Vineet Mehta

Depression mediates impaired glucose tolerance and cognitive dysfunction: A neuromodulatory role of rosiglitazone

Comorbidity of depression and diabetes is a serious risk factor worsening the complications such as cognitive function and locomotion. Treatment under this condition becomes extremely complicated. Insulin signaling and autophagy pathways are involved in modulation of learning and memory. Rosiglitazone (ROSI) ameliorate cognitive deficit associated with depression and insulin resistance. In the present study, we investigated the effect of ROSI against chronic unpredictable stress (CUS) induced depression as a risk factor for diabetes and behavioral dysfunctions. Adult male Swiss albino mice were exposed to CUS alongside ROSI (5mg/kg/day) treatment for 21days. Thereafter, animals were subjected to different behavioral studies to assess depressive like behavior, cognition and locomotion. The effect of ROSI on insulin signaling, autophagy and apoptosis were evaluated in the hippocampus. CUS resulted in depressive like behavior, cognitive impairment and hypolocomotion associated with oxidative stress, impaired glucose tolerance and hypercorticosteronemia. CUS significantly impaired hippocampal insulin signaling, membrane translocation of glucose transporter type 4 (GLUT4) as well as decreased the expression of autophagy5, autophagy7, B-cell lymphoma 2 and apoptosis inhibitory protein 2. ROSI significantly reduced depressive like behavior, postprandial blood glucose, hypercorticosteronemia, oxidative and inflammatory stress, and apoptosis in stressed mice. Moreover, ROSI treatment effectively improved hippocampal insulin signaling, GLUT4 membrane translocation and cognitive performance in depressed mice. ROSI administration might prove to be effective for neurological disorders associated with depressive like behavior and impaired glucose tolerance.

Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress

It is now evident that chronic stress is associated with anxiety, depression and cognitive dysfunction and very few studies have focused on identifying possible methods to prevent these stress-induced disorders. Previously, we identified abundance of quercetin in Urtica dioica extract, which efficiently attenuated stress related complications. Therefore, current study was designed to investigate the effect of quercetin on chronic unpredicted stress (CUS) induced behavioral dysfunction, oxidative stress and neuroinflammation in the mouse hippocampus. Animals were subjected to unpredicted stress for 21days, during which 30mg/kg quercetin was orally administered to them. Effect of CUS and quercetin treatment on animal behavior was assessed between day 22-26. Afterward, the hippocampus was processed to evaluate neuronal damage, oxidative and inflammatory stress. Results revealed that stressed animals were highly anxious (Elevated Plus Maze and Open Field), showed depressive-like behavior (sucrose preference task), performed poorly in short-term and long-term associative memory task (passive avoidance step-through task) and displayed reduced locomotion (open field). Quercetin alleviated behavioral dysfunction in chronically stressed animals. Compared to CUS, quercetin treatment significantly reduced anxiety, attenuated depression, improved cognitive dysfunction and normalized locomotor activity. Further, CUS elevated the levels of oxidative stress markers (TBARS, nitric oxide), lowered antioxidants (total thiol, catalase), enhanced expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β and COX-2) in the hippocampus and damaged hippocampal neurons. Quercetin treatment significantly lowered oxidative and inflammatory stress and prevented neural damage. In conclusion, quercetin can efficiently prevent stress induced neurological complications by rescuing brain from oxidative and inflammatory stress.

Quercetin ameliorates chronic unpredicted stress mediated memory dysfunction in male Swiss albino mice by attenuating insulin resistance and elevating hippocampal GLUT4 levels independent of insulin receptor expression.

&NA; Chronic stress is associated with impaired neuronal functioning, altered insulin signaling, and behavioral dysfunction. Quercetin has shown neuroprotective and antidiabetic effects, besides modulating cognition and insulin signaling. Therefore, in the present study, we explored whether or not quercetin ameliorates stress‐mediated cognitive dysfunction and explored the underlying mechanism. Swiss albino male mice were subjected to an array of unpredicted stressors for 21 days, during which 30 mg/kg quercetin treatment was given orally. The effect of chronic unpredicted stress (CUS) and quercetin treatment on cognition were evaluated using novel object recognition (NOR) and Morris water maze (MWM) tests. Hippocampal neuronal integrity was observed by histopathological examination. Blood glucose, serum corticosterone, and insulin levels were measured by commercial kits and insulin resistance was evaluated in terms of HOMA‐IR index. Hippocampal insulin signaling was determined by immunofluorescence staining. CUS induced significant cognitive dysfunction (NOR and MWM) and severely damaged hippocampal neurons, especially in the CA3 region. Quercetin treatment alleviated memory dysfunction and rescued neurons from CUS‐mediated damage. Fasting blood glucose, serum corticosterone, and serum insulin were significantly elevated in stressed animals, besides, having significantly higher HOMA‐IR index, suggesting the development of insulin resistance. Quercetin treatment alleviated insulin resistance and attenuated altered biochemical parameters. CUS markedly down‐regulated insulin signaling in CA3 region and quercetin treatment improved neuronal GLUT4 expression, which seemed to be independent of insulin and insulin receptor levels. These results suggest that intact insulin functioning in the hippocampus is essential for cognitive functions and quercetin improves CUS‐mediated cognitive dysfunction by modulating hippocampal insulin signaling. Graphical abstract Figure. No caption available. HighlightsChronic Unpredicted Stress (CUS) induced cognitive dysfunction, insulin resistance and impaired glucose homeostasis.CUS disrupted neuronal integrity and insulin signaling in the CA3 region of hippocampus.CUS reduced insulin receptor and GLUT4 expression in CA3 neurons.Quercetin alleviated cognitive dysfunction, improved insulin resistance, and preserved hippocampal neuronal integrity.Quercetin up‐regulated GLUT4 expression independent of insulin receptor levels in the CA3 region of hippocampus.

Rutin alleviates chronic unpredictable stress-induced behavioral alterations and hippocampal damage in mice

Chronic stress results in neurological complications like depression, cognitive dysfunction, and anxiety disorders. In our previous study, we observed that Urtica dioica leaf extract attenuated chronic stress-induced complications. Further, we observed that Urtica dioica contained a great amount of the flavonoid rutin in it. Hence, we aimed to evaluate the effect of rutin on 21days chronic unpredictable stress (CUS) mouse model. CUS led to a decline in locomotion & muscle coordination abilities, cognitive deficits, anxiety, and depression. These neurobehavioral outcomes were associated with neurodegeneration in the CA3 region of the hippocampus as found by H&E staining. Rutin efficiently rescued the CUS-induced behavioral deficits by reducing depression, anxiety, improving cognition, and locomotor & muscle coordination skills. Further, rutin treatment protected the CUS-induced hippocampal neuronal loss. This study establishes the neuroprotective effect of rutin in chronic stress.

Quercetin ameliorates chronic unpredicted stress-induced behavioral dysfunction in male Swiss albino mice by modulating hippocampal insulin signaling pathway

Chronic stress is associated with impaired neurogenesis, neurodegeneration and behavioral dysfunction, whereas the mechanism underlying stress-mediated neurological complications is still not clear. In the present study, we aimed to investigate whether chronic unpredicted stress (CUS) mediated neurological alterations are associated with impaired hippocampal insulin signaling or not, and studied the effect of quercetin in this scenario. Male Swiss albino mice were subjected to 21day CUS, during which 30mg/kg quercetin treatment was given orally. After 21days, behavioral functions were evaluated in terms of locomotor activity (Actophotometer), muscle coordination (Rota-rod), depression (Tail Suspension Test (TST), Forced Swim Test (FST)) and memory performance (Passive-avoidance step-down task (PASD)). Further, hippocampal insulin signaling was evaluated in terms of protein expression of insulin, insulin receptor (IR) and glucose transporter 4 (GLUT-4) and neurogenesis was evaluated in terms of doublecortin (DCX) expression. 21day CUS significantly impaired locomotion and had no effect on muscle coordination. Stressed animals were depressed and showed markedly impaired memory functions. Quercetin treatment significantly improvement stress-mediated behavior dysfunction as indicated by improved locomotion, lesser immobility time and greater frequency of upward turning in TST and FST and increased transfer latency on the day 2 (short-term memory) and day 5 (long-term memory) in PASD test. We observed significantly higher IR expression and significantly lower GLUT-4 expression in the hippocampus of stressed animals, despite of nonsignificant difference in insulin levels. Further, chronic stress impaired hippocampal neurogenesis, as indicated by the significantly reduced levels of hippocampal DCX expression. Quercetin treatment significantly lowered insulin and IR expression and significantly enhanced GLUT-4 and DCX expression in the hippocampus, when compared to CUS. In conclusion, quercetin treatment efficiently alleviated stress mediated behavioral dysfunction by modulating hippocampal insulin signaling and neurogenesis.

Type 2 Diabetes Mellitus Is Associated with Social Recognition Memory Deficit and Altered Dopaminergic Neurotransmission in the Amygdala

Objective: Diabetic neuropathy is a chronic and often disabling condition that affects a significant number of individuals with diabetes mellitus (DM). It is now established that DM causes various CNS complications like Alzheimers, dementia, anxiety, depression, neurodegeneration, mood disorders, cognitive dysfunctioning, and so on. Since amygdala and dopaminergic circuitry are critical in controlling several aspects of social behavior, even social recognition memory (SRM), we aimed to study the expression analysis of dopaminergic circuitry in amygdala using real-time polymerase chain reaction. Material and Methods: Animals were divided into 2 age- and weight-matched groups: group I-control group and group II-diabetic group. Diabetes was induced by injecting 50 mg/kg streptozotocin (STZ; in 0.1 mL ice cold citrate buffer, pH 4.5) i.p. for 5 consecutive days. Behavioral tests were performed 8 weeks after diabetes was introduced. On day 60, animals were sacrificed, amygdala was dissected, and the total RNA was isolated. Expression analysis was carried out using real time PCR. Results: No significant changes were observed in social interaction and social isolation aspects of diabetic mice, but SRM was significantly dysregulated. Additionally, we found that dopaminergic neurotransmission (dopaminergic receptor expression and expression of enzymes controlling dopamine turnover) was significantly downregulated in the amygdala of STZ mice as compared to controls. Conclusion: We hypothesize that the altered SRM could be due to the dysregulated dopaminergic circuitry in amygdala, although a detailed investigation is required to establish a causal relationship.