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Neurological disorders are devastating conditions affecting both cognitive and motorrelated functions in aged people. Yet there is no proper medication to treat these illnesses, and the currently available medications can only provide symptomatic relief to the patients. All neurological disorders share the same etiology, such as oxidative stress, mitochondrial dysfunction, neurochemical deficiency, neuronal loss, apoptosis, endoplasmic reticulum stress, neuroinflammation, and disease-related protein aggregation. Nowadays, researchers use antioxidant-based strategies to prevent or halt the disease progression. Nerolidol, a strong antioxidant, possesses various biological activities and properties that treat cardiotoxicity, nephrotoxicity, neurotoxicity, and many other diseases. Many recent publications and research studies highlight the beneficial effect of nerolidol on brain disorders. In Alzheimer's disease, nerolidol shows neuroprotection by decreasing amyloid plaque formation, lipid peroxidation, cholinergic neuronal loss, locomotor dysfunction, neuroinflammation, and hippocampal damage via enhancing antioxidant expression. Also, it shows neuroprotection against rotenone-induced neurotoxicity by inhibiting microglial activation. Another study reported that nerolidol shows antiepileptic effects in animal models by suppressing kindling-induced memory impairment by decreasing oxidative stress. It has been found that NRL administration increases the antioxidant levels, decreasing the proinflammatory cytokine release as well as decreasing the apoptotic protein and cerebral infarct size. In conclusion, nerolidol tends to reverse the harmful effects of disease-related factors, including OS, neuroinflammation, protein aggregation, and apoptosis, making nerolidol a choiceable drug for the management of neurological disorders. The purpose of this review is to discuss the mechanism of nerolidol in treating various neurological disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neurodegenerative disease is mainly characterized by the accumulation of misfolded proteins, contributing to mitochondrial impairments, increased production of proinflammatory cytokines and reactive oxygen species, and neuroinflammation resulting in synaptic loss and neuronal loss. These pathophysiological factors are a serious concern in the treatment of neurodegenerative diseases. Based on the symptoms of various neurodegenerative diseases, different treatments are available, but they have serious side effects and fail in clinical trials, too. Therefore, treatments for neurodegenerative diseases are still a challenge at present. Thus, it is important to study an alternative option. Capsaicin is a naturally occurring alkaloid found in capsicum. Besides the TRPV1 receptor activator in nociception, capsaicin showed a protective effect in brain-related disorders. Capsaicin also reduces the aggregation of misfolded proteins, improves mitochondrial function, and decreases ROS generation. Its antioxidant role is due to increased expression of an nrf2-mediated signaling pathway. Nrf2 is a nuclear erythroid 2-related factor, a transcription factor, which has a crucial role in maintaining the normal function of mitochondria and the cellular defense system against oxidative stress. Intriguingly, Nrf2 mediated pathway improved the upregulation of antioxidant genes and inhibition of microglial-induced inflammation, improved mitochondrial resilience and functions, leading to decreased ROS in neurodegenerative conditions, suggesting that Nrf2 activation could be a better therapeutic approach to target pathophysiology of neurodegenerative disease. Therefore, the present review has evaluated the potential role of capsaicin as a pharmacological agent for the treatment and management of various neurodegenerative diseases via the Nrf2-mediated signaling pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: In the present work, fixed-dose combination of bilayer tablets for piroxicam as and curcumin as immediate-release and sustained-release layer (SRL) respectively for management of inflammatory response. Materials & methods: The SRL include Curcumin polycaprolactone microparticles from spray drying. The tablet layers include Pearlitol 200SD, Microcrystalline cellulose PH101, Aerosil 200, talc each layer. Results: SEM studies confirm spherical microparticles. PXRD and DSC studies confirm the amorphous microparticles. In vitro studies exhibit, an immediate release and sustained release for Piroxicam and Curcumin after 2 h. Cellular uptake studies on RAW 264.7 cells confirm the complete internalization of microparticles. Conclusion: Therefore, it was concluded that microparticles can be formulated into a unit dosage form for the management of inflammation.

Purpose: Complicated intra-abdominal infection (cIAI) management involves administering antibiotics that destroy the cell wall and the genesis of bacterial lipopolysaccharide (LPS). During the infectious state, the expression of transferrin receptors upregulates on the intestinal epithelial cells, which are considered the site of infection. In the present research, transferrin decorated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) encapsulated moxifloxacin (MOX) were developed for possible targeting of the receptors in the colon., Significance: This study will explore more about the incorporation of transferrin as effective coating material in targeted drug delivery., Methods: Nanoparticles were prepared using nano-emulsification and surface modification with transferrin was done by layer-by-layer methodology and evaluated by powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), FTIR, SEM, antibacterial activity, and cellular uptake studies., Results: The formulated NPs exhibit a size of ≈170 nm, PDI ≈ 0.25, zeta potential ≈-4.0 mV, drug loading ≈ 6.8%, and entrapment efficiency of 82%. Transferrin-decorated NPs exhibit tailored release for almost 12 h and in vitro antibacterial activity for 14 h. The cellular uptake studies were done on a RAW264.7 cell line for better determination of transferrin uptake of fabricated NPs., Conclusion: The above study circumvents around the preparation of transferrin decorated PLGA encumbered MOX NPs intended for cIAI-induced sepsis. PLGA NPs provide tailored release of MOX with primary burst and followed by sustained release. These observations confines with antibacterial activity studies. The prepared transferrin-coated NPs were stable and effectively uptaken by RAW264.7 cells. However, future studies include the preclinical investigation of these NPs in sepsis-induced murine models.

Bacopa monnieri L. (BM; Family: Scrophulariaceae), commonly known as Brahmi, is traditionally used as a nootropic agent. BM also exhibits significant analgesic activity in experimental models of pain. However, the effect of Bacopa monnieri against glutamate-induced nociception in zebrafish is yet to be explored in experimental condition. Therefore, the present study was designed to evaluate the effect of BM against glutamate-induced nociception and brain mitochondrial toxicity in adult zebrafish (Danio rerio). BM at 0.625, 1.25 and 2.5 mg/ml was administered to adult zebrafish and after half an hour glutamate was injected through i.m. route of administration. Indomethacin was used as standard drug. After behavioral analysis, the fish were euthanized and the brain was isolated and stored for further biochemical analysis. BM (1.25 and 2.5 mg/ml) and indomethacin significantly attenuated the glutamate-induced increase in number of line crossing compared to control group animals. Additionally, BM (1.25 and 2.5 mg/ml) and indomethacin significantly reduced the glutamate induced increase in cytosolic calcium level. Further, there was a substantial improvement in mitochondrial function, integrity and bioenergetics in term of respiratory control rate and ADP/O in zebrafish brain. Moreover, BM (1.25 and 2.5 mg/ml) and indomethacin significantly reduced the glutamate-induced mitochondria-dependent apoptosis in zebrafish brain. Therefore, BM could be a potential alternative drug candidate in the management of pain., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ethnopharmacological Relevance: Bacopa monnieri L. (Scrophulariaceae) is commonly known as Brahmi and traditionally used as a neuroprotective herbal medicine. Recently, Bacopa monnieri exhibited significant therapeutic activity against animal model of neuropathic pain. However, the therapeutic potential of methanolic extract of Bacopa monnieri in experimental animal model is yet to establish., Aim of the Study: The present study was designed to evaluate the anti-nociceptive potential of standardized methanolic extract of Bacopa monnieri in experimental adult zebrafish (Danio rerio) model of pain., Materials and Methods: The methanolic extract of Bacopa monnieri (BME) was standardized to bacoside-A using chromatographic method. Subsequently, BME (0.75, 1.25 and 5.0 mg/ml) was evaluated for anti-nociceptive activity using adult zebrafish model., Results: Standardized BME showed antioxidant effect through radical quenching activity in in vitro study. BME at 1.25 mg/ml significantly decreased the nociceptive effect induced by different noxious agents like acetic acid where as BME at 2.5 mg/ml exhibited significant antinociceptive activity against glutamate, formalin, capsaicin, cinnamaldehyde when compared to control and sham group animals., Conclusion: BME exerted antinociceptive activity in adult zebrafish. It could be presumed that BME may involve glutamatergic receptor, ASIC and TRP channel activity in its anti-nociceptive effect. BME could be considered as a potential therapeutic option in the management of pain., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Parkinson's disease is a chronic and gradually progressive neurodegenerative disorder triggered due to the loss of dopamine-releasing neurons in the region of substantia nigra pars compacta characterized by the motor symptoms, such as tremor, bradykinesia, akinesia, and postural instability. Proteinopathies, mitochondrial dysfunction induced dopaminergic neuronal deterioration, and gene mutations are the hallmarks of Parkinson's disease. The bioactive components of Brahmi, such as Bacoside A, Bacoside B, and Bacosaponins, belong to various chemical families. Brahmi's neuroprotective role includes reducing neuronal oxidative stress, dopaminergic neuronal degeneration, mitochondrial dysfunction, inflammation, inhibition of α-synuclein aggregation, and improvement of cognitive and learning behaviour. Researchers found that Bacopa monnieri significantly increased brain levels of glutathione, vitamin C, vitamin E, and vitamin A in rats exposed to cigarette smoke. Brahmi has a potent antioxidant property and neuroprotective effects against PD that help reduce oxidative stress and neuroinflammation and enhance dopamine levels. The review collates all the preclinical studies that prove the beneficial neuroprotective effect of Brahmi for treating PD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The objective of the present study was to investigate the α7nAChR-mediated Nrf2-dependant protective activity against streptozotocin (STZ)-induced brain mitochondrial toxicity in Alzheimer's disease (AD)-like rats. STZ (3 mg/kg) was injected through an intracerebroventricular route to induce AD-like dementia. Repeated Quercetin (50 mg/kg, i.p.) administration attenuated cognitive impairments in the STZ-challenged animals during Morris water-maze and Y-maze tests. Quercetin significantly mitigated the STZ-induced increase in cholinergic dysfunction, such as the increase in acetylcholinesterase activity, decrease in acetylcholine level, and activity of choline acetyltransferase, and increase in amyloid-beta aggregation and mitochondrial toxicity in respect of mitochondrial bioenergetics, integrity, and oxidative stress in memory-challenged rat hippocampus, prefrontal cortex and, amygdala. Further, Quercetin significantly attenuated STZ-induced reduction in the α7nAChRs and HO-1 expression levels in the selected rat brain regions. On the contrary, trigonelline (10 mg/kg, i.p.) and methyllycaconitine (2 mg/kg; i.p.) abolished the neuroprotective effects of Quercetin against STZ-induced behavioral, molecular, and biochemical alterations in the AD-like animals. Hence, Quercetin exhibits α7nAChR/Nrf2/HO-1-mediated neuroprotection against STZ-challenged AD-like animals. Thus, Quercetin could be considered as a potential therapeutic option in the management of AD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with clinical manifestation of loss in cognitive functions in an individual. Though several drug candidates have been developed in the management of AD, an alternative option is still required due to serious adverse effects of the former. Recently, naringin exerts therapeutic benefits through rennin angiotensin system in experimental animals. However, its report  on Mas receptor-mediated action against amyloid beta (Aβ)-induced mitochondrial dysfunction in AD-like animals is lacking. The experimental dementia was induced in the male rats by intracerebroventricular administration of Aβ (1-42) on day 1 (D-1) of the experimental schedule of 14 days. Naringin treatment for 14 days attenuated Aβ-induced cognitive impairments of the animals in Morris water maze (MWM) and Y-maze tests. Further, naringin ameliorated the Aβ-induced cholinergic dysfunction in terms of decrease in the activity of choline acetyl transferase (ChAT) and level of acetylcholine (ACh) and increase in the activity of acetylcholine esterase (AChE) in rat hippocampus, prefrontal cortex, and amygdala. Furthermore, naringin attenuated Aβ-induced decrease in mitochondrial function, integrity, and bioenergetics in all the brain regions. Naringin also attenuated Aβ-induced increase in mitochondrial and cytosolic calcium level in all the brain regions. Moreover, naringin reversed Aβ-induced increase in apoptosis and level of mitochondrial calcium uniporter and decrease in the level of hemeoxygenase-1 in all the brain regions. On the contrary, A779 significantly abolished the therapeutic potential of naringin on Aβ-induced alteration in behavioral, biochemical, and molecular observations in these experimental animals. Thus, these observations indicate that naringin could be potential alternative in the management of AD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits in an individual. Ang(1-7) exhibits neuroprotection against amyloid beta (Aβ)-induced mitochondrial dysfunction and neurotoxicity in experimental conditions. Further, Ang(1-7) also exhibits nrf2-mediated antioxidant activity in experimental conditions. However, its therapeutic role on nrf2-mediated mitochondrial function is yet to be established in the Aβ-induced neurotoxicity. The experimental dementia was induced in the male rats by intracerebroventricular administration of Aβ (1-42) on day-1 (D-1) of the experimental schedule of 14 days. Ang(1-7) was administered once daily from D-1 toD-14 to the Aβ-challenged rodents. Ang(1-7) attenuated Aβ-induced increase in escape latency and decrease in the time spent in the target quadrant during Morris water maze and percentage of spontaneous alteration behavior during Y-maze tests in the rats. Further, Ang(1-7) attenuated Aβ-induced cholinergic dysfunction in terms of decrease in the level of acetylcholine and activity of choline acetyltransferase, and increase in the activity of acetylcholinesterase, and increase in the level of Aβ in rat hippocampus, pre-frontal cortex and amygdala. Furthermore, Ang(1-7) reversed Aβ-induced decrease in the mitochondrial function, integrity and bioenergetics in all brain regions. Additionally, Ang(1-7) attenuated Aβ-induced increase in the extent of apoptosis and decrease in the level of heme oxygenase-1 in all selected brain regions. Trigonelline significantly abolished the therapeutic effectiveness of Ang(1-7) on Aβ-induced alterations in the behavioral, neurochemicals and molecular observations in the animals. Ang(1-7) may exhibit nrf2-mediated neuroprotection in these rodents. Hence, Ang(1-7) could be a potential therapeutic option in the pharmacotherapy of AD.

Renin Angiotensin System plays significant role in the memory acquisition and consolidation apart from its hemodynamic function in the pathophysiology of Alzheimer's disease (AD). It has been reported that Ang (1-7) ameliorates the cognitive impairment in experimental animals. However, the effect of Ang (1-7)/Mas receptor signaling is yet to be explored in Aβ42-induced memory impairment. Aβ42 was intracerebroventricularly injected into the male rats on day-1 (D-1) of the experimental schedule of 14 days. All the drugs were administered from D-1 to D-14 in the study design. Aβ42 significantly increased the escape latency during Morris water maze (MWM) test on D-10 to13 in the animals. Further, Aβ42 significantly decreased the time spent and percentage of total distance travelled in the target quadrant of the rats on D-14 in the MWM test. Aβ42 also significantly decreased the spontaneous alteration behavior on D-14 during Y-maze test. Moreover, there was a significant increase in the level of Aβ42, decrease in the cholinergic function (in terms of decreased acetylcholine and activity of cholinesterase, and increased activity of acetylcholinesterase), mitochondrial function, integrity and bioenergetics, and apoptosis in all the rat brain regions. Further, Aβ42 significantly decreased the level of expression of heme oxygenase-1 in all the rat brain regions. Ang (1-7) attenuated Aβ42-induced changes in the behavioral, biochemical and molecular observations in all the selected rat brain regions. However, A779, Mas receptor blocker, significantly abolished the beneficial effects of Ang (1-7) in Aβ42-induced cognitive deficit animals. These observations clearly indicate that the Ang (1-7)/Mas receptor activation could be a potential alternative option in the management of AD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Manilkara hexandra (Roxb; Family:sapotaceae) is reported to exert preventive effect in several experimental ulcer models. However, there is no report of M. hexandra on gastric ulcer healing property. Thus, the present study was designed to evaluate the gastric ulcer healing activity of methanolic stem bark extract of M. hexandra (MH) and to derive a plausible molecular level of mechanism of action. MH was subjected to several phytochemical screening tests and standardized to quercetin by HPTLC. In the first pharmacological experiment, the standardized MH (50, 100 and 200 mg/kg) was carried out for ulcer healing activity against acetic acid (AA)-induced gastric ulcer in male rats. MH (100 and 200 mg/kg) ameliorated AA-induced rat gastric lesions. Further, MH (100 and 200 mg/kg) attenuated AA-induced changes in the levels of lipid peroxidation (LPO), reduced glutathione (GSH), oxidized glutathione (GSSG) and ratio of GSH/GSSG and activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) enzymes, and level of hame oxygenase-1 (HO-1) in stomach tissue. In the subsequent set of experiment, trigonelline (30 mg/kg; p.o.), a potent Nrf2 antagonist, significantly abrogated the gastric ulcer healing activity of MH (100 mg/kg) in AA challenged animals. Further, trigonelline attenuated the effects of MH (100 mg/kg) on the levels of LPO, GSH, GSSG and ratio of GSH/GSSG and activity of SOD, CAT, GPx and GR enzymes, and level of HO-1 in AA challenged rodents. These observations implicate the fact that MH could be a better therapeutic alternative in the management of gastric ulcer.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment. Adenosinergic receptors are considered as a potential alternative in the management of several neurodegenerative disorders. However, there is no information available on the role of A2b receptor in the pathophysiology of AD. Therefore, the effect of Aβ on the level of expression of A2b receptor was investigated in discrete memory-sensitive mouse brain regions. Aβ (1-42) was injected intracerebroventricularly to healthy male mouse to induce AD-like behavioral manifestations on Day-1 (D-1) of the experimental protocol. The animals were subjected to the Morris water maze (MWM) test on D-14 to D-18. On D-18, the animals were subjected to the Y-maze test after 30 min lag to the MWM paradigm. Aβ significantly attenuated the spatial working memory in MWM and Y-maze tests. In addition, Aβ significantly increased cholinergic dysfunction in terms of decrease in the activity of ChAT and ACh level and increase in the AChE activity in the hippocampus, pre-frontal cortex and amygdala of AD-like animals. Further, there was a significant increase in the extent of apoptosis in the selected mouse brain regions. Moreover, Aβ caused a substantial reduction in the mitochondrial function, integrity and bioenergetics in all the mouse brain regions. Furthermore, there was a significant decrease in the level of expression of A2b receptors in the selected brain regions of the rodents. Hence, it can be assumed that A2b receptor downregulation could be another therapeutic target in the management of AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss in memory as one of the cardinal features. 5-N-ethyl carboxamidoadenosine (NECA), an agonist of adenosine-2b receptor, exerts neuroprotective activity against several experimental conditions. Further, NECA activates mitogen-activated protein kinase (MAPK) and also attenuates mitochondrial toxicity in mammalian tissues other than brain. Moreover, there is no report on the role of A2b/MAPK-mediated signaling pathway in Aβ-induced mitochondrial toxicity in the brain of the experimental animals. Therefore, the present study evaluated the neuroprotective activity of NECA with or without MAPK inhibitor against Aβ-induced cognitive deficit and mitochondrial toxicity in the experimental rodents. Further, the effect of NECA with or without MAPK inhibitor was evaluated on Aβ-induced mitochondrial toxicity in the memory-sensitive mice brain regions. Intracerebroventricular (ICV) injection of Aβ 1-42 was injected to healthy male mice through Hamilton syringe via polyethylene tube to induce AD-like behavioral manifestations. NECA attenuated Aβ-induced cognitive impairments in the rodents. In addition, NECA ameliorated Aβ-induced Aβ accumulation and cholinergic dysfunction in the selected memory-sensitive mouse HIP, PFC, and AMY. Further, NECA significantly attenuated Aβ-induced mitochondrial toxicity in terms of decrease in the mitochondrial function, integrity, and bioenergetics in the brain regions of these animals. However, MAPKI diminished the therapeutic effects of NECA on behavioral, biochemical, and molecular observations in AD-like animals. Therefore, it can be speculated that NECA exhibits neuroprotective activity perhaps through MAPK activation in AD-like rodents. Moreover, A2b-mediated MAPK activation could be a promising target in the management of AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal features of cognitive dysfunction in an individual. Recently, the blockade of mitochondrial calcium uniporter (MCU) exhibits neuroprotective activity in experimental animals. However, the therapeutic potential of MCU has not yet been established in the management of AD. Therefore, the present study explored the therapeutic potential of either Ruthenium red (RR), a MCU blocker, or Spermine, a MCU opener, on the extent of mitochondrial calcium accumulation, function, integrity and bioenergetics in hippocampus, pre-frontal cortex and amygdale of ICV-STZ challenged rats. Experimental AD was induced in male rats by intracerebroventricular injection of streptozotocin (ICV-STZ) on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. RR attenuated ICV-STZ-induced memory-related behavioral abnormalities in Morris water maze and Y-maze tests. RR also attenuated ICV-STZ-induced decrease in the level of acetylcholine and activity of choline acetyltransferase and, increase in the activity of acetylcholinestarase in memory-sensitive rat brain regions. Further, RR attenuated mitochondrial toxicity in terms of reducing mitochondrial calcium accumulation and improving the mitochondrial function, integrity and bioenergetics in memory-sensitive brain regions of ICV-STZ challenged rats. Furthermore, RR attenuated the percentage of apoptotic cells in ICV-STZ challenged rat brain regions. However, Spermine did not alter ICV-STZ-induced behavioral, biochemical and molecular observations in any of the brain regions. These observations indicate the fact that the MCU blockage could be a potential therapeutic option in the management of sporadic type of AD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal manifestation of cognitive dysfunction. The limitation to avail a successful drug candidate encourages researchers to establish an appropriate animal model in the novel anti-AD drug discovery process. In this context, the mechanism of mitochondrial dysfunction in cognitive deficit animals is yet to be established for intracerebroventricular injection of streptozotocin (ICV-STZ). Experimental dementia was induced in male rats by ICV-STZ on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. ICV-STZ caused cognitive decline in terms of increase in the escape latency on D-14 to D-17 and, decrease in the time spent and percentage of distance travelled in the target quadrant during Morris water maze and decrease in the spontaneous alteration behavior during Y-maze tests in rats. Further, ICV-STZ decreased the level of acetylcholine and activity of choline acetyltransferase and increased the activity of acetylcholinesterase in rat hippocampus, pre-frontal cortex and amygdala. Interestingly, ICV-STZ increased the mitochondrial calcium in addition to decrease in the mitochondrial function, integrity and bioenergetics in all rat brain regions. Further, ICV-STZ enhanced the levels of expression of NR1 subunit of N-methyl-D-aspartate receptor, mitochondrial calcium uniporter and sodium-calcium exchanger in these rat brain regions. Thus, NR1-dependent mitochondrial calcium accumulation could be considered as a major attribute to the animal model of ICV-STZ-induced AD-like manifestations. Further, drugs targeting to manage mitochondrial calcium homeostasis could best be studied in this animal model.

Estrogen replacement therapy including specific estrogen receptor alpha (ERα) agonist, 4,4',4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) trisphenol (PPT), improves cognitive function in the females with estrogen insufficiency condition. It is well suggested that the cyclic nucleotides are considered as one of the downstream mediators to ERα receptor activity and they can be hypothesized as a potential target in the management of estrogen insufficiency condition. Roflumilast, a phosphodiesterase-4 inhibitor, increases the level of cyclic adenosine monophosphate (cAMP) in most of the tissues including the brain, and is reported to have procognitive activity in the experimental animals. Hence, the present study evaluated the therapeutic effect of roflumilast with or without PPT in rats with experimentally-induced estrogen insufficiency. Estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Roflumilast (0.3 and 1.0 mg/kg; p.o.) and PPT (333µg/kg; i.p.) attenuated ovariectomy-induced cognitive deficits in the rodents during behavioral tests. Roflumilast and PPT increased the cholinergic function and cAMP level in the rat hippocampus and prefrontal cortex. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in both the brain regions was attenuated with the monotherapy of either roflumilast or PPT. Interestingly, the combination of 1.0 mg/kg roflumilast and PPT exhibited better therapeutic effectiveness than their monotherapy. In addition, roflumilast facilitated PPT-induced increase in the level of expression of phosphorylated protein kinase-B (Akt) in both the rat brain regions. Hence, it can be assumed that the combination of roflumilast and PPT could be a therapeutic option in the management of estrogen insufficiency-induced disorders.

Background: Post-traumatic stress disorder (PTSD) develops after exposure to a severe traumatic event. Stress re-stress (SRS) model of PTSD using forced swim as a re-stress shows hypocortisolism, an index of hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Despite this, the SRS model lacks development of hyperarousal and intrusive memory which are prominent symptoms of PTSD. Aim: Developing a model which shows more clinical similarities to PTSD. We used intense foot-shock (FS) (2 mA for 10 sec) instead of the forced-swim test (FST) as a re-stress cue. Methods: The stress session was performed on D-2 except control group. The FST group rats were forced to swim for 20 min, and FS group rats were exposed to foot shock of 2 mA for 10 sec. The re-stress sessions of FST and FS were performed on D-8, 14, 20, 26 and 32. The freezing behavior was evaluated after the FS re-stress cue, and remaining behavioral assessments such as anxiety and depressive-like behavior, and cognitive dysfunction were performed on last day of the experiment. Results: The FS-induced PTSD-like (anxiety and depressive-like behavior, and cognitive dysfunction) symptoms and a decrease in plasma corticosterone were more significant compared to FST. The hyperarousal and intrusive memory induced by FS were additional symptoms in the SRS model. Treatment with paroxetine significantly attenuated FST and FS-induced behavioral deficits in PTSD rats. Conclusion: FS as a re-stress model shows prominent PTSD-like symptoms with HPA axis dysfunction compared to FST.

The fluctuation in plasma estrogen level influences the cognitive function in the females. The specific estrogen receptor alpha (ERα) agonist, (4,4',4″-(4-propyl-[1 H] pyrazole-1,3,5-triyl) tris phenol (PPT), is reported to exhibit therapeutic activity similar to that of estrogen replacement therapy. However, the former can also exert cyclic adenosine monophosphate (cAMP)-dependent carcinogenic activity in the uterus of the ovariectomized animals. Moreover, there is no report of cGMP on ERα-mediated phosphorylation of Akt in the experimental condition. Vinpocetine increases the rate of formation of cGMP than cAMP in several tissues. Hence, the present study evaluated the neuroprotective effect of vinpocetine with or without PPT against ovariectomy-induced dementia in experimental rodents. The condition of estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Vinpocetine (20 mg/kg) and PPT attenuated ovariectomy-induced cognitive deficits in behavioral tests and increase in body weight in the rodents. Vinpocetine and PPT increased the cholinergic function and the ratio of cGMP/cAMP in the hippocampus, pre-frontal cortex and amygdala of the ovariectomized animals. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in all brain regions was attenuated with the monotherapy of either vinpocetine or PPT. Interestingly, the combination of vinpocetine and PPT exhibited better effectiveness than their monotherapy. However, vinpocetine attenuated the PPT-induced increased level of phosphorylated Akt in discrete brain regions and weight of uterus of these rodents. Hence, the combination could be considered as a better alternative candidate with minimal side effects in the management of estrogen insufficiency-induced disorders., Competing Interests: Decleration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disease that is accompanied with the loss of dopaminergic neurons in the substantia nigra pars compacta which subsequently leads to a reduction in the dopamine level in the striatum. The flavonoids are gaining critical attention in the management of PD due to the toxic effects of the synthetic drugs. Naringin, a potent flavonoid, exerts neuroprotective activity against experimental animal models of PD. It also exhibits protective activity against rotenone-induced neurotoxicity in cell line studies. Therefore, the present study was designed to evaluate the therapeutic potential of naringin against rotenone-induced animal model of PD. The rotenone was injected through intracerebroventricular route into substantia nigra pars compacta (SNpc) to induce PD-like manifestations in the male rats. The behavioral deficits of the animals due to dopaminergic toxicity were evaluated in actophotometer, OFT, bar catalepsy, narrow beam walk, rota-rod, grip strength and foot print analysis. Naringin-attenuated rotenone-induced behavioral abnormalities in the experimental rats. Further, naringin reduced the rotenone-induced dopaminergic toxicity in striatum and SNpc the animals. At the sub-cellular level, naringin attenuated the rotenone-induced decrease in the mitochondrial function, integrity and bioenergetics in the SNpc of the animals. Furthermore, naringin reduced the rotenone-induced mitochondria-dependent apoptosis in the rat SNpc. However, Trigonelline significantly abolished the therapeutic effects of naringin on behavioral, biochemical and molecular observations in rotenone-induced PD-like animals. These observations indicate that naringin may exert neuroprotective activity against rotenone-induced toxicity in the animals possibly through Nrf2-mediated pathway. Thus, it can be presumed that naringin could be an alternative option in the management of PD.

Multiple sclerosis (MS) is a chronic neurodegenerative disorder with clinical symptoms of neuroinflammation and demyelination in the central nervous system. Recently, herbal medicines are clinically effective against MS as the current disease-modifying drugs have limited effectiveness. Hence, the present study evaluated the therapeutic potential of Ocimum basilicum essential oil (OB) in ethidium bromide (EB)-induced cognitive deficits in the male rats. Further, the effect of OB (50, 100 and 200 μL/kg) was evaluated on EB-induced neuroinflammation, astrogliosis and mitochondrial dysfunction in the pre-frontal cortex (PFC) of the animals. The EB was injected through bilateral intracerebroventricular route into hippocampus to induce MS-like manifestations in the rats. OB (100 and 200 μL/kg) and Ursolic acid (UA) significantly reduced the EB-induced cognitive deficits in Morris water maze and Y-maze test paradigms. OB (100 and 200 μL/kg) and UA significantly attenuated the EB-induced neuroinflammation in terms of increase in the levels of pro-inflammatory cytokines (TNF-alpha and IL-6) in the rat PFC. Further, OB (100 and 200 μL/kg) and UA significantly attenuated the EB-induced astrogliosis in terms of increase in the levels of GFAP (Glial fibrillary acidic protein) and Iba-1 (Ionized calcium binding adaptor molecule-1) in the rat PFC. In addition, OB (100 and 200 μL/kg) and UA significantly attenuated the EB-induced decrease in the mitochondrial function, integrity, respiratory control rate and ADP/O in the PFC of the rodents. Moreover, OB (100 and 200 μL/kg) and UA significantly reduced the EB-induced mitochondria-dependent apoptosis in the PFC of the rat. Hence, it can be presumed that OB could be a potential alternative drug candidate in the pharmacotherapy of MS.

Background: Preclinical experimental models historically play a critical role in the exploration and characterization of disease pathophysiology. Further, these in-vivo and in-vitro preclinical experiments help in target identification, evaluation of novel therapeutic agents and validation of treatments., Introduction: Diabetes mellitus (DM) is a multifaceted metabolic disorder of multidimensional aetiologies with the cardinal feature of chronic hyperglycemia. To avoid or minimize late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic manifestations, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies., Methods: The study included electronic databases such as Pubmed, Web of Science and Scopus. The datasets were searched for entries of studies up to June, 2018., Results: A large number of in-vivo and in-vitro models have been presented for evaluating the mechanism of anti-hyperglycaemic effect of drugs in hormone-, chemically-, pathogen-induced animal models of diabetes mellitus. The advantages and limitations of each model have also been addressed in this review., Conclusion: This review encompasses the wide pathophysiological and molecular mechanisms associated with diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. This review may further contribute to discover a novel drug to treat diabetes more efficaciously with minimum or no side effects. Furthermore, it also highlights ongoing research and considers the future perspectives in the field of diabetes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The cognitive function in the females is observed to modulate with the fluctuation in plasma estrogen level. The specific estrogen receptor alpha (ERα) agonist, (4,4',4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) tris phenol (PPT), exerts similar therapeutic activity to that of estrogen replacement therapy. It can also exert cyclic adenosine monophosphate (cAMP)-dependent carcinogenic activity in the uterus of the ovariectomized animals. However, there is no report of cGMP on the ERα-mediated phosphorylation of Akt in the experimental condition. Sildenafil increases the level of cGMP in most of the tissues including brain. Hence, the present study evaluated the therapeutic effect of Sildenafil with or without PPT in rats with experimentally-induced estrogen insufficiency. The condition of estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Sildenafil (1.0 and 10.0 mg/kg) and PPT attenuated ovariectomy-induced cognitive deficits in behavioural tests and increase in body weight in the rodents. Sildenafil and PPT increased the cholinergic function and the ratio of cGMP/cAMP in the hippocampus, pre-frontal cortex and amygdala of the animals. Further, the ovariectomy-induced decrease in the extent of phosphorylation of ERα in all the brain regions was attenuated with the monotherapy of either Sildenafil or PPT. Interestingly, the combination of Sildenafil and PPT exhibited better therapeutic effectiveness than their monotherapy. However, Sildenafil attenuated the PPT-induced increase in the level of expression of phosphorylated protein kinase-B (Akt) in the discrete brain regions and the weight of uterus of these rodents. Hence, it can be assumed that the combination could be a better therapeutic alternative with minimal side effect in the management of estrogen insufficiency-induced disorders., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Calotropis procera (CP; Apocynaceae) is reported to have several neuroprotective activities however it's anti-depressant activity yet to be established. Therefore, the present study was proposed to evaluate the anti-depressant activity of the standardized ethanolic extract of CP (ECP) in chronic unpredictable mild stress (CUMS) paradigm exposed male rats. Animals were exposed to CUMS from day-1 (D-1) to D-28 except control group animals of the experimental schedule. ECP (50, 100 and 200 mg/kg, p.o.) and Imipramin (15.0 mg/kg, p.o.) were administered for seven consecutive days after CUMS paradigm. On D-35, ECP (200 mg/kg) significantly attenuated immobility period of the animals in both forced-swim and tail suspension and improved behavioural parameters in open-field and anhedonia in sucrose feeding tests. ECP (200 mg/kg) attenuated CUMS-induced hyperactivity of HPA-axis function. Further, ECP (200 mg/kg) mitigated CUMS-induced decrease in serotonin (5-HT), increase in 5-hydroxy indole acetic acid (5-HIAA) and increase in the ratio of 5-HIAA/5-HT in hippocampus and pre-frontal cortex. The CUMS-induced decrease in the level of expression of BDNF was significantly reversed with ECP (200 mg/kg) treatment. Moreover, ECP (200 mg/kg) significantly reduced the CUMS-induced decrease in the mitochondrial function and integrity in terms of level of formazan formed and intensity of tetramethyl rhodamine methylester dye in both the brain regions respectively. Therefore, ECP (200 mg/kg) mitigates CUMS-induced alterations in the behaviours, HPA-axis function, serotonergic activity, neurogenesis and mitochondrial function in the rodents. Thus, it can be assumed that ECP could be a potential alternative candidate in the management of depression.

Neurodegenerative disorders have been considered as a growing health concern for decades. Increasing risk of neurodegenerative disorders creates a socioeconomic burden to both patients and care givers. Mitochondria are organelle that are involved in both neuroinflammation and neurodegeneration. There are few reports on the effect of mitochondrial metabolism on the progress of neurodegeneration and neuroinflammation. Therefore, the present review summarizes the potential contribution of mitochondrial metabolic pathways in the pathogenesis of neuroinflammation and neurodegeneration. Mitochondrial pyruvate metabolism plays a critical role in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. However, there its potential contribution in other neurodegenerative disorders is as yet unproven. The mitochondrial pyruvate carrier and pyruvate dehydrogenase can modulate mitochondrial pyruvate metabolism to attenuate neuroinflammation and neurodegeneration. Further, it has been observed that the mitochondrial citric acid cycle can regulate the pathogenesis of neuroinflammation and neurodegeneration. Additional research should be undertaken to target tricarboxylic acid cycle enzymes to minimize the progress of neuroinflammation and neurodegeneration. It has also been observed that the mitochondrial urea cycle can potentially contribute to the progression of neurodegenerative disorders. Therefore, targeting this pathway may control the mitochondrial dysfunction-induced neuroinflammation and neurodegeneration. Furthermore, the mitochondrial malate-aspartate shuttle could be another target to control mitochondrial dysfunction-induced neuroinflammation and neurodegeneration in neurodegenerative disorders.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, disorientation and gradual deterioration of intellectual ability. In the pharmacotherapy of AD, the mitochondrial protective activity of Exendin-4 in experimental studies is yet to be established though its effectiveness is demonstrated in these patients. Therefore, the mitochondria protective activity of Exendin-4 (5 μg/kg, i.p.) was investigated in hippocampus and pre-frontal cortex (PFC) of AD-like animals. The amyloid beta (Aβ) was injected through bilateral intracerebroventricular route into lateral ventricles to induce AD-like manifestations in the male rats. Exendin-4 significantly attenuated Aβ-induced memory-deficits in the Morris water maze and Y-maze test protocols. Exendin-4 significantly decreased Aβ-induced increase in the level of Aβ in both brain regions. Exendin-4 significantly increased Aβ-induced decrease in acetylcholine level and activity of cholineacetyl transferase in all brain regions. Moreover, Exendin-4 significantly decreased Aβ-induced increase in the activity of acetylcholinestrase in both the brain regions. E4 significantly increased Aβ-induced decrease in mitochondrial function, integrity, respiratory control rate and ADP/O in all brain regions. Further, Exendin-4 significantly decreased Aβ-induced increase in the mitochondrial complex enzyme-I, IV and V activities in all brain regions. Furthermore, Exendin-4 significantly increased Aβ-induced decrease in the level of phosphorylated Akt and the ratio of phosphorylated Akt to Akt in both brain regions. However, LY294002 diminished the therapeutic effects of Exendin-4 on behavioral, biochemical and molecular observations in AD-like animals. Pearson's analysis showed that the attributes of mitochondrial dysfunction (MMP and RCR) exhibited significant correlation to the loss in memory formation, level of Aβ and cholinergic dysfunction in these animals. Thus, it can be speculated that Exendin-4 may mitigate AD-like manifestations including mitochondrial toxicity perhaps through PI3K/Akt-mediated pathway in the experimental animals. Hence, Exendin-4 could be a potential therapeutic alternative candidate in the management of AD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Eugenol is one of the essential chemical constituents of several functional food plants including Eugenia caryophyllata Thunb. (Family: Myrtaceae). Eugenol exhibits neuroprotective and anti-stress activities through multimodal mechanisms of action. Further, eugenol exerts anti-amnesic activity in Alzheimer's disease (AD)-like animals perhaps through anti-oxidant mechanism to date. Hence, the present study was designed to elaborate the anti-amnesic activity of eugenol in scopolamine-challenged rodents. Scopolamine (3 mg/kg/day, i.p.) and eugenol (12.5, 25.0, and 50.0 mg/kg) were administered to male rats for 14 consecutive days of the experimental schedule at a time lag of 30 min. Eugenol (25.0 and 50.0 mg/kg) attenuated scopolamine-induced loss in learning ability in terms of increased escape latency at day-4 (D-4) and memory function in terms of decreased time spent in target quadrant at D-5 of Morris water maze test protocol. Moreover, eugenol attenuated scopolamine-induced loss in spatial memory in terms of decreased percentage of spontaneous alteration behavior in Y-maze test. Additionally, eugenol attenuated scopolamine-induced hippocampal cholinergic dysfunction (decrease in acetylcholine level, increase in acetylcholinesterase activity, and decrease in density and affinity of M 1 and total muscarinic receptor), glutamate neurotoxicity (increase in levels of glutamate, calcium, calcium-dependent calpain-2, and brain-derived neurotropic factor), and mitochondrial dysfunction (decrease in formazan produced, membrane potential, and oxidative stress) in rats. Thus, it could be considered as an alternate candidate in the management of AD. Moreover, inclusion of functional foods containing eugenol could be a better option to manage memory formation in neurological disorders.

Obsessive-compulsive disorder (OCD) is considered a heterogeneous anxiety disorder that includes compulsions. Celecoxib is considered an adjuvant to fluoxetine in the management of OCD in a clinical study. However, the experimental evidence is yet to be established. Therefore, the antianxiety and anticompulsive-like activity of celecoxib (20 mg/kg, orally) was evaluated in the presence or absence of fluoxetine (20 mg/kg, orally) in mice who were exposed to chronic unpredictable mild stress (CUMS) for 14 consecutive days. Seven-day treatment of celecoxib significantly attenuated the CUMS-induced anxiety in open-field, hole-board, elevated plus maze tests, and compulsion in the marble-burying test. Celecoxib significantly reversed the CUMS-induced decrease and increase in the levels of serotonin (5-HT) and its metabolite (5-hydroxyindole acetic acid) in the prefrontal cortex, and attenuated the CUMS-induced increase in the levels of inflammatory markers such as interleukin-6 and tumor necrosis factor-α, and apoptosis marker caspase-3 in the prefrontal cortex. Celecoxib also potentiated the anxiolytic, anticompulsive, serotonergic, anti-inflammatory, and antiapoptotic activity of 7-day treatment with fluoxetine in CUMS-challenged animals compared with their monotherapy. Thus, it can be speculated that the combination of an anti-inflammatory agent with selective serotonin reuptake inhibitor could be a better therapeutic option in the management of stress-related disorders including selective serotonin reuptake inhibitor-resistant OCD.

Ethnopharmacological Relevance: Clitoria ternatea flower is traditionally used in the treatment of respiratory disorders including bronchitis and is one of the ingredients in different Ayurvedic preparations that are used in respiratory disorders. However, till date there is no scientific report on the anti-asthmatic activity of this flower., Aim of the Study: Ethanolic extract of Clitoria ternatea flowers (ECT) was evaluated for its anti-allergy and anti-tussive potential in experimental animals. Additionally, the anti-inflammatory potential of ECT was carried out to draw a plausible mechanism of action of the drug., Materials and Methods: In-vitro anti-asthmatic activity of ECT was evaluated in goat tracheal chain and isolated guinea pig ileum preparations. Acute and chronic anti-asthmatic activity of ECT (100, 200 and 400 mg/kg; p.o.) was estimated in histamine aerosol exposed guinea pigs and in OVA sensitized and challenged mice respectively. Anti-tussive activity of ECT (100, 200 and 400 mg/kg; p.o.) was evaluated against sulfur dioxide- and citric acid-induced cough in experimental animals. Moreover, the anti-inflammatory activity of ECT (100, 200 and 400 mg/kg; p.o.) was evaluated against carrageenan- and acetic acid-induced inflammation in rats., Results: ECT attenuated histamine-induced contraction in both goat tracheal chain and isolated guinea pig ileum preparations. ECT (400 mg/kg) attenuated histamine-induced dyspnoea and OVA-induced changes in differential cell count in broncheoalveolar fluid, levels of interleukins (IL-1beta and IL-6) and immunoglobulin (OVA-sensitive IgG1) in animals. ECT (400 mg/kg) further ameliorated sulfur dioxide- and citric acid-induced cough in experimental animals. Additionally, ECT (400 mg/kg) attenuated inflammation in carrageenan and acetic acid challenged rodents., Conclusions: Standardized ECT could be considered as a potential therapeutic alternative in the management of allergy-induced asthma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Context: Metformin attenuates type-2 diabetes mellitus (T2DM)-induced hepatic dysfunction and altered PI3K/Akt/GLUT-4 signalling in experimental studies. However, its effect on bicuculline-sensitive gamma amino butyric acid (GABA)-A receptor (GABA A R)-mediated calcium-dependent PI3K/Akt/GLUT-4 signalling in liver challenged to T2DM has not been established., Objective: The effectiveness of metformin on bicuculline-sensitive GABA A R-mediated hepatic insulin signalling was carried out in presence or absence of bicuculline (2.0 mg/kg, i.p.) in experimental T2DM rats., Materials and Methods: The whole experimental design was divided into three independent sets of experiments. Each set comprised seven groups of six male rats each. T2DM was induced in the animals by administering streptozotocin (45 mg/kg, i.p.) and nicotinamide (110 mg/kg, i.p.) at a time lag of 15 min except control group rats in three experiments. Metformin and/or bicuculline or wortmannin were administered once daily for one week from seventh day of streptozotocin injection in all the experimental sets., Results: Metformin attenuated T2DM-induced hyperglycaemia in glucose (40%) and insulin (50%) tolerance tests in rats. Metformin also attenuated T2DM-induced hyperglycaemia (40%), hyperinsulinaemia (30%), insulin resistance (50%) and β-cell dysfunction (300%) in the animals. Metformin did not attenuate T2DM-induced decrease in rat hepatic intracellular calcium. Further, metformin mitigated T2DM-induced decrease in hepatic phosphorylated Akt and GLUT-4 translocation in the animals. The anti-diabetic activity of metformin was abolished by wortmannin but not with bicuculline co-administration in T2DM animals., Discussion and Conclusion: These results suggest that metformin ameliorated T2DM-induced hepatic insulin resistance through bicuculline-sensitive GABA A receptor-independent PI3K/Akt/GLUT-4 signalling pathway in animals.

Piracetam exhibits anti-amnesic activity in several animal models of dementia. However, its anti-amnesic potential has yet to be evaluated in type-2 diabetes mellitus (T2DM)-induced encephalopathy. Therefore, in the present study, piracetam (25, 50 and 100 mg/kg) was screened for anti-amnesic and anti-diabetic activity in T2DM-induced encephalopathic male rats. Subsequently, anti-amnesic and anti-diabetic activities were evaluated for piracetam, metformin and their combination in T2DM-induced encephalopathic animals. Rats received streptozotocin (45 mg/kg) and nicotinamide (110 mg/kg) injections on day-1 (D-1) of the experimental schedule and were kept undisturbed for 35 days to exhibit T2DM-induced encephalopathy. All drug treatments were continued from D-7 to D-35 in both experiments. Piracetam (100 mg/kg) attenuated loss in learning and memory in terms of increase in escape latency on D-4 (D-34) and decrease in time spent in the target quadrant on D-5 (D-35) of Morris water maze test protocol, and spatial memory in terms of reduced spontaneous alternation behavior in Y-maze test of encephalopathic rats. Additionally, piracetam attenuated altered levels of fasting plasma glucose and insulin, HOMA-IR and HOMA-B in encephalopathic animals, comparatively lesser than metformin. In the next experiment, combination of piracetam and metformin exhibited better anti-amnesic but not anti-diabetic activity than respective monotherapies in encephalopathic rats. Further, the combination attenuated reduced acetylcholine level and increased acetylcholinesterase activity, increased glycogen synthase kinase-3β level and decreased brain-derived neurotropic factor level in hippocampus and pre-frontal cortex of encephalopathic animals. Thus, piracetam could be used as an adjuvant to metformin in the management of dementia in T2DM-induced encephalopathy.

Ischemic preconditioning (IPC) is one of the most promising strategies used to protect the myocardium from ischemia-reperfusion injury. Ang (1-7) exhibits cardioprotective activity; however, its therapeutic potential on IPC-induced cardioprotection has not been reported in ischemia-reperfusion injury till date. Therefore, the first set of experiment was designed to evaluate the direct effect of Ang (1-7), in perfusion medium, on cardioprotective activity of IPC in rat heart challenged to ischemia-reperfusion injury. In addition, the acute and chronic effects of pretreated Ang (1-7) were investigated on cardioprotection of IPC in ischemia-reperfusion-challenged hearts in subsequent sets of experiments. The results showed that Ang (1-7) potentiated the IPC-induced increase in coronary flow and heart rate, decrease in lactate dehydrogenase and creatine kinase activity, ventricular fibrillation, and infarct size in ischemia-reperfusion-challenged animals in direct and chronic sets of experiments. Further, Ang (1-7) enhanced the IPC-induced attenuation in mitochondrial dysfunction, oxidative stress, and apoptosis in ischemia-reperfusion-challenged hearts in both sets of experiments. A-779, Mas receptor antagonist, abrogated potentiation effects of Ang (1-7) on IPC-induced cardioprotection in ischemia-reperfusion-challenged rats in the above set of experiments. These observations indicate that Ang (1-7)/Mas receptor activation could be a potential adjuvant to IPC during ischemia-reperfusion-induced cardiac injury.

Atorvastatin (ATV) generally used to treat dyslipidemia is also reported to have effect against 6-hydroxydopamine (6-OHDA) induced neurotoxicity. Additionally, atorvastatin can interfere with mitochondrial function by reducing the level of Q10. Therefore, the therapeutic effect of atorvastatin (20 mg/kg) could be compromised. In this context, the present study evaluated the effect of ATV supplemented with Q10. 6-OHDA was unilaterally injected into the right striatum of male rats. On day 8 of 6-OHDA infusion, ATV (20 mg/kg), Q10 (200 mg/kg), and their combination were administered per oral for 14 days. On day 21, there was significant loss of striatal dopamine indicating neurotoxicity. The combination of ATV+Q10 showed significant amelioration of dopamine (DA) toxicity compared to individual treatments. Similarly, ATV+Q10 compared to individual treatment significantly decreased the motor deficits induced by 6-OHDA. Further, 6-OHDA induced mitochondrial dysfunction in the substantia nigra pars compacta (SNpc). There was significant decrease in mitochondrial complex enzyme activities and mitochondrial membrane potential (MMP). Treatment with ATV and ATV+Q10 ameliorated mitochondrial dysfunction by increasing complex enzyme activities; however, only ATV+Q10 were able to stabilize MMP and maintained mitochondrial integrity. Moreover, there was significant induction of oxidative stress as observed from increase in lipid peroxidases (LPO) and nitrite (NO), and decrease in super oxide dismutase (SOD). Treatment with ATV+Q10 significantly altered the above effects indicating antioxidant activity. Furthermore, only combination of ATV and Q10 decreased the 6-OHDA induced expression of cytochrome-C, caspase-9 and caspase-3. Therefore, current results provide evidence that supplementation of Q10 with ATV shows synergistic effect in reducing dopamine toxicity.

Context: Eugenol, an essential constituent found in plants such as Eugenia caryophyllata Thunb. (Myrtaceae) is reported to possess neuroprotective and anti-stress activities. These activities can potentially be useful in the treatment of stress-induced irritable bowel syndrome (IBS)., Objective: The protective effect of eugenol was assessed against restraint stress (RS)-induced IBS-like gastrointestinal dysfunction in rats. Further, its centrally mediated effect was evaluated in this model., Materials and Methods: Eugenol (12.5, 25, and 50 mg/kg), ondansetron (4.0 mg/kg, p.o.), and vehicle were administered to rats for 7 consecutive days before exposure to 1 h RS. One control group was not exposed to RS-induction. The effect of eugenol (50 mg/kg) with and without RS exposure was evaluated for mechanism of action and per se effect, respectively. The hypothalamic-pituitary-adrenal cortex (HPA)-axis function was evaluated by estimating the plasma corticosterone level. The levels of brain monoamines, namely serotonin, norepinephrine, dopamine, and their metabolites were estimated in stress-responsive regions such as hippocampus, hypothalamus, pre-frontal cortex (PFC), and amygdala. Oxidative damage and antioxidant defenses were also assessed in brain regions., Results: Eugenol (50 mg/kg) reduced 80% of RS-induced increase in fecal pellets similar to that of ondansetron. Eugenol attenuated 80% of stress-induced increase in plasma corticosterone and modulated the serotonergic system in the PFC and amygdala. Eugenol attenuated stress-induced changes in norepinephrine and potentiated the antioxidant defense system in all brain regions., Conclusion: Eugenol protected against RS-induced development of IBS-like gastrointestinal dysfunction through modulation of HPA-axis and brain monoaminergic pathways apart from its antioxidant effect.

Mitochondria play a significant role in the pathophysiology of post-traumatic stress disorder (PTSD). Risperidone and paroxetine were evaluated for their effect on mitochondrial dysfunction and mitochondria-dependent apoptosis in discrete brain regions in modified stress re-stress (SRS) animal model of PTSD. Male rats were subjected to stress protocol of 2 h restraint and 20 min forced swim followed by halothane anesthesia on day 2 (D-2). Thereafter, rats were exposed to re-stress (forced swim) on D-8 and at 6-day intervals on D-14, D-20, D-26, and D-32. The rats were treated with risperidone (0.01, 0.1, and 1.0 mg/kg p.o.) and paroxetine (10.0 mg/kg p.o.) from D-8 to D-32. Risperidone at median dose and paroxetine ameliorated modified SRS-induced depressive-like symptom (increase in immobility period) in forced swim, anxiety-like behavior (decrease in percentage of open arm entries and time spent) in elevated plus maze and cognitive deficits (loss in spatial recognition memory) in Y-maze tests on D-32. Risperidone, but not paroxetine, attenuated modified SRS-induced decreases in plasma corticosterone levels. Risperidone ameliorated increase in the activity of mitochondrial respiratory complex (I, II, IV, and V), decreases in the levels of mitochondrial membrane potential, cytochrome-C and caspase-9 in the hippocampus, hypothalamus, pre-frontal cortex, and amygdala. However, both drugs attenuated modified SRS-induced increase in the number of apoptotic cells and caspase-3 levels in all the brain regions indicating anti-apoptotic activity of these drugs. Hence, these results suggest that anti-apoptotic activity could be a common mechanism for anti-PTSD-like effect irrespective of the pathways of apoptosis in the modified SRS model.

The present study evaluates the protective effect of citalopram against cold-restraint stress (CRS) paradigm. Rats were pretreated with citalopram (0.1, 1.0, and 10.0 mg/kg) acutely and repeatedly for 21 days before exposure to the CRS procedure. None of the doses of citalopram attenuated CRS-induced gastric ulcers in the acute study. In contrast, repeated pretreatment of citalopram at a dose level of 0.1 mg/kg attenuated the CRS-induced gastric ulcers. Citalopram (0.1 mg/kg) diminished CRS-induced increase in plasma corticosterone, but not plasma norepinephrine level in the chronic study indicating its effect on hypothalamic-pituitary-adrenal axis function. Repeated citalopram (0.1 mg/kg) pretreatment attenuated CRS-induced changes in serotonin turnover in the hippocampus and amygdala. Moreover, repeated pretreatment with citalopram (0.1 mg/kg) mitigated the CRS-induced increase in the expression of brain-derived neurotrophic factor (BDNF) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) in the hippocampus and amygdala. These results suggest that there is a region- and a dose-specific effect of citalopram on CRS-induced BDNF-NFκB activation. Therefore, citalopram showed antistress activity in the CRS model through changes in the stress-responsive pathways such as hypothalamic-pituitary-adrenal-axis and brain serotonergic system apart from decreasing the expression of BDNF and NFκB.

Neuroinflammation is considered as one of the predisposing factor in the etiology of several neurodegenerative disorders. Therefore, the objective of the present study was to evaluate the protective effect of silibinin (SIL) in the lipopolysaccharide (LPS)-induced neuroinflammatory model. The effect of SIL on memory function was also evaluated on normal rats without LPS administration. In the first experiment, male rats were divided into five groups. Except control group animals, all rats received bilateral intracerebroventricular injection of LPS (5 μg/5 μl) into lateral ventricles on the first day of the experimental schedule. Control rats received bilateral intracerebroventricular injection of artificial cerebrospinal fluid into lateral ventricles. SIL in doses of 50, 100 and 200 mg/kg, p.o. was administered 1h before LPS injection and continued for 7 days. On Day-7, SIL attenuated the LPS-induced long-term and working memory loss in elevated plus and Y-maze test respectively. Further, SIL dose-dependently attenuated LPS-induced decrease in acetylcholine level and increase in the acetylcholinestrase activity in hippocampus and pre-frontal cortex. SIL ameliorated LPS-induced decrease in the mitochondrial complex activity (I, IV and V) and integrity, increase in lipid peroxidation and decrease in the activity of superoxide dismutase in both the brain regions. SIL attenuated amyloidogenesis in the hippocampus, while it decreased the LPS-induced increase in the level of NFκB in the pre-frontal cortex. In another study, SIL dose-dependently, enhanced memory functions in the normal rats, indicating its nootropic activity. Hence, SIL could be a potential candidate in the management of neuroinflammation-related memory disorders., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The present study was carried out to evaluate the anticonvulsant activity and probable mechanism of action of the methanol root extract from I. frutescens (MEIF) using different experimental animal models. Anticonvulsant activity of the single dose of MEIF (100, 200, and 400 mg/kg, p.o.) was evaluated in maximal electroshock- (MES-), pentylenetetrazole- (PTZ-), and isoniazid- (INH-) induced convulsions models in rats. The levels of γ-amino butyric acid (GABA), glutamate, GABA-transaminase (GABA-T) activity and oxidative stress markers were measured in pretreated rat's brain homogenate to corroborate the mechanism of observed anticonvulsant activity. MEIF (200-400 mg/kg, p.o.) protected the animals in all the behavioral models used. Pretreatment of MEIF (200-400 mg/kg, p.o.) and diazepam (1.0 mg/kg, i.p.) to the animals in INH-induced convulsion model showed 100% and 80% protection, respectively, as well as significant restoration of GABA and glutamate level in the rat's brain. MEIF and vigabatrin (50 mg/kg, i.p.) reduced the PTZ-induced increase in the activity of GABA-T (46%) in the brain. Further, MEIF reversed the PTZ-induced increase in lipid peroxidase (LPO) and decrease in reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. The findings of this study validate the anticonvulsant activity of I. frutescens.

Asparagus racemosus Linn. (AR) is used worldwide as a medicinal plant. In the present study, the anxiolytic activity of standardized methanolic extract of root of AR (MAR) was evaluated in open-field test (OFT), hole-board, and elevated plus maze (EPM) tests. Rats received oral pretreatment of MAR in the doses of 50, 100, and 200 mg/kg daily for 7 days and then were evaluated for the anxiolytic activity in different animal models. Both MAR (100 and 200 mg/kg) and diazepam (1 mg/kg, p.o.) increased the grooming behavior, number of central squares crossed, and time spent in the central area during OFT. Further, MAR (100 and 200 mg/kg) increased the head-dip and head-dip/sniffing behavior, and decreased sniffing activity in hole-board test. Furthermore, MAR (100 and 200 mg/kg) increased the percentage entries and time spent to open arm in EPM test paradigm. The anxiolytic activity in the experimental models was similar to that of diazepam. MAR (100 and 200 mg/kg) enhanced the level of amygdalar serotonin and norepinephrine. It also increased the expression of 5-HT2A receptors in the amygdala. In another set of experiment, flumazenil attenuated the anxiolytic effect of minimum effective dose of MAR (100 mg/kg) in OFT, hole-board, and EPM tests, indicating GABAA-mediated mechanism. Moreover, the anxiolytic dose of MAR did not show sedative-like effect in OFT and EPM tests compared to diazepam (6 mg/kg, p.o.). Thus, the anxiolytic response of MAR may involve GABA and serotonergic mechanisms. These preclinical data show that AR can be a potential agent for treatment of anxiety disorders.

Silymarin commonly known for its hepatoprotective effect is reported to show protection against 6-hydroxydopamine-induced neurotoxicity. Silibinin forms the major active constituent of silymarin. Therefore, the neuroprotective effect of silibinin (50, 100 and 200 mg/kg) was evaluated in the unilaterally injected 1-methyl-4-phenylpyridinium (MPP(+))-induced dopaminergic neurotoxicity in male rats. A battery of tests such as elevated plus maze (EPM), narrow beam walk, open field, bar catalepsy, grip strength, and foot print analysis was performed to evaluate the behavioral symptoms of striatal dopaminergic toxicity. Furthermore, the mechanism of action of silibinin was investigated by evaluating the mitochondrial complex enzyme activities, mitochondrial integrity and oxidative status. Striatal caspase-3 and NFκB were expressed to evaluate the effect of silibinin on apoptosis and inflammation respectively. Silibinin (100 and 200 mg/kg) protected against MPP(+)-induced dopamine depletion in striatum. Silibinin reversed MPP(+)-induced decrease in transfer latency indicating memory consolidation in the EPM test. Silibinin (100 and 200 mg/kg) attenuated MPP(+)-induced motor deficits, such as fine motor movements and gait. MPP(+)-induced mitochondrial dysfunction, loss of integrity and oxidative stress were attenuated by silibinin. Silibinin decreased striatal caspase-3 and NFκB expression indicating potential anti-apoptotic and anti-inflammatory effects respectively. Hence, silibinin exhibited neuroprotective effect in the MPP(+) induced striatal toxicity augmenting dopamine levels. The mechanism of action may be linked to maintenance of mitochondrial bioenergetics and integrity apart from anti-apoptotic and anti-inflammatory activities., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Psychological stress is considered as one of the limiting factors in the management of type-2 diabetes mellitus (T2DM). Therefore, the basic objective of the present study was to evaluate the antidiabetic effect of metformin, diazepam, and their combination in cooccurring T2DM and stress condition (DMS). T2DM was induced in the male rats by administering streptozotocin (45 mg/kg, i.p.) and nicotinamide (110 mg/kg, i.p.) with time lag of 15 min. Rats were subjected to two sessions of cold restraint stress paradigm for one hour on the sixth and seventh day after streptozotocin injection. Administration of metformin (25 mg/kg, p.o.) and diazepam (1 mg/kg, p.o.) in combination from the seventh to thirteenth day after streptozotocin injection showed better improvement in glucose tolerance and insulin sensitivity compared to monotherapy of either drug. In addition, the combination significantly attenuated DMS-induced hyperglycemia, hypertriglyceridaemia, hypercorticosteronemia, anxiety-like behavior, and insulin resistance through modulating insulin signaling pathway in the liver compared to monotherapy. Further, improvement of mitochondrial function, integrity, and oxidative stress in hippocampus, hypothalamus, prefrontal cortex, striatum, amygdala, and nucleus accumbens was observed with the combination. Therefore, metformin in combination with diazepam may be a better therapeutic option in the management of T2DM with cooccurring stress condition.

The management for post-traumatic stress disorder (PTSD) involves chronic administration of drugs. We have modified the stress re-stress (SRS) model to study the effect of chronic administration of risperidone (RIS) after induction of PTSD in rats. On day-1 (D-1) rats underwent training session for elevated-plus maze (EPM) test. On D-2, rats were subjected to stress protocol of 2 h restraint and 20 min forced-swim test (FST) followed by halothane anesthesia. The rats were exposed to re-stress (FST) on D-8 and at six day intervals on D-14, D-20, D-26 and D-32. The rats were treated with RIS (0.01, 0.1 and 1.0 mg/kg; p.o.) and standard drug, paroxetine (PAX; 10.0 mg/kg; p.o.) from D-8 to D-32. RIS (0.1 mg/kg) and PAX ameliorated SRS-induced immobility. RIS in median dose reversed SRS-induced hypocorticosteronemia both in urine and plasma. RIS in median dose improved SRS-induced behavioral perturbations such as memory impairment and anxiety-like behavior in EPM and Y-maze tests. RIS (0.1 mg/kg) reversed SRS-induced increase in amygdalar serotonin level. RIS (0.1 mg/kg) increased the expression of hippocampal MR thereby reversing the SRS-induced decrease in MR/GR ratio. Pearson's analysis of data on D-32 showed that there was significant correlation of plasma corticosterone, amygdalar serotonin and hippocampal ratio of mineralocorticoid (MR)/glucocorticoid receptor (GR) with SRS-induced behavioral abnormalities. Hence, median dose of RIS shows anti-PTSD-like effect in the modified SRS model. PAX had earlier onset of action in ameliorating behavioral effects of PTSD compared to RIS. However, RIS showed anti-PTSD like effect in sub-therapeutic dose. The mode of anti-PTSD action of RIS seems to involve the HPA-axis and serotonergic system, whereas PAX did not show any significant action on these pathways. The effect of repeated treatment of drugs for PTSD can be evaluated using the modified SRS model., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: Asparagus racemosus (AR) is classified as an adaptogen, an important medicinal plant and food. Even though AR is widely used as food and nutraceutical, it has only been evaluated in the context of experimental disorders. Hence, the present study was designed to evaluate the effect of standardized methanolic extract of AR (MAR) on experimentally un-manipulated animals to observe the per se effects on stress pathways., Methods: MAR (50, 100, and 200 mg/kg, per oral) was administered for 7 days. Lorazepam (0.5 mg/kg, intraperitoneal) was used as a positive control. On the seventh day, plasma was collected for the estimation of corticosterone (CORT) and norepinephrine (NE), and brain was microdissected into hippocampus, hypothalamus (HYP), pre-frontal cortex, amygdala, and nucleus accumbens to estimate tissue level of monoamines (serotonin, dopamine, and NE), their metabolites, and turnover., Results: MAR dose-dependently decreased the plasma CORT and NE levels, indicating its effects on the hypothalamic-pituitary-adrenal cortex axis and the sympathetic-noradrenergic system, respectively. MAR increased the levels of all monoamines in the HYP. However, MAR showed region-specific changes in monoamines and their metabolites, and turnover in other brain regions., Discussion: MAR showed a physiological modulation of the stress pathways. Interestingly, in most brain regions the change in monoaminergic systems was limited by a ceiling effect at a dose of 100 mg/kg. These observations could explain the traditional use of AR as an adaptogen and a functional food.

The present investigation evaluates the anti-stress activity of risperidone (RIS) in the cold restraint stress (CRS) model and related stress pathways. Rats were pretreated with RIS (0.1 and 1.0 mg/kg) for 21 days before subjecting to CRS. Ultra low dose of RIS (ULD; 0.1 mg/kg) in contrast to higher dose (1.0 mg/kg) significantly reduced stress in terms of ulcer index. ULD also reversed stress-induced increase in plasma corticosterone and norepinephrine levels used as markers for the function of hypothalamo-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) respectively. ULD caused dose and brain region (hippocampus, prefrontal cortex and striatum) specific changes to stress-induced perturbations of serotonin, dopamine and its metabolites indicating modulation of brain monoaminergic system (BMS). ULD did not show any extrapyramidal side effects. Thus, the anti-stress effect ULD is probably mediated through the HPA axis, SNS and BMS. The study indicates a potential use of ULD in stress disorders.

Stress is the leading psychopathological cause for several mental disorders. Physiological and psychological responses to stress are mediated by the hypothalamic?pituitary?adrenal (HPA), sympathoadrenal system (SAS), and brain monoaminergic systems (BMS). Eugenol is reported to substantially modulate brain functions by regulating voltage-gated cation channels and release of neurotransmitters. This study was designed to evaluate the anti-stress effect of eugenol in the 4-h restraint model using rats. Ulcer index was measured as a parameter of the stress response. HPA axis and the SAS were monitored by estimating plasma corticosterone and norepinephrine (NE), respectively. Analysis of NE, serotonin (5-HT), dopamine, and their metabolites in discrete brain regions was performed to understand the role of BMS in the anti-stress effect of eugenol. Stress exposure increased the ulcer index as well as plasma corticosterone and NE levels. Eugenol pretreatment for 7 days decreased the stress-induced increase in ulcer index and plasma corticosterone but not NE levels, indicating a preferential effect on the HPA axis. Furthermore, eugenol showed a ?U?-shaped dose?response curve in decreasing ulcer index and plasma corticosterone levels. Eugenol also reversed the stress-induced changes in 5-HT levels in all brain regions, whereas NE levels were reversed in all brain regions except hippocampus. These results suggest that eugenol possesses significant anti-stress activity in the 4-h restraint model and the effect is due to modulation of HPA and BMS.

Asparagus racemosus Linn. (AR) is an Ayurvedic rasayana used as an adaptogen. Adaptogenic drugs are those which are useful as anti-stress agents by promoting non-specific resistance of the body. Although, the adaptogenic effect of AR is well documented, its use in psychological disorders like depression is not scientifically evaluated. Hence, the present investigation evaluates the antidepressant effect of methanolic extract of roots of AR (MAR) standardized to saponins (62.2% w/w). Rats were given MAR in the doses of 100, 200 and 400 mg/kg daily for 7 days and then subjected to forced swim test (FST) and learned helplessness test (LH). The results show that MAR decreases immobility in FST and increases avoidance response in LH indicating antidepressant activity. In behavioral experiments, MAR increased the number of head twitches produced by 5-HTP and increased clonidine-induced aggressive behavior indicating facilitatory effect on both serotonergic and adrenergic systems respectively. However, MAR had insignificant effect on l-DOPA-induced aggressive behavior indicating absence of activity on dopaminergic system. MAR also reversed changes to the endogenous antioxidant system induced by FST. Thus, MAR has significant antidepressant activity and this effect is probably mediated through the serotonergic and the noradrenergic systems and augmentation of antioxidant defenses.