Differential modulation of GR signaling and HDACs in the development of resilient/vulnerable phenotype and antidepressant-like response of vorinostat.

The present study explored the antidepressant potential of vorinostat (VOR) against chronic social defeat stress (CSDS) in mice. Since this model has the remarkable capacity to delineate the resilient and the defeated mice, we also looked for their molecular deviations. Defeated mice showed classical phenotypic alterations such as anhedonia, social avoidance, anxiety and despair. Whereas, resilient mice were immune to the development of those. Both defeated and resilient mice demonstrated marked CORT elevation in blood. Development of resilience vs. defeat to CSDS was found to be associated with the differential nuclear levels of GR, HDAC3 and HDAC6 in the hippocampus. Activation of a stress responsive adaptive mechanism involving these mediators at the nuclear level might be offering resilience while maladaptive mechanisms leading to defeat. Interestingly, an elevated hippocampal HDAC6 level in defeated mice was also observed, which was restored by VOR treatment. Further studies will be necessary to delineate the HDAC6 associated antidepressant mechanisms. As HDAC3 and HDAC6 are crucial mediators of GR signaling, further molecular studies may aid in understanding the basis of development of resilience to target MDD with new prospective.

Transient global cerebral ischemia differentially affects cortex, striatum and hippocampus in Bilateral Common Carotid Arterial occlusion (BCCAo) mouse model.

Despite the advancements in medical sciences in last few decades, we are yet to develop promising therapeutics for stroke, which is one of the current global non-communicative disease concerns. The occurrence of stroke is likely to increase further due to the transition in our lifestyles. Inadequate knowledge of the sequential region-specific pathological events induced by cerebral ischemia is one of the underlying reasons. Hence to address this, we have used Bilateral Common Carotid Arterial occlusion (BCCAo) model that mimics human cardiac arrest condition. After ischemic insult, motor coordination and cognitive functions were analysed through series of behavioral tasks. Animals were sacrificed and brain regions viz. cortex, striatum and hippocampus, were isolated further for histopathology and molecular investigations. All the molecular studies were performed at 1d and 7d post-ischemia and reperfusion by immunohistochemistry, RT-qPCR and western blot analysis, for hypoxic, inflammatory and apoptotic markers. Our study indicates that unlike cortex and striatum, hippocampus was found to be consistently late ischemic susceptible at a behavioral and molecular level which might be regulated by c-Jun N-terminal kinases (JNK) and AKT signaling mechanism with associative changes in NMDA receptors. This study shows a region-specific temporal molecular response to global ischemia in the brain, which is important to get better insight into the pathophysiology since each region consists of different subsets of neurons that are having different susceptibility and tolerance pattern/level. This insight into a temporally different ischemic response and the underlying molecular basis might help in strategizing the effective therapeutics against stroke.

A 2-oxa-spiro[5.4]decane scaffold displays neurotrophic, neurogenic and anti-neuroinflammatory activities with high potential for development as a versatile CNS therapeutic.

Following our recent discovery of a new scaffold exhibiting significant neurotrophic and neurogenic activities, a structurally tweaked analogue, embodying a 2-oxa-spiro [5.4]decane framework, has been conceptualised and found to be more potent and versatile. It exhibits enhanced neurotrophic and neurogenic action in in vitro, ex vivo and in vivo models and also shows robust neuroprotection in mouse acute cerebral stroke model. The observed attributes are traceable to the predominant activation of the TrkB-PI3K-AKT-CREB pathway. In addition, it also exhibits remarkable anti-neuroinflammatory activity by concurrently down-regulating pro-inflammatory cytokines IL-1α and IL-6, thereby providing a unique molecule with a trinity of neuroactivities, i.e. neurotrophic, neurogenic and anti-inflammatory. The new chemical entity disclosed here has the potential to be advanced as a versatile therapeutic molecule to treat stroke, depression, and possibly other neuropsychiatric disorders associated with attenuated neurotrophic/ neurogenic activity, together with heightened neuroinflammation.

Differential effect of chronic stress on mouse hippocampal memory and affective behavior: Role of major ovarian hormones.

Molecular mechanisms of depression-like pathophysiology in female rodent models are less reported compared to males, despite its higher prevalence in human females. Moreover, the stress-response in brain circuitries including reward and cognition circuitries varies with age or hormonal status of the females. So, to understand the stress-induced mood and cognitive disorders in intact females (with ovaries) and ovariectomized (OVX) females, we studied changes in mouse hippocampus, a functionally heterogeneous neural structure involved in both affective and cognitive behaviors. Here, we used a 6-day Chronic Unpredictable Stress (CUS) paradigm in mice to induce depression and related mood disorders. Interestingly, intact females and OVX females showed difference in mood disorder sub-phenotypes to CUS. Similar to an earlier report of CUS affecting the critical reward circuitry structure the nucleus accumbens differently in females with and without ovaries, cognitive behavior in intact females and OVX females also responded differentially to CUS, as evident from Morris Water Maze (MWM) test results. We report that the presence or absence of ovarian hormones, particularly the estrogen, has a significant impact in altering the hippocampus related spatial memory and affective behavior, in females. Our results also illustrate that estrogen administration improves both reward and cognitive behavior, and plays a significant role in alleviating stress-induced despair behavior and enhancing spatial reference memory following a brief 6-day stressful paradigm. Further, it also indicates that the NMDA receptor subunits, GRIN2A and GRIN2B, might mediate the effects of estrogen in the hippocampal functions, thus suggestive of a translational significance of the finding.