An insight into crosstalk among multiple signalling pathways contributing to the pathophysiology of PTSD and depressive disorders.

Post-traumatic stress disorder (PTSD) and depressive disorders represent two significant mental health challenges with substantial global prevalence. These are debilitating conditions characterized by persistent, often comorbid, symptoms that severely impact an individual's quality of life. Both PTSD and depressive disorders are often precipitated by exposure to traumatic events or chronic stress. The profound impact of PTSD and depressive disorders on individuals and society necessitates a comprehensive exploration of their shared and distinct pathophysiological features. Although the activation of the stress system is essential for maintaining homeostasis, the ability to recover from it after diminishing the threat stimulus is also equally important. However, little is known about the main reasons for individuals' differential susceptibility to external stressful stimuli. The solution to this question can be found by delving into the interplay of stress with the cognitive and emotional processing of traumatic incidents at the molecular level. Evidence suggests that dysregulation in these signalling cascades may contribute to the persistence and severity of PTSD and depressive symptoms. The treatment strategies available for this disorder are antidepressants, which have shown good efficiency in normalizing symptom severity; however, their efficacy is limited in most individuals. This calls for the exploration and development of innovative medications to address the treatment of PTSD. This review delves into the intricate crosstalk among multiple signalling pathways implicated in the development and manifestation of these mental health conditions. By unravelling the complexities of crosstalk among multiple signalling pathways, this review aims to contribute to the broader knowledge base, providing insights that could inform the development of targeted interventions for individuals grappling with the challenges of PTSD and depressive disorders.

Attenuation of type-1 diabetes-induced cardiovascular dysfunctions by direct thrombin inhibitor in rats: a mechanistic study.

Chronic diabetes is associated with ventricular dysfunctions in the absence of hypertension and coronary artery diseases. This condition is termed as diabetic cardiomyopathy (DCM). There is no favourable treatment available for the management of diabetic cardiomyopathy. Recent studies have reported increase in circulating thrombin level among diabetic patients which is responsible for hypercoagulability of blood. Thrombin induces inflammation and fibrosis, and enhances cardiac cell growth and contractility in vitro. In this study, we have investigated the effects of argatroban; a direct thrombin inhibitor against DCM in streptozotocin-induced type-1 diabetes. Diabetes was induced by single dose of streptozotocin (STZ; 50 mg/kg, i.p.) in male Sprague-Dawley rats. After 4 weeks of diabetes induction, the animals were treated with argatroban (0.3 and 1 mg/kg, i.p. daily) for the next 4 weeks. The effect of argatroban was evaluated against diabetes-associated cardiac dysfunction, structural alteration and protein expression. STZ-induced diabetic rats exhibited significant decline in left ventricular functions. Four weeks of treatments with argatroban significantly improved ventricular functions without affecting heart rate. Further, it also protected heart against structural changes induced by diabetes as shown by reduction in fibrosis, hypertrophy and apoptosis. The improvement in cardiac functions and structural changes was associated with significant reduction in left ventricular expression of thrombin receptor also termed as protease-activated receptor-1 or PAR1, p-AKT (ser-473), p-50 NFκB and caspase-3 proteins. This study demonstrates beneficial effects of argatroban via improvement in cardiac functions and structural changes in STZ-induced DCM. These effects may be attributed through reduction in cardiac inflammation, fibrosis and apoptosis.

Edaravone offers neuroprotection in a diabetic stroke model via inhibition of endoplasmic reticulum stress.

Recent investigations have postulated a link between oxidative stress and endoplasmic reticulum (ER) dysfunction in cerebral ischaemic/reperfusion (I/R) injury. Diabetes is common amongst elderly patients with stroke and has been postulated to aggravate brain I/R damage by triggering oxidative as well as ER stress. We investigated whether treatment with edaravone (1-10 mg/kg), a potent free radical scavenger protects against cerebral I/R injury in rats associated with comorbid type 2 diabetes. Diabetic rats exposed to 2-hr middle cerebral artery occlusion (MCAO) and 22 hr of reperfusion significantly had increased infarct, oedema volume and functional neurological deficits as compared to sham-operated rats. Also, the massive DNA fragmentation accompanied by significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) positive cells was noticed in the ipsilateral penumbral brain region of diabetic I/R rats. The effects of I/R injury were associated with significant up-regulation of 78 kDa-glucose-regulated protein (GRP78), CCAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153) and activation of caspase-12, markers of ER stress/apoptosis. Treatment with edaravone (3 and 10 mg/kg) significantly diminished the cerebral infarct, oedema volume and improved functional recovery of neurological deficits. In addition, edaravone treatment ameliorated the DNA fragmentation concomitantly with a significant decrease in induction of GRP78, CHOP/GADD153 immunoreactivity/expression and activation of caspase-12 in the ischaemic brain hemispheres. Overall, the present data indicate that edaravone offers good neuroprotection against diabetic stroke by interrupting the ER stress-mediated apoptotic pathways involving CHOP/GADD153 and caspase-12.

3-Bromo-7-nitroindazole attenuates brain ischemic injury in diabetic stroke via inhibition of endoplasmic reticulum stress pathway involving CHOP.

AIMS: The role of nitric oxide (NO) and endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of cerebral ischemic/reperfusion (I/R) injury and diabetes. The aim of the study was to investigate the neuroprotective potential of 3-bromo-7-nitroindazole (3-BNI), a potent and selective neuronal nitric oxide synthase (nNOS) inhibitor against ER stress and focal cerebral I/R injury associated with comorbid type 2 diabetes in-vivo. MAIN METHODS: Type 2 diabetes was induced by feeding high-fat diet and streptozotocin (35 mg/kg) treatment in rats. Focal cerebral ischemia was induced by 2h middle cerebral artery occlusion (MCAO) followed by 22 h of reperfusion. Immunohistochemistry and western blotting methods were employed for the detection and expression of ER stress/apoptosis markers [78 kDa glucose regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)]. TUNEL assay for DNA fragmentation was also performed. KEY FINDINGS: The diabetic rats subjected to cerebral I/R had prominent neurological damage and functional deficits compared with sham-operated rats. Massive DNA fragmentation was observed in ischemic penumbral region of diabetic brains. Concomitantly, the enhanced immunoreactivity and expression of ER stress/apoptosis markers were noticed. 3-BNI (30 mg/kg, i.p.) treatment significantly inhibited the cerebral infarct, edema volume and improved functional recovery of neurological deficits. The neuroprotection was further evident by lesser DNA fragmentation with a concomitant reduction of GRP78 and CHOP. SIGNIFICANCE: The study demonstrates the neuroprotective potential of 3-BNI in diabetic stroke model which may be partly due to inhibition of ER stress pathway involving CHOP.

Augmentation of endoplasmic reticulum stress in cerebral ischemia/reperfusion injury associated with comorbid type 2 diabetes.

OBJECTIVE: Diabetes is one of the major risk factors for ischemic stroke and is reported to aggravate the ischemic brain damage in different experimental models as well as clinical situations. However, the mechanisms underlying the exacerbated ischemia/reperfusion (I/R) brain injury associated with comorbid diabetes are still not clear. This study investigated the role of endoplasmic reticulum (ER) stress in pathophysiology of aggravated I/R brain injury associated with diabetes. METHODS: Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 hours followed by 22 hours of reperfusion in high-fat diet-fed and low-dose streptozotocin-treated type 2 diabetic rats. Immunohistochemistry and western blotting analysis were performed to detect the changes in expression of various ER stress and apoptotic markers such as 78 kDa glucose-regulated protein (GRP78), CCAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153), and caspase-12. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay was performed to detect the extent of DNA fragmentation and cell death. RESULTS: The diabetic rats subjected to I/R manifested significantly larger brain infarct volume and severe deterioration in neurological deficits than their normal, non-diabetic counterparts. There was a marked upregulation of GRP78 observed in brains of diabetic rats after 22 hours of reperfusion. Furthermore, augmentation of CHOP/GADD153 expression and activation of caspase-12 (ER stress-induced apoptotic factors) were observed in parallel with enhanced TUNEL-positive cells or DNA fragmentation in diabetic rats compared to normal rats following cerebral I/R. DISCUSSION: Taken together, the current experimental findings demonstrate that diabetes exacerbates brain I/R injury which may be mediated through enhanced ER stress and cell death involving CHOP/GADD153 and caspase-12 activation.

Sodium phenylbutyrate ameliorates focal cerebral ischemic/reperfusion injury associated with comorbid type 2 diabetes by reducing endoplasmic reticulum stress and DNA fragmentation.

Endoplasmic reticulum (ER) stress has been postulated to play a crucial role in the pathophysiology of cerebral ischemic/reperfusion (I/R) injury and diabetes. Diabetes is a major risk factor and also common amongst the people who suffer from stroke. In this study, we have investigated the neuroprotective potential of sodium 4-phenylbutyrate (SPB; 30-300mg/kg), a chemical chaperone by targeting ER stress in a rat model of transient focal cerebral ischemia associated with comorbid type 2 diabetes. Intraperitoneal treatment with SPB (100 and 300mg/kg) significantly ameliorated brain I/R damage as evidenced by reduction in cerebral infarct and edema volume. It also significantly improved the functional recovery of various neurobehavioral impairments (neurological deficit score, grip strength and rota rod) evoked by I/R compared with vehicle-treatment. Further, SPB (100mg/kg) significantly reduced the DNA fragmentation as shown by prominent reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells. This effect was observed concomitantly with significant attenuation in upregulation of 78kDa glucose regulated protein (GRP78), CCAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153) and activation of caspase-12, specific markers of ER stress/apoptosis. The neuroprotection observed with SPB was independent of its effect on cerebral blood flow and blood glucose. In conclusion, this study demonstrates the neuroprotective effect of SPB owing to amelioration of ER stress and DNA fragmentation. It also suggest that targeting ER stress might offer a promising therapeutic approach and benefits against ischemic stroke associated with comorbid type 2 diabetes.

Effect of tempol on altered angiotensin II and acetylcholine-mediated vascular responses in thoracic aorta isolated from rats with insulin resistance.

The altered vascular responses to various vasopressors and relaxants have been well reported in various animal models of hypertension, insulin resistance and diabetes. Though the role of oxidative stress (increased superoxide levels) associated with these altered vascular responses in hyperglycemic/diabetic state is well documented, the role of the same remains to be largely unknown in vascular dysfunction coupled with prediabetic insulin resistant state. The objective of the present study was therefore to elucidate the role of free radicals particularly superoxides if any associated with vascular dysfunction in diet-induced insulin resistance of rats. In this regard, the effect of tempol (a membrane permeable superoxide dismutase mimetic/free radical scavenger) on the enhanced Ang II-induced contraction and impaired-ACh mediated relaxation in thoracic aorta of rats with insulin resistance was studied. Ang II-induced contraction and ACh-mediated relaxation responses were recorded isometrically in endothelium intact and denuded thoracic aortic ring preparations isolated from male Sprague-Dawley rats which were fed with either normal pellet diet (NPD) (control group) or high fat diet (HFD) (insulin resistant group) for 4 weeks. The HFD-fed rats exhibited characteristic features of insulin resistance syndrome viz., obesity, hyperinsulinaemia, mild hyperglycemia, hypertriglyceridemia, hypercholesterolemia, glucose intolerance and hypertension. Maximal contractile response (E(max)) to Ang II was increased in endothelium intact aortic ring preparations obtained from HFD-fed rats as compared to NPD-fed control rats. Denudation of endothelium significantly increased Ang II-mediated E(max) responses in thoracic aortic rings of NPD-fed rats, whereas it produced only minimal alteration to the E(max) in the HFD-fed rats. In addition, ACh-mediated relaxation response was impaired in endothelium intact aortic rings isolated from HFD-fed rats. Tempol (30-300 microM) significantly and dose dependently inhibited enhanced vascular responses (E(max)) of Ang II in endothelium intact, but not in endothelium denuded aortic ring preparations. Tempol (30 microM) reversed the impaired acetylcholine (ACh)-mediated relaxations in endothelium intact aortic ring preparations of HFD-fed rats. Endothelium independent vasorelaxations (EIV) to sodium nitroprusside (SNP) were similar for both NPD and HFD. In conclusion, our results indicate that superoxide radicals play crucial role in enhanced contractile and impaired vasodilatory responses to Ang II and ACh, respectively, in thoracic aortic rings isolated from diet-induced insulin resistant rats.

Design, synthesis and evaluation of carbazole derivatives as PPAR alpha/gamma dual agonists and antioxidants.

A series of hydroxycarbazole derivatives were synthesized and evaluated for PPAR alpha/gamma dual agonist as well as antioxidant activities. While most compounds showed good antioxidant activity, some compounds were identified as potential PPAR alpha/gamma dual agonists as well. Compounds 10a and 16 were found to be active in animal studies.

Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats.

Intracerebroventricular (ICV) injection of streptozotocin (STZ) causes cognitive impairment in rats. ICV STZ is known to impair cholinergic neurotransmission by decreasing choline acetyltransferase (ChAT) levels, glucose and energy metabolism in brain and synthesis of acetyl CoA. However, no reports are available regarding the cholinesterase inhibitors in this model. In aging brain, reduced energy metabolism increases glutamate release, which is blocked by L-type calcium channel blockers. These calcium channel blockers have shown beneficial effects on learning and memory in various models of cognitive impairment. The present study was designed to investigate the influence of chronic administration of donepezil (cholinesterase inhibitor, 1 and 3 mg/kg) and lercanidipine (L-type calcium channel blocker, 0.3 and 1 mg/kg) on cognitive impairment in male Sprague-Dawley rats injected twice with ICV STZ (3 mg/kg) bilaterally on days 1 and 3. ICV STZ injected rats developed a severe deficit in learning and memory indicated by deficits in passive avoidance paradigm and elevated plus maze as compared to control rats. Cholinesterase activity in brain was significantly increased in ICV STZ injected rats. Donepezil dose-dependently inhibited cholinesterase activity and improved performance in memory tests at both the doses. Lercanidipine (0.3 mg/kg) showed significant improvement in memory. When administered together, the effect of combination of these two drugs on memory and cholinesterase activity was higher than that obtained with either of the drugs when used alone.

Studies on some glitazones having pyridine as the linker unit.

Molecular modeling on various well-known glitazones carrying a pyridine ring instead of benzene ring as the middle linker unit showed conformational rigidity as compared to their parent molecules. Blocking the lone pair of electrons on the pyridine N, made them flexible once again. A few representatives of these analogues were synthesized and their efficacy as PPARgamma agonists evaluated.