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.
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.
Background
Accumulating evidences indicate that the combined antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV infected individuals. However, existing HIV population on cART show several complications including liver or pancreas damage, cardiovascular diseases and central nervous system disorders. Unexpectedly the prevalence of HIV+ associated neurotoxicity is on the rise. Hence, the current study is undertaken to determining the potential therapeutic effects of rapamycin against anti‐retroviral therapy induced neuronal dysfunction.
Objective
This study is aimed at exploring the therapeutic potential of rapamycin on cART induced central nervous system disorder.
Methodology
Primary midbrain neuronal cells (PMNC) were treated with antiretroviral drugs like Ritonavir (protease inhibitor) and Abacavir (reverse transcriptase inhibitor) in the combined form.
Results
After 24 hours treatment, immunoblot analysis shows that there is upregulation of autophagy marker proteins LC3 II, P62 levels in cART treated primary midbrain neuronal cells compared to control cells. Similarly, cART treated cells shows upregulation of endoplasmic reticulum (ER) resident proteins expression with mitochondrial dysfunction. These results are suggesting that neuronal cells treated with cART have dysregulated autophagy, higher ER stress and mitochondrial dysfunction. The beneficial effects of rapamycin are well described; though, it is unknown whether rapamycin ameliorates the harmful effects of cART‐induced toxicity in neuronal cells. Hence, in this study, we intend to investigate the effects of rapamycin on PMNC treated with cART. Our results indicate that rapamycin treatment ameliorates the autophagy dysfunction as well as, it normalizes the mitochondrial function and reduces the ER stress.
Conclusion
This study shows that rapamycin have a good potential in reversing cART‐induced autophagy and mitochondrial dysfunction in primary midbrain neuronal cells.
Schematic representation of therapetic effects of rapamycin
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