A Mild Dose of Aspirin Promotes Hippocampal Neurogenesis and Working Memory in Experimental Ageing Mice.

Aspirin has been reported to prevent memory decline in the elderly population. Adult neurogenesis in the hippocampus has been recognized as an underlying basis of learning and memory. This study investigated the effect of aspirin on spatial memory in correlation with the regulation of hippocampal neurogenesis and microglia in the brains of ageing experimental mice. Results from the novel object recognition (NOR) test, Morris water maze (MWM), and cued radial arm maze (cued RAM) revealed that aspirin treatment enhances working memory in experimental mice. Further, the co-immunohistochemical assessments on the brain sections indicated an increased number of doublecortin (DCX)-positive immature neurons and bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN) double-positive newly generated neurons in the hippocampi of mice in the aspirin-treated group compared to the control group. Moreover, a reduced number of ionized calcium-binding adaptor molecule (Iba)-1-positive microglial cells was evident in the hippocampus of aspirin-treated animals. Recently, enhanced activity of acetylcholinesterase (AChE) in circulation has been identified as an indicative biomarker of dementia. The biochemical assessment in the blood of aspirin-treated mice showed decreased activity of AChE in comparison with that of the control group. Results from this study revealed that aspirin facilitates hippocampal neurogenesis which might be linked to enhanced working memory.

Ranitidine Alleviates Anxiety-like Behaviors and Improves the Density of Pyramidal Neurons upon Deactivation of Microglia in the CA3 Region of the Hippocampus in a Cysteamine HCl-Induced Mouse Model of Gastrointestinal Disorder.

Elevated levels of histamine cause over-secretion of gastric hydrochloric acid (HCl), leading to gastrointestinal (GI) disorders and anxiety. Ranitidine is an antihistamine drug widely used in the management of GI disorders, as it works by blocking the histamine-2 receptors in parietal cells, thereby reducing the production of HCl in the stomach. While some reports indicate the neuroprotective effects of ranitidine, its role against GI disorder-related anxiety remains unclear. Therefore, we investigated the effect of ranitidine against anxiety-related behaviors in association with changes in neuronal density in the hippocampal cornu ammonis (CA)-3 region of cysteamine hydrochloride-induced mouse model of GI disorder. Results obtained from the open field test (OFT), light and dark box test (LDBT), and elevated plus maze (EPM) test revealed that ranitidine treatment reduces anxiety-like behaviors in experimental animals. Nissl staining and immunohistochemical assessment of ionized calcium-binding adapter molecule (Iba)-1 positive microglia in cryosectioned brains indicated enhanced density of pyramidal neurons and reduced activation of microglia in the hippocampal CA-3 region of brains of ranitidine-treated experimental mice. Therefore, this study suggests that ranitidine mediates anxiolytic effects, which can be translated to establish a pharmacological regime to ameliorate anxiety-related symptoms in humans.

Pathogenomic Signature and Aberrant Neurogenic Events in Experimental Cerebral Ischemic Stroke: A Neurotranscriptomic-Based Implication for Dementia.

BACKGROUND: Cerebral ischemic stroke is caused due to neurovascular damage or thrombosis, leading to neuronal dysfunction, neuroinflammation, neurodegeneration, and regenerative failure responsible for neurological deficits and dementia. The valid therapeutic targets against cerebral stroke remain obscure. Thus, insight into neuropathomechanisms resulting from the aberrant expression of genes appears to be crucial. OBJECTIVE: In this study, we have elucidated how neurogenesis-related genes are altered in experimental stroke brains from the available transcriptome profiles in correlation with transcriptome profiles of human postmortem stroke brain tissues. METHODS: The transcriptome datasets available on the middle cerebral artery occlusion (MCAo) rat brains were obtained from the Gene Expression Omnibus, National Center for Biotechnology Information. Of the available datasets, 97 samples were subjected to the meta-analysis using the network analyst tool followed by Cytoscape-based enrichment mapping analysis. The key differentially expressed genes (DEGs) were validated and compared with transcriptome profiling of human stroke brains. RESULTS: Results revealed 939 genes are differently expressed in the brains of the MCAo rat model of stroke, in which 30 genes are key markers of neural stem cells, and regulators of neurogenic processes. Its convergence with DEGs from human stroke brains has revealed common targets. CONCLUSION: This study has established a panel of highly important DEGs to signify the potential therapeutic targets for neuroregenerative strategy against pathogenic events associated with cerebral stroke. The outcome of the findings can be translated to mitigate neuroregeneration failure seen in various neurological and metabolic disease manifestations with neurocognitive impairments.

Resveratrol Mediated Regulation of Hippocampal Neuroregenerative Plasticity via SIRT1 Pathway in Synergy with Wnt Signaling: Neurotherapeutic Implications to Mitigate Memory Loss in Alzheimer's Disease.

Alzheimer's disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD.

Plausible computational insights and new atomic-level perspective of epicathechin gallate from Crataegus oxycantha extract in preventing caspase 3 activation in conditions like post-myocardial infarction.

Cardiovascular disease (CVD) is the leading cause of mortality among the human species, however the non-existence of successful therapies to curtail the effect of Myocardial Infarction (MI) is a disquieting reality. Even though successful herbal formulations using Crataegus oxycantha (COC) is available, however, it is not recognized as an alternative medicine due to the lack of explanation on the molecular mechanism of COC extract on CVD conditions. In vivo studies revealed that COC extract significantly prevented caspase activation in conditions like post-MI; however, the role of a specific secondary metabolite that could be involved in this action is under quest. The present study, therefore, aims at predicting the plausible mechanism of action of key secondary metabolite in COC extract on apoptotic executioner caspase - caspase 3 during MI through in silico tools. The protein-protein interaction network, QikProp, and molecular docking studies were performed to identify the lead compound that revealed Epicatechin Gallate (ECG) of COC as an effective inhibitor against candidate MI/apoptosis mediator - caspase 3. The docked complex was further taken for molecular dynamics simulation, which was achieved through Desmond. Molecular dynamics further confirmed the stability of the binding interactions between the docked complex. The overall in silico results proved that ECG could prevent the dissociation of cleaved caspases, which is essential for their activation. Computational observations were strongly supported by experimental evidence obtained from in vivo studies in the MI-model system. From the above observations, it was concluded that computational analysis was in good agreement with the experimental analysis on ECG's potential to prevent caspase 3 activation during MI.

Decoding information on COVID-19: Ontological approach towards design possible therapeutics.

To date, no effective preventive or curative medical interventions exist against COVID-19, caused by Severe Acute Respiratory Syndrome corona virus 2 (SARS CoV-2). The available interventions are only supportive and palliative in nature. Popular among the emerging explanations for the mortality from COVID-19 is "cytokine storm", attributed to the body's aggressive immune response to this novel pathogen. In less than a year the disease has spread to almost all countries, though the mortality rates have varied significantly from country to country based on factors such as the demographical mix of the population, prevalence of comorbidities, as well as prior exposure to viruses from the corona family. This review examines the current literature on mortality rates across the globe, explores the possible reasons, thereby decoding variations. COVID-19 researchers have noted unique characteristics in the structural and host-pathogen interaction and identified several possible target proteins and sites that could exhibit control over the entry of SARS CoV-2 into the host, which this paper reviews in detail. Identification of new targets, both in the virus and the host, may accelerate the search for effective vaccines and curative drugs against COVID-19. Further, the ontological approach of this review is likely to provide insights for researchers to anticipate and be ready for future mutant viruses that may emerge in future.

Intramuscular Injection of BOTOX® Boosts Learning and Memory in Adult Mice in Association with Enriched Circulation of Platelets and Enhanced Density of Pyramidal Neurons in the Hippocampus.

BOTOX® is a therapeutic form of botulinum neurotoxin. It acts by blocking the release of acetylcholine (ACh) from the synaptic vesicles at the neuromuscular junctions, thereby inhibiting the muscle contraction. Notably, many neurological diseases have been characterized by movement disorders in association with abnormal levels of ACh. Thus, blockade of aberrant release of ACh appears to be a potential therapeutic strategy to mitigate many neurological deficits. BOTOX® has widely been used to manage a number of clinical complications like neuromuscular disorders, migraine and neuropathic pain. While the beneficial effects of BOTOX® against movement disorders have extensively been studied, its possible role in the outcome of cognitive function remains to be determined. Therefore, we investigated the effect of BOTOX® on learning and memory in experimental adult mice using behavioural paradigms such as open field task, Morris water maze and novel object recognition test in correlation with haematological parameters and histological assessments of the brain. Results revealed that a mild dose of BOTOX® treatment via an intramuscular route in adult animals improves learning and memory in association with increased number of circulating platelets and enhanced structural plasticity in the hippocampus. In the future, this minimally invasive treatment could be implemented to ameliorate different forms of dementia resulting from abnormal ageing and various neurocognitive disorders including Alzheimer's disease (AD).

TGF-ß Signaling: A Therapeutic Target to Reinstate Regenerative Plasticity in Vascular Dementia?

Vascular dementia (VaD) is the second leading form of memory loss after Alzheimer's disease (AD). Currently, there is no cure available. The etiology, pathophysiology and clinical manifestations of VaD are extremely heterogeneous, but the impaired cerebral blood flow (CBF) represents a common denominator of VaD. The latter might be the result of atherosclerosis, amyloid angiopathy, microbleeding and micro-strokes, together causing blood-brain barrier (BBB) dysfunction and vessel leakage, collectively originating from the consequence of hypertension, one of the main risk factors for VaD. At the histopathological level, VaD displays abnormal vascular remodeling, endothelial cell death, string vessel formation, pericyte responses, fibrosis, astrogliosis, sclerosis, microglia activation, neuroinflammation, demyelination, white matter lesions, deprivation of synapses and neuronal loss. The transforming growth factor (TGF) ß has been identified as one of the key molecular factors involved in the aforementioned various pathological aspects. Thus, targeting TGF-ß signaling in the brain might be a promising therapeutic strategy to mitigate vascular pathology and improve cognitive functions in patients with VaD. This review revisits the recent understanding of the role of TGF-ß in VaD and associated pathological hallmarks. It further explores the potential to modulate certain aspects of VaD pathology by targeting TGF-ß signaling.

Possible Existence of the Hypothalamic-Pituitary-Hippocampal (HPH) Axis: A Reciprocal Relationship Between Hippocampal Specific Neuroestradiol Synthesis and Neuroblastosis in Ageing Brains with Special Reference to Menopause and Neurocognitive Disorders.

The hippocampus-derived neuroestradiol plays a major role in neuroplasticity, independent of circulating estradiol that originates from gonads. The response of hypothalamus-pituitary regions towards the synthesis of neuroestradiol in the hippocampus is an emerging scientific concept in cognitive neuroscience. Hippocampal plasticity has been proposed to be regulated via neuroblasts, a major cellular determinant of functional neurogenesis in the adult brain. Defects in differentiation, integration and survival of neuroblasts in the hippocampus appear to be an underlying cause of neurocognitive disorders. Gonadotropin receptors and steroidogenic enzymes have been found to be expressed in neuroblasts in the hippocampus of the brain. However, the reciprocal relationship between hippocampal-specific neuroestradiol synthesis along neuroblastosis and response of pituitary based feedback regulation towards regulation of estradiol level in the hippocampus have not completely been ascertained. Therefore, this conceptual article revisits (1) the cellular basis of neuroestradiol synthesis (2) a potential relationship between neuroestradiol synthesis and neuroblastosis in the hippocampus (3) the possible involvement of aberrant neuroestradiol production with mitochondrial dysfunctions and dyslipidemia in menopause and adult-onset neurodegenerative disorders and (4) provides a hypothesis for the possible existence of the hypothalamic-pituitary-hippocampal (HPH) axis in the adult brain. Eventually, understanding the regulation of hippocampal neurogenesis by abnormal levels of neuroestradiol concentration in association with the feedback regulation of HPH axis might provide additional cues to establish a neuroregenerative therapeutic management for mood swings, depression and cognitive decline in menopause and neurocognitive disorders.

Identification of salt-tolerant cowpea genotypes using ISSR markers and proteome analysis.

Soil salinity globally affects the productivity of staple food crops. Therefore, an understanding of the molecular mechanisms that lead to salt tolerance induced by antioxidant mechanisms can assist in the development of salt-tolerant crops. To decipher the molecular fingerprint of salt resistance, in this study, six salt-tolerant cowpea genotypes at the seedling stage were assessed for their antioxidant responses, yield, genetic polymorphism and proteomics under salt stress. Leaves and roots showed distinct tissue-specific responses to salinity, and leaves showed a better protection against salt stress-induced oxidative stress than roots. Inter simple sequence repeat (ISSR) fingerprinting allowed molecular discrimination between salt-tolerant cowpea genotypes. Proteome analysis of cowpea leaves under salt stress revealed up-regulation of ATP synthase, vacuolar ATPase, pentatricopeptide repeat protein, flavanone 3-hydroxylase and outer envelope pore protein. Thus, ISSR and proteome analysis allow the identification of salt-tolerant cowpea cultivars.

Genetic reprogramming of somatic cells into neuroblasts through a co-induction of the doublecortin gene along the Yamanaka factors: A promising approach to model neuroregenerative disorders.

Neural stem cell (NSC) mediated adult neurogenesis represents the regenerative plasticity of the brain. The functionality of the neurogenic process appears to be operated by neuroblasts, the multipotent immature neuronal population of the adult brain. While neuroblasts have been realized to play a major role in synaptic remodeling and immunogenicity, neurodegenerative disorders have been characterized by failure in the terminal differentiation, maturation, integration and survival of newborn neuroblasts. Advancement in understanding the impaired neuroregenerative process along the neuropathological conditions has currently been limited by lack of an appropriate experimental model of neuroblasts. The genetic reprogramming of somatic cells into pluripotent state offers a potential strategy for the experimental modeling of brain disorders. Thus, the induced pluripotent stem cell (iPSC) based direct reprogramming of somatic cells into neuroblasts would represent a potential tool to understand the regenerative biology of the adult brain. Therefore, this concise article discusses the significance of iPSCs, the functional roles of neuroblasts in the adult brain and provides a research hypothesis for the direct reprogramming of somatic cells into neuroblasts through the co-induction of a potential proneurogenic marker, the doublecortin (DCX) gene along with the Yamanaka factors. The proposed cellular model of adult neurogenesis may provide us with further insights into neuropathogenesis of many neurodegenerative disorders and will provide a potential experimental platform for diagnostic, drug discovery and regenerative therapeutic strategies.

Time-dependent effect of oligomeric amyloid-ß (1-42)-induced hippocampal neurodegeneration in rat model of Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) is characterized with an abnormal deposition of insoluble amyloid-beta (Aß) peptide plaques, tangles formation and synaptic dysfunction. These result in impaired functioning of neuronal circuits and alter the behavioral response owing to activation of neurotransmitter receptors. Recently, it has been implicated that Aß influences N-methyl d-aspartate (NMDA) receptor activation in AD; however, the molecular mechanism underlying remains unclear. Thus, emerged specific aim to study the time-course effect of oligomeric Aß(1-42) (oAß1-42) on the mRNA expression of genes encoding NMDA and acetylcholine receptors in the rat model of AD. METHODS:  Aggregated forms of synthetic Aß peptides were injected bilaterally into the intrahippocampal region of rat brain using stereotaxic surgery. Behavioral analysis was performed using eight-arm Radial Arm Maze task at the end of experimental period. Euthanized rat brain hippocampal tissue was used to study the mRNA expression of glutamatergic and cholinergic receptor using semiquantitative reverse transcription-polymerase chain reaction. RESULTS: oAß1-42 decreased the gene expression level of α7-nicotinic acetylcholine receptor and increased the mRNA expression of NMDA receptor 2A, and -2B subunits. In particular, oAß1-42 aggregates increased the retention time and altered the behavioral response in rats after 15 days of injection. Further, amyloid-ß1-42 are highly expressed in 15 days after postinjection in hippocampus of adult rats. CONCLUSION: Acute exposure of oAß1-42 modulated differential gene expression of glutamatergic and cholinergic receptors in hippocampus of adult rats and is duration dependent reflecting changes in hippocampal circuitry system underlying learning and memory impairments. ABBREVIATIONS: AD: Alzheimer's disease, Aß: amyloid-ß; oAß1-42: oligomeric amyloid-ß 1-42 full length peptide; CAM: calmodulin; CNS: central nervous system; CR: Congo red; DG: dentate gyrus; EC: entorhinal cortex; HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol; IBO: ibotenic acid; NMDA: N-methyl d-aspartate; NMDAR: N-methyl d-aspartate receptor; NR2A: N-methyl d-aspartate receptor 2A; NR2B: N-methyl d-aspartate receptor 2B; ACh: acetylcholine; α7-nAChR: α7-nicotinic acetylcholine receptor; PBS: phosphate buffered saline; RAM: Radial Arm Maze; ThT: thioflavin T.

Biophysical interaction of resveratrol with sirtuin pathway: Significance in Alzheimer's disease.

Alzheimer disease (AD) is a widespread neurodegenerative condition that leads to progressive cognitive dysfunction in elderly population. Despite several attempts aimed at molecular determinants of AD, effective disease modifying treatment options are highly limited. Recently, use of natural supplements has gained considerable attention in AD research due to their cost effective and long lasting health beneficial properties. Resveratrol (RSV) is a naturally occurring polyphenolic compound found majorly in grapes. RSV has been shown to exert a plethora of medical benefits due to its anti-oxidant, anti-aging, anti-inflammatory, anti-malignant and neuroprotective properties. In particular, RSV has been shown to increase memory performance. The neuroprotective effect of RSV has strongly been linked to the depolymerization of amyloid ß fibrils. However, the molecular targets of RSV remain the subject of investigation. This review was aimed to comprehend the existing knowledge on the neuroprotective effects of RSV and recent progress made on understanding the role RVS in the regulation of neural plasticity through a molecular target Sirtuin 1, a potential homeostatic regulator in AD.

Association Studies of Specific Cholesterol Related Genes (APOE, LPL, and CETP) with Lipid Profile and Memory Function: A Correlative Study Among Rural and Tribal Population of Dharmapuri District, India.

 Epidemiological studies state that dementia has multiple etiologies including genetic mutation, genetic variation, and environmental factors. Accumulating evidence suggests that dysregulation of cholesterol homeostasis is the major etiological factor in initiating neurodegeneration. Apolipoprotein E (APOE) polymorphic alleles and associated polymorphism of lipoprotein lipase (LPL) and cholesteryl ester transfer protein (CETP) that are important components in regulating cholesterol metabolism are implicated in neurodegenerative diseases. Therefore, the current study focused on identifying the association between several common polymorphism (viz., APOE, CETP, and LPL) to that of change in serum lipid levels and memory symptoms. Volunteer subjects aged 50 and above from rural and tribal areas of the Dharmapuri district, Tamilnadu, India were chosen for the current study and polymorphism was analyzed using PCR-RFLP. Fasting lipid profile and memory function using simplified version of Global Clinical Dementia rating were assessed. Significant difference in the major lipid profile parameters were observed (TC, TGL, LDL, VLDL) among rural and tribal populations that were associated with significant genotypic variation of APOE, CETP, and LPL. Regression analysis revealed significant risk for memory loss that are dependent on age and genetic variants like CETP. These data predict positive correlation between cholesterol-associated genes and their relationship to altered lipid profile and memory symptoms, which possibly link gene-polymorphism and susceptibility ratio for aging and dementia.

Protective Effect of Antioxidants on Neuronal Dysfunction and Plasticity in Huntington's Disease.

Huntington's disease (HD) is characterised by movement disorders, cognitive impairments, and psychiatric problems. The abnormal generation of reactive oxygen species and the resulting oxidative stress-induced mitochondrial damage in neurons upon CAG mutations in the HTT gene have been hypothesized as the contributing factors of neurodegeneration in HD. The potential use of antioxidants against free radical toxicity has been an emerging field in the management of ageing and many neurodegenerative disorders. Neural stem cells derived adult neurogenesis represents the regenerative capacity of the adult brain. The process of adult neurogenesis has been implicated in the cognitive functions of the brain and is highly modulated positively by different factors including antioxidants. The supportive role of antioxidants to reduce the severity of HD via promoting the functional neurogenesis and neuroprotection in the pathological adult brain has great promise. This review comprehends the recent studies describing the therapeutic roles of antioxidants in HD and other neurologic disorders and highlights the scope of using antioxidants to promote adult neurogenesis in HD. It also advocates a new line of research to delineate the mechanisms by which antioxidants promote adult neurogenesis in HD.

Resveratrol Intervenes Cholesterol- and Isoprenoid-Mediated Amyloidogenic Processing of AßPP in Familial Alzheimer's Disease.

Deterioration of cholesterol metabolism has recently been a frontier subject of investigation in the field of Alzheimer's disease (AD). Though amyloid-ß protein precursor (AßPP) primes the pathological cascade, changes in cholesterol levels and its intermediates, geranyl geranyl pyrophosphate and farnesyl pyrophosphate, is expected to have a different consequence on AßPP processing and amyloid-ß (Aß) generation. However, the use of statins (HMG-COA reductase inhibitor) has been widely implicated in slowing down the pathogenic progression of AD, while the epidemiological reports on its biological effect remains controversial. Considering this fact, the choice of drug that could maintain cholesterol homeostasis without altering its biosynthesis may yield a better therapeutic efficacy on AD. Thus, the present study focused on determining the influence of cholesterol and isoprenoids on amyloidogenic-cleavage of AßPP, in addition to resveratrol as a potent therapeutic drug in CHO-APPswe cell lines. High levels of cholesterol were found to enhance the maturation of AßPP and altered the expression and subcellular localization of ADAM10, BACE1, and PS1 thereby promoting Aß generation, whereas high isoprenoids increased both maturation as well as amyloidogenic-cleavage of AßPP, which was evident through ß-CTF production. Interestingly, the therapeutic efficacy of resveratrol maintained cholesterol homeostasis and reduced the amyloidogenic burden through its ability to enhance SIRT1 expression and thereby regulating differential expression of AD determinants.

Intrahippocampal Administration of Ibotenic Acid Induced Cholinergic Dysfunction via NR2A/NR2B Expression: Implications of Resveratrol against Alzheimer Disease Pathophysiology.

Although several drugs revealed moderate amelioration of symptoms, none of them have sufficient potency to prevent or reverse the progression toward Alzheimer's disease (AD) pathology. Resveratrol (RSV), a polyphenolic compound has shown an outstanding therapeutic effect on a broad spectrum of diseases like age-associated neurodegeneration, inflammation etc. The present study was thus conducted to assess the therapeutic efficacy of RSV in ameliorating the deleterious effects of Ibotenic acid (IBO) in male Wistar rats. Stereotactic intrahippocampal administration of IBO (5 µg/µl) lesioned rats impairs cholinergic transmission, learning and memory performance that is rather related to AD and thus chosen as a suitable model to understand the drug efficacy in preventing AD pathophysiology. Since IBO is an agonist of glutamate, it is expected to exhibit an excitotoxic effect by altering glutamatergic receptors like NMDA receptor. The current study displayed significant alterations in the mRNA expression of NR2A and NR2B subunits of NMDA receptors, and further it is surprising to note that cholinergic receptors decreased in expression particularly α7-nAChR with increased m1AChR. RSV administration (20 mg/kg body weight, i.p.) significantly reduced these changes in IBO induced rats. Glutamatergic and cholinergic receptor alterations were associated with significant changes in the behavioral parameters of rats induced by IBO. While RSV improved spatial learning performance, attenuated immobility, and improvised open field activity in IBO induced rats. NR2B activation in the present study might mediate cell death through oxidative stress that form the basis of abnormal behavioral pattern in IBO induced rats. Interestingly, RSV that could efficiently encounter oxidative stress have significantly decreased stress markers viz., nitrite, PCO, and MDA levels by enhancing antioxidant status. Histopathological analysis displayed significant reduction in the hippocampal pyramidal layer thickness and live neurons in IBO induced rats, with slight pathological changes in the entorhinal cortex (EC) of rat brain, which was prevented on RSV administration. Our study thus concludes that RSV administration significantly ameliorated the deleterious effects in the IBO lesioned rat model for AD by alleviating cholinergic pathways, reducing oxidative stress and thereby improving spatial memory.

High throughput virtual screening and E-pharmacophore filtering in the discovery of new BACE-1 inhibitors.

Alzheimer's disease is a progressive neurodegenerative disorder, which is characterized by amyloid ß peptide deposition in the brain. Aß peptide, the major component of amyloid plaques is generated by the sequential processing of a larger protein called amyloid Precursor Protein by ß-amyloid cleaving enzyme (BACE-1). In this study, we appllied computer assisted methodology unifying molecular docking and pharmacophore filtering to identify potent inhibitors against BACE-1. In order to inspect the pharmacophore region and binding mode of BACE-1 135 reported co-crystallized ligands of BACE-1 were docked into the active site using Glide XP. The present molecular docking studies provided critical information on protein ligand interactions that revealed imminent information on chemical features essential to inhibiting BACE-1. Based on the docking results we proposed structure based pharmacophore features that hold well as potent BACE-1 inhibitors. A huge set of compounds was docked into the active site of BACE-1 and the hits from the docking were filtered to match the chemical features of the pharmacophore model. The compounds resulting from the pharmacophore filtering were again re-docked into the active site of BACE-1 and the three hits bound well into the active sites and matched the pharmacophore models which were identified as possible potential inhibitors of BACE-1. Molecular dynamics simulation reveals that lead 3 shows constant RMSD and the number of hydrogen bonding with the protein among the identified three lead molecules.

Homology modeling, molecular docking and electrostatic potential analysis of MurF ligase from Klebsiella pneumonia.

In spite of availability of moderately protective vaccine and antibiotics, new antibacterial agents are urgently needed to decrease the global incidence of Klebsiella pneumonia infections. MurF ligase, a key enzyme, which participates in the bacterial cell wall assembly, is indispensable to existence of K. pneumonia. MurF ligase lack mammalian vis-à-vis and have high specificity, uniqueness, and occurrence only in eubacteria, epitomizing them as promising therapeutic targets for intervention. In this study, we present a unified approach involving homology modeling and molecular docking studies on MurF ligase enzyme. As part of this study, a homology model of K. pneumonia (MurF ligase) enzyme was predicted for the first time in order to carry out structurebased drug design. The accuracy of the model was further validated using different computational approaches. The comparative molecular docking study on this enzyme was undertaken using different phyto-ligands from Desmodium sp. and a known antibiotic Ciprofloxacin. The docking analysis indicated the importance of hotspots (HIS 281 and ASN 282) within the MurF binding pocket. The Lipinski's rule of five was analyzed for all ligands considered for this study by calculating the ADME/Tox, drug likeliness using Qikprop simulation. Only ten ligands were found to comply with the Lipinski rule of five. Based on the molecular docking results and Lipinki values 6-Methyltetrapterol A was confirmed as a promising lead compound. The present study should therefore play a guiding role in the experimental design and development of 6-Methyltetrapterol A as a bactericidal agent.

Cytochrome c oxidase rather than cytochrome c is a major determinant of mitochondrial respiratory capacity in skeletal muscle of aged rats: role of carnitine and lipoic acid.

The release of mitochondrial cytochrome c followed by activation of caspase cascade has been reported with aging in various tissues, whereas little is known about the caspase-independent pathway involved in mitochondrial dysfunction. To determine the functional impact of cytochrome c loss on mitochondrial respiratory capacity, we monitored NADH redox transitions and oxygen consumption in isolated skeletal muscle mitochondria of 4- and 24-month-old rats in the presence and absence of exogenous cytochrome c; and assessed the efficacy of cosupplementation of carnitine and lipoic acid on age-related alteration in mitochondrial respiration. The loss of mitochondrial cytochrome c with age was accompanied with alteration in respiratory transition, which in turn was not rescued by exogenous addition of cytochrome c to isolated mitochondria. The analysis of mitochondrial and nuclear-encoded cytochrome c oxidase subunits suggests that the decreased levels of cytochrome c oxidase may be attributed for the irresponsiveness to exogenously added cytochrome c on mitochondrial respiratory transitions, possibly through reduction of upstream electron carriers. Oral supplementation of carnitine and lipoic acid to aged rats help to maintaining the mitochondrial oxidative capacity by regulating the release of cytochrome c and improves cytochrome c oxidase transcript levels. Thus, carnitine and lipoic acid supplementation prevents the loss of cytochrome c and their associated decline in cytochrome c oxidase activity; thereby, effectively attenuating any putative decrease in cellular energy and redox status with age.