Unraveling the Role of the Blood-Brain Barrier in the Pathophysiology of Depression: Recent Advances and Future Perspectives.

Depression is a highly prevalent psychological disorder characterized by persistent dysphoria, psychomotor retardation, insomnia, anhedonia, suicidal ideation, and a remarkable decrease in overall well-being. Despite the prevalence of accessible antidepressant therapies, many individuals do not achieve substantial improvement. Understanding the multifactorial pathophysiology and the heterogeneous nature of the disorder could lead the way toward better outcomes. Recent findings have elucidated the substantial impact of compromised blood-brain barrier (BBB) integrity on the manifestation of depression. BBB functions as an indispensable defense mechanism, tightly overseeing the transport of molecules from the periphery to preserve the integrity of the brain parenchyma. The dysfunction of the BBB has been implicated in a multitude of neurological disorders, and its disruption and consequent brain alterations could potentially serve as important factors in the pathogenesis and progression of depression. In this review, we extensively examine the pathophysiological relevance of the BBB and delve into the specific modifications of its components that underlie the complexities of depression. A particular focus has been placed on examining the effects of peripheral inflammation on the BBB in depression and elucidating the intricate interactions between the gut, BBB, and brain. Furthermore, this review encompasses significant updates on the assessment of BBB integrity and permeability, providing a comprehensive overview of the topic. Finally, we outline the therapeutic relevance and strategies based on BBB in depression, including COVID-19-associated BBB disruption and neuropsychiatric implications. Understanding the comprehensive pathogenic cascade of depression is crucial for shaping the trajectory of future research endeavors.

Advanced drug delivery and therapeutic strategies for tuberculosis treatment.

Tuberculosis (TB) remains a significant global health challenge, necessitating innovative approaches for effective treatment. Conventional TB therapy encounters several limitations, including extended treatment duration, drug resistance, patient noncompliance, poor bioavailability, and suboptimal targeting. Advanced drug delivery strategies have emerged as a promising approach to address these challenges. They have the potential to enhance therapeutic outcomes and improve TB patient compliance by providing benefits such as multiple drug encapsulation, sustained release, targeted delivery, reduced dosing frequency, and minimal side effects. This review examines the current landscape of drug delivery strategies for effective TB management, specifically highlighting lipid nanoparticles, polymer nanoparticles, inorganic nanoparticles, emulsion-based systems, carbon nanotubes, graphene, and hydrogels as promising approaches. Furthermore, emerging therapeutic strategies like targeted therapy, long-acting therapeutics, extrapulmonary therapy, phototherapy, and immunotherapy are emphasized. The review also discusses the future trajectory and challenges of developing drug delivery systems for TB. In conclusion, nanomedicine has made substantial progress in addressing the challenges posed by conventional TB drugs. Moreover, by harnessing the unique targeting abilities, extended duration of action, and specificity of advanced therapeutics, innovative solutions are offered that have the potential to revolutionize TB therapy, thereby enhancing treatment outcomes and patient compliance.

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.

Rapid acting antidepressants in the mTOR pathway: Current evidence.

Despite the growing burden of major depressive disorder (MDD) on the society, therapeutic management that is mostly based on the conventional monoaminergic mechanisms, is significantly delimited especially from low response rate and time lag for treatment response; thus, often prolonging the distress for patients. The mechanistic exploration of drug candidates that could exert antidepressant effects rapidly has highlighted the significance of modulating mammalian target of rapamycin (mTOR) pathway in MDD. Fast acting antidepressants acts at different receptors, subunits and sites, including NMDA, AMPA, m1ACh, mGluR2/3 and GluN2B to enhance mTOR function, leading to increase in synaptic protein synthesis, synaptogenesis and spine-remodeling, which in turn contribute to the rapid antidepressant effects. This review focuses on the preclinical and clinical evidences on the fast acting antidepressants that can modulate mTOR pathway. It can be understood that modulating mTOR pathway for rapid onset of antidepressant effect in MDD is not without challenges as some of the drugs have failed in advanced stages of clinical trials. However, considering the recent approval of esketamine as a breakthrough in decades, fast acting antidepressants in the mTOR pathway may have promising prospects in the drug discovery pipeline.

Cognitive Improvement by Vorinostat through Modulation of Endoplasmic Reticulum Stress in a Corticosterone-Induced Chronic Stress Model in Mice.

Chronic stress is the leading cause of memory impairment today. Various stress-based models are being developed for studying cognitive impairment. Repurposing of existing drugs in a new pharmacology class is the safest and cheapest option for treatment instead of new drug discovery. Vorinostat (VOR) is the first histone deacetylase (HDAC) inhibitor approved for the treatment of cutaneous T-cell lymphoma by the U.S. FDA. VOR follows the rule of five and is reported to cross the blood-brain barrier. Therefore, we aimed to evaluate the procognitive potential of VOR (25 mg/kg) administered by intraperitoneal (ip) route in a stress-based model of chronic corticosterone (CORT) injections (20 mg/kg, subcutaneously (sc)). The study comprised six groups. Normal mice were administered vehicle (VEH) (days 1-21, sc) in the first group, VOR (days 8-21, 25 mg/kg, ip) in the second group, and fluoxetine (FLX) (days 8-21, 15 mg/kg, oral) in the third group. Mice in the remaining three groups were given 20 mg/kg (sc) CORT for 21 days, and VOR (days 8-21, 25 mg/kg, ip) or FLX (days 8-21, 15 mg/kg, oral) was additionally administered to the treatment groups. Behavioral tests such as Morris water maze test, novel object recognition test, and object in place test were performed at the end of the dosing schedule to assess cognition. After behavior tests, mice were sacrificed, and hippocampus was separated from brain tissue for reverse transcriptase polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry studies. VOR treatment attenuated endoplasmic reticulum (ER) stress in CORT mice as evident from the reduction in DNA damage-inducible transcript 3 (Ddit3) (gene encoding CHOP), caspase 12 (Casp12), and calpain-2 (Capn2) mRNA levels, and cleaved caspase 3 (CASP3) protein expression. Bax inhibitor-1 (BI-1) was significantly increased in VOR-treated CORT mice. VOR also reversed CORT induced increase in HDAC2 level in the CA3 region. The protective effects of VOR were comparable to that of FLX in CORT mice. Thus, VOR has the potential to reverse cognitive dysfunction via modulation of ER stress markers and HDAC2.

Morin Hydrate Mitigates Cisplatin-Induced Renal and Hepatic Injury by Impeding Oxidative/Nitrosative Stress and Inflammation in Mice.

Cisplatin is a widely used chemotherapeutic drug; however, it induces damage on kidney and liver at clinically effective higher doses. Morin hydrate possesses antioxidant, anti-inflammatory, and anticancer properties. Therefore, we aimed to investigate the effects of morin hydrate (50 and 100 mg/kg, orally) against the renohepatic toxicity induced by a high dose of cisplatin (20 mg/kg, intraperitoneally). Renal and hepatic function, oxidative/nitrosative stress, and inflammatory markers along with histopathology were evaluated. Morin hydrate ameliorated cisplatin-induced renohepatic toxicity significantly at 100 mg/kg as evidenced from the significant reversal of cisplatin-induced body weight loss, mortality, functional and structural alterations of kidney, and liver. The protective role offered by morin hydrate against cisplatin-induced renohepatic toxicity is by virtue of its free radical scavenging property, thereby abating the depletion of cellular antioxidant defense components and through modulation of inflammatory cytokines. We speculate morin hydrate as a protective candidate against renohepatic toxicity of cisplatin.

Resveratrol ameliorates depressive-like behavior in repeated corticosterone-induced depression in mice.

A mouse model of depression has been recently developed by exogenous corticosterone (CORT) administration, which has shown to mimic HPA-axis induced depression-like state in animals. The present study aimed to examine the antidepressant-like effect and the possible mechanisms of resveratrol, a naturally occurring polyphenol of phytoalexin family, on depressive-like behavior induced by repeated corticosterone injections in mice. Mice were injected subcutaneously (s.c.) with 40mg/kg corticosterone (CORT) chronically for 21days. Resveratrol and fluoxetine were administered 30min prior to the CORT injection. After 21-days treatment with respective drugs, behavioral and biochemical parameters were estimated. Since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant activity of many drugs, we also evaluated the effect of resveratrol on BDNF in the hippocampus. Three weeks of CORT injections in mice resulted in depressive-like behavior, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test and tail suspension test. Further, there was a significant increase in serum corticosterone level and a significant decrease in hippocampus BDNF level in CORT-treated mice. Treatment of mice with resveratrol significantly ameliorated all the behavioral and biochemical changes induced by corticosterone. These results suggest that resveratrol produces an antidepressant-like effect in CORT-induced depression in mice, which is possibly mediated by rectifying the stress-based hypothalamic-pituitary-adrenal (HPA) axis dysfunction paradigm and upregulation of hippocampal BDNF levels.