. The hyperactivity of the hypothalamic-pituitary-adrenal axis, spatial learning, and Aβ development were sex specific, showing persistent high levels of stress and further memory loss in females than males, especially in PS mice. The Aβ deposition was started earlier, by 2–3 months, and exhibited a heightened progression in PS animals. The PS also created a long-lasting anxiety-like behavior and impairment in cognitive function and motor coordination. Our results suggested PS as a risk to exacerbate AD-like neuropathological changes during the lifespan, with higher susceptibility of females. The findings were discussed in line with the most likely mechanisms for the PS effects, that is, dysregulation of the neuroendocrine system and the placenta by the PS. • Prenatal stress (PS) resulted in a persistent HPA-axis hyperactivity across age. • The PS created an enduring anxiety-like behavior and impairment in cognitive and motor performances. • The PS led to an earlier onset and overproduction of the Aβ plaques. • The PS was sex-specific in HPA-axis activity, learning function, and Aβ burden. • Females displayed higher susceptibility for developing Alzheimer's disease. [ABSTRACT FROM AUTHOR]

• Anesthetic dose of isoflurane conditioning provides protection against DCI. • Subanesthetic dose of isoflurane conditioning provides protection against DCI. • This finding may have wide therapeutic implications in SAH patients. Delayed cerebral ischemia (DCI) is identified as one of the significant contributors to poor patient outcome after aneurysmal subarachnoid hemorrhage (SAH). We previously reported that a supratherapeutic dose of isoflurane conditioning (2%) provided robust protection against SAH-induced DCI. The aim of our current study is to compare the efficacy of the supratherapeutic dose of isoflurane to that typically used to establish general anesthesia or sedation. After IRB approval for animal studies, ten to fourteen-week-old wild-type male mice (C57BL/6) were divided into five groups – sham, SAH alone, or SAH with isoflurane conditioning (0.5%, 1%, and 2%). Conditioning was performed with one-hour of isoflurane initiated one-hour after induction of SAH via endovascular perforation technique. Vasospasm measurement in the middle cerebral artery was assessed 72 h after SAH. Neurological assessment was performed at baseline and for next three days after SAH. It was identified that all tested doses of isoflurane conditioning (0.5%, 1%, and 2%) significantly attenuated large artery vasospasm and markedly improved neurological deficits following SAH. No significant differences in neurovascular outcome were noted between the three doses of isoflurane conditioning. Our data show that isoflurane dosing typically used for general anesthesia (1%) or sedation (0.5%) provide similar levels of DCI protection in SAH as that provided by a supratherapeutic dose (2%). This result has important implications for future translational studies. Additional studies examining the therapeutic potential of anesthetic conditioning for SAH are therefore warranted. [ABSTRACT FROM AUTHOR]