Dual Role of TRPV1 Channels in Cerebral Stroke: An Exploration from a Mechanistic and Therapeutic Perspective.

Transient receptor potential vanilloid subfamily member 1 (TRPV1) has been strongly implicated in the pathophysiology of cerebral stroke. However, the exact role and mechanism remain elusive. TPRV1 channels are exclusively present in the neurovascular system and involve many neuronal processes. Numerous experimental investigations have demonstrated that TRPV1 channel blockers or the lack of TRPV1 channels may prevent harmful inflammatory responses during ischemia-reperfusion injury, hence conferring neuroprotection. However, TRPV1 agonists such as capsaicin and some other non-specific TRPV1 activators may induce transient/slight degree of TRPV1 channel activation to confer neuroprotection through a variety of mechanisms, including hypothermia induction, improving vascular functions, inducing autophagy, preventing neuronal death, improving memory deficits, and inhibiting inflammation. Another factor in capsaicin-mediated neuroprotection could be the desensitization of TRPV1 channels. Based on the summarized evidence, it may be plausible to suggest that TPRV1 channels have a dual role in ischemia-reperfusion-induced cerebral injury, and thus, both agonists and antagonists may produce neuroprotection depending upon the dose and duration. The current review summarizes the dual function of TRPV1 in ischemia-reperfusion-induced cerebral injury models, explains its mechanism, and predicts the future.

Therapeutic potential and pharmacological mechanism of visnagin.

Visnagin is a furanochromone and one of the most important compound in the Ammi visnaga (L.) Lam (a synonym of Visnaga daucoides Gaertn.) plant, which is used to cure various ailments. Many investigations into the bioactive properties of visnagin have been studied to date. The literature on visnagin demonstrates its biological properties, including anti-inflammatory, anti-diabetic, and beneficial effects in cardiovascular and renal diseases. Moreover, visnagin improves sperm quality parameters, stimulates steroidogenesis, and increases serum gonadotropins and testosterone levels, while decreasing pro-inflammatory cytokines, oxidative damage, genomic instability, and it modulates apoptosis. Thus, visnagin has emerged as an exciting lead for further research, owing to its potential in various unmet clinical needs. The current review summarized its basic structure, pharmacokinetics, and pharmacological effects, focusing on its mechanisms of action. The review will help to understand the potential of visnagin as an alternative treatment strategy for several diseases and provide insight into research topics that need further exploration for visnagin's safe clinical use. Please cite this article as: Yadav P, Singh SK, Datta S, Verma S, Verma A, Rakshit A, Bali A, Bhatti JS, Khurana A, Navik U. Therapeutic potential and pharmacological mechanism of visnagin. J Integr Med. 2024; Epub ahead of print.

Multifaceted role of dynamin-related protein 1 in cardiovascular disease: From mitochondrial fission to therapeutic interventions.

Mitochondria are central to cellular energy production and metabolic regulation, particularly in cardiomyocytes. These organelles constantly undergo cycles of fusion and fission, orchestrated by key proteins like Dynamin-related Protein 1 (Drp-1). This review focuses on the intricate roles of Drp-1 in regulating mitochondrial dynamics, its implications in cardiovascular health, and particularly in myocardial infarction. Drp-1 is not merely a mediator of mitochondrial fission; it also plays pivotal roles in autophagy, mitophagy, apoptosis, and necrosis in cardiac cells. This multifaceted functionality is often modulated through various post-translational alterations, and Drp-1's interaction with intracellular calcium (Ca2 + ) adds another layer of complexity. We also explore the pathological consequences of Drp-1 dysregulation, including increased reactive oxygen species (ROS) production and endothelial dysfunction. Furthermore, this review delves into the potential therapeutic interventions targeting Drp-1 to modulate mitochondrial dynamics and improve cardiovascular outcomes. We highlight recent findings on the interaction between Drp-1 and sirtuin-3 and suggest that understanding this interaction may open new avenues for therapeutically modulating endothelial cells, fibroblasts, and cardiomyocytes. As the cardiovascular system increasingly becomes the focal point of aging and chronic disease research, understanding the nuances of Drp-1's functionality can lead to innovative therapeutic approaches.

Naringin: A flavanone with a multifaceted target against sepsis-associated organ injuries.

BACKGROUND: Sepsis causes multiple organ dysfunctions and raises mortality and morbidity rates through a dysregulated host response to infection. Despite the growing research interest over the last few years, no satisfactory treatment exists. Naringin, a naturally occurring bioflavonoid with vast therapeutic potential in citrus fruits and Chinese herbs, has received much attention for treating sepsis-associated multiple organ dysfunctions. PURPOSE: The review describes preclinical evidence of naringin from 2011 to 2024, particularly emphasizing the mechanism of action mediated by naringin against sepsis-associated specific injuries. The combination therapy, safety profile, drug interactions, recent advancements in formulation, and future perspectives of naringin are also discussed. METHODS: In vivo and in vitro studies focusing on the potential role of naringin and its mechanism of action against sepsis-associated organ injuries were identified and summarised in the present manuscript, which includes contributions from 2011 to 2024. All the articles were extracted from the Medline database using PubMed, Science Direct, and Web of Science with relevant keywords. RESULTS: Research findings revealed that naringin modulates many signaling cascades, such as Rho/ROCK and PPAR/STAT1, PIP3/AKT and KEAP1/Nrf2, and IkB/NF-kB and MAPK/Nrf2/HO-1, to potentially protect against sepsis-induced intestinal, cardiac, and lung injury, respectively. Furthermore, naringin treatment exhibits anti-inflammatory, anti-apoptotic, and antioxidant action against sepsis harm, highlighting naringin's promising effects in septic settings. Naringin could be employed as a treatment against sepsis, based on studies on combination therapy, synergistic effects, and toxicological investigation that show no reported severe side effects. CONCLUSION: Naringin might be a promising therapeutic approach for preventing sepsis-induced multiple organ failure. Naringin should be used alongside other therapeutic therapies with caution despite its great therapeutic potential and lower toxicity. Nonetheless, clinical studies are required to comprehend the therapeutic benefits of naringin against sepsis.

Ephrin B/EphB in neuropathic pain: Role and molecular mechanisms.

Ephrins are protein ligands that act through the tyrosine kinase receptor family, Eph receptors. The role of ephrin/Eph in the critical processes involved in the development of the nervous system, including axon guidance and cell migration, has been well documented. Moreover, studies have shown an upregulation of ephrin B1/EphB1 and ephrin B2/EphB2 in neuropathic pain of different etiology. The activation of the ephrin B/EphB system in the dorsal root ganglion and dorsal horn of the spinal cord may be essential in initiating and maintaining neuropathic pain. Accordingly, it can be proposed that the pharmacological inhibitors of EphB receptors may be potentially employed to manage the manifestations of pain. One of the primary mechanisms involved in ephrin B/EphB-mediated synaptic plasticity includes phosphorylation and activation of NMDA receptors, which may be secondary to activation of different kinases, including MAP kinases (MAPK), protein kinase C (PKC), and Src family kinases (SFK). The other molecular mechanisms may include activation of inflammatory cytokines in the spinal cord, caspase-3, calpain-1, phosphoinositide 3-kinase (PI3K), protein kinase A (PKA), and cAMP Response Element-Binding Protein (CREB). The present review discusses the role and molecular mechanisms involved in ephrin B/EphB-mediated neuropathic pain of different etiology.

Exploring the ameliorative potential of Bacopa monnieri in acetic acid induced ulcerative colitis in mice.

The aim of the present study was to evaluate the role of Bacopa monnieri in acetic-acid-induced ulcerative colitis in mice. Acetic acid (3%v/v, in 0.9% saline) was infused intrarectally to induce ulceration in mice. Administration of acetic acid resulted in severe inflammation of the colon along with an increase in the myeloperoxidase (MPO) activity assessed on 7th day. Treatment with Bacopa monnieri extract (20 mg/kg and 40 mg/kg, p.o) and saponin-rich fraction (5 mg/kg and 10 mg/kg; p.o) for 7 days i.e. 2 days before and 5 days after acetic acid infusion, significantly attenuated the colonic inflammation in a dose-dependent manner. Furthermore, it also reduced the MPO levels and the disease activity score as compared to the control group. It may be concluded that Bacopa monnieri has the potential for ameliorating acetic-acid-induced colitis and its saponin-rich fraction may be responsible for this effect.

A focus on Rho/ROCK signaling pathway: An emerging therapeutic target in depression.

Depression is the most common mental health disorder worldwide; however, the exact cellular and molecular mechanisms of this major depressive disorder are unclear so far. Experimental studies have demonstrated that depression is associated with significant cognitive impairment, dendrite spine loss, and reduction in connectivity among neurons that contribute to symptoms associated with mood disorders. Rho/Rho-associated coiled-coil containing protein kinase (ROCK) receptors are exclusively expressed in the brain and Rho/ROCK signaling has gained considerable attention as it plays a crucial role in the development of neuronal architecture and structural plasticity. Chronic stress-induced activation of the Rho/ROCK signaling pathway promotes neuronal apoptosis and loss of neural processes and synapses. Interestingly, accumulated evidence has identified Rho/ROCK signaling pathways as a putative target for treating neurological disorders. Furthermore, inhibition of the Rho/ROCK signaling pathway has proven to be effective in different models of depression, which signify the potential benefits of clinical Rho/ROCK inhibition. The ROCK inhibitors extensively modulate antidepressant-related pathways which significantly control the synthesis of proteins, and neuron survival and ultimately led to the enhancement of synaptogenesis, connectivity, and improvement in behavior. Therefore, the present review refines the prevailing contribution of this signaling pathway in depression and highlighted preclinical shreds of evidence for employing ROCK inhibitors as disease-modifying targets along with possible underlying mechanisms in stress-associated depression.

Investigations on Rho/ROCK signaling in post-traumatic stress disorder-like behavior in mice.

Post-Traumatic Stress Disorder (PTSD) is a chronic condition that occurs in response to a traumatic event, and consequently, enhances the threat sensitivity. Rho/ROCK signaling has been implicated in the consolidation of fear memory, stress, depression, anxiety, and traumatic brain injury. However, its role in post-traumatic stress disorder remains elusive. Therefore, the present study was designed to explore the role of fasudil, a Rho/ROCK inhibitor, a mouse model of PTSD. Mice were subjected to underwater trauma stress followed by three situational reminders. Underwater trauma (UWT) significantly increased the freezing behavior, a marker of the formation of aversive memory, in response to situational reminders on the 3rd, 7th, and 14th days, suggesting the significant development of PTSD. Trauma and situational reminders were also associated with significant changes in behavioral parameters in open field, social interaction and actophotometer tests, along with a reduction in serum corticosterone levels. Fasudil (10 and 15 mg/kg) and sertraline (15 mg/kg), a standard drug for PTSD, significantly decreased the freezing behaviour in response to situational reminders, suggesting the inhibition of the formation of aversive fear memory. However, fasudil and sertraline did not modulate normal memory functions, as assessed on elevated plus maze test, before subjecting mice to traumatic stress. Treatment with fasudil and sertraline significantly restored the behavioral changes and normalized the corticosterone levels. Fasudil-mediated blockade of the Rho/ROCK pathway may be responsible for blocking the formation of aversive memory during the traumatic event, which may be manifested in form of decreased contextual fear response during situational reminders.

Exogenous fetuin-A protects against sepsis-induced myocardial injury by inhibiting oxidative stress and inflammation in mice.

Sepsis-induced myocardial injury is a consequence of septicemia and is one of the major causes of death in intensive care units. A serum glycoprotein called fetuin-A is secreted largely by the liver, tongue, placenta, and adipose tissue. Fetuin-A has a variety of biological and pharmacological properties. The anti-inflammatory and antioxidant glycoprotein fetuin-A has shown its efficacy in a number of inflammatory disorders including sepsis. However, its protective role against sepsis-induced myocardial injury remains elusive. The purpose of this work is to explore the role of fetuin-A in mouse models of myocardial injury brought on by cecal ligation and puncture (CLP). CLP significantly induced the myocardial injury assessed in terms of elevated myocardial markers (serum CK-MB, cTnI levels), inflammatory markers (IL-6, TNF-α) in the serum, and oxidative stress markers (increased MDA levels and decreased reduced glutathione) in heart tissue homogenate following 24 h of ligation and puncture. Further, hematoxylin and eosin (H&E) staining showed considerable histological alterations in the myocardial tissue of sepsis-developed mice. Interestingly, fetuin-A pretreatment (50 and 100 mg/kg) for 4 days before the CLP procedure significantly improved the myocardial injury and was evaluated in perspective of a reduction in the CK-MB, cTnI levels, IL-6, and TNF-α in sepsis-developed animals. Fetuin-A pretreatment significantly attenuated the oxidative stress and improved the myocardial morphology in a dose-dependent manner. The present study provides preliminary evidence that fetuin-A exerts protection against sepsis-induced cardiac dysfunction in vivo via suppression of inflammation and oxidative damage.

Demystifying the dual role of the angiotensin system in neuropathic pain.

Neuropathic Pain is caused by damage to a nerve or disease of the somatosensory nervous system. Apart from the blood pressure regulating actions of angiotensin ligands, studies have shown that it also modulates neuropathic pain. In the animal models including surgical, chemotherapeutic, and retroviral-induced neuropathic pain, an increase in the levels of angiotensin II has been identified and it has been proposed that an increase in angiotensin II may participate in the induction of neuropathic pain. The pain-inducing actions of the angiotensin system are primarily due to the activation of AT1 and AT2 receptors, which trigger the diverse molecular mechanisms including the induction of neuroinflammation to initiate and maintain the state of neuropathic pain. On the other hand, the pain attenuating action of the angiotensin system has been attributed to decreasing in the levels of Ang(1-7), and Ang IV and an increase in the levels of bradykinin. Ang(1-7) may attenuate neuropathic pain via activation of the spinal Mas receptor. However, the detailed molecular mechanism involved in Ang(1-7) and Ang IV-mediated pain attenuating actions needs to be explored. The present review discusses the dual role of angiotensin ligands in neuropathic pain along with the possible mechanisms involved in inducing or attenuating the state of neuropathic pain.

Investigating the role of nitric oxide in stress adaptive process in electric foot shock stress-subjected mice.

AIM: The present study was designed to investigate the role of nitric oxide (NO) in the non-development of stress adaptation in high-intensity foot-shock stress (HIFS) subjected mice. METHODS: Mice were subjected to low-intensity shocks (LIFS i.e. 0.5 mA) or HIFS (1.5 mA) for 5 days. Stress-induced behavioral changes were assessed by actophotometer, hole board, open field and social interaction tests. Biochemically, the serum corticosterone levels were measured as a marker of stress. L-arginine (100 mg/kg and 300 mg/kg), as NO donor, and L-NAME (10 mg/kg and 30 mg/kg), as nitric oxide synthase (NOS) inhibitor, were employed as pharmacological agents. RESULTS: A single exposure of LIFS and HIFS produced behavioral and biochemical alterations. However, there was the restoration of behavioral and biochemical alterations on 5th day in response to repeated LIFS exposure suggesting the development of stress adaptation. However, no stress adaptation was observed in HIFS subjected mice. Administration of L-arginine (300 mg/kg) abolished the stress adaptive response in LIFS-subjected mice, while L-NAME (30 mg/kg) induced the development of stress adaptation in HIFS subjected mice. CONCLUSION: It is concluded that an increase in the NO release may possibly impede the process of stress adaptation in HIFS-subjected mice.

Beneficial role of central anticholinergic agent in preventing the development of symptoms in mouse model of post-traumatic stress disorder.

Objectives The present study was designed to investigate the effectiveness of trihexyphenidyl, a central anticholinergic drug, in preventing the post-traumatic stress disorder (PTSD) symptoms in a mouse model. Methods Mice were subjected to underwater trauma stress for 30 s on day 1 followed by three situational reminders (3rd, 7th and 14th day). Thereafter, the behavioral alterations including freezing behavior were noted on 21st day. The serum corticosterone levels were measured as a biochemical marker of trauma. Elevated plus maze test was done on day 1 and day 2 to assess the memory formation following exposure to trauma. Results Trauma and situational reminders were associated with a significant development of behavioral changes and freezing behavior on the 21st day. Moreover, there was also a significant decrease in the serum corticosterone levels. A single administration of trihexyphenidyl (2 and 5 mg/kg) significantly restored trauma associated-behavioral changes and serum corticosterone levels. Moreover, it significantly increased the transfer latency time on day 2 following stress exposure in comparison to normal mice suggesting the inhibition of memory formation during trauma exposure. Trihexyphenidyl also led to significant reduction in freezing behavior in response to situational reminders again suggesting the inhibition of formation of aversive fear memory. Conclusion The blockade of central muscarinic receptors may block the formation of aversive memory during the traumatic event, which may be manifested in form of decreased contextual fear response during situational reminders. Central anticholinergic agents may be potentially useful as prophylactic agents in preventing the development of PTSD symptoms.

Exploring the therapeutic potential of sodium benzoate in acetic acid-induced ulcerative colitis in rats.

Background Ulcerative colitis is a chronic mucosal inflammation of the large intestine mainly affecting the colon and rectum. The lack of effective and safe therapeutic agents led to the identification of new therapeutic agents to effectively manage the symptoms and complications of ulcerative colitis. The present study aimed to evaluate the protective effect of sodium benzoate in acetic acid-induced ulcerative colitis in rats. Methods Infusion of 3% acetic acid in the colon through the rectum was done to construct a rat model of ulcerative colitis. After 5 days of infusion, macroscopic, biochemical, and histopathological examinations and disease activity scoring of the colon were done to assess colonic damage. Results Acetic acid infusion resulted in severe inflammation in the colon assessed macroscopically and histopathologically. Moreover, it also led to increase in myeloperoxidase (MPO) and reduction in glutathione (GSH) levels. In the present study, repeated administration of sodium benzoate (400 and 800 mg/kg i.p.) and sulfasalazine (500 mg/kg orally) for 7 days, i.e. 2 days before and continued for 5 days after acetic acid infusion, significantly attenuated macroscopic damage and disease activity score as compared to disease control. Further, it also significantly reduced the levels of MPO and enhanced colonic levels of reduced GSH. However, the lower dose of sodium benzoate (200 mg/kg) did not show sufficient protective effect in acetic acid-induced ulcerative colitis. Further, sodium benzoate per se did not show any effect in normal rats. Conclusions The observed protective effect of sodium benzoate may be due to its antioxidant and anti-inflammatory activities in an ulcerative colitis model.

An integrated review on new targets in the treatment of neuropathic pain.

Neuropathic pain is a complex chronic pain state caused by the dysfunction of somatosensory nervous system, and it affects the millions of people worldwide. At present, there are very few medical treatments available for neuropathic pain management and the intolerable side effects of medications may further worsen the symptoms. Despite the presence of profound knowledge that delineates the pathophysiology and mechanisms leading to neuropathic pain, the unmet clinical needs demand more research in this field that would ultimately assist to ameliorate the pain conditions. Efforts are being made globally to explore and understand the basic molecular mechanisms responsible for somatosensory dysfunction in preclinical pain models. The present review highlights some of the novel molecular targets like D-amino acid oxidase, endoplasmic reticulum stress receptors, sigma receptors, hyperpolarization-activated cyclic nucleotide-gated cation channels, histone deacetylase, Wnt/ß-catenin and Wnt/Ryk, ephrins and Eph receptor tyrosine kinase, Cdh-1 and mitochondrial ATPase that are implicated in the induction of neuropathic pain. Studies conducted on the different animal models and observed results have been summarized with an aim to facilitate the efforts made in the drug discovery. The diligent analysis and exploitation of these targets may help in the identification of some promising therapies that can better manage neuropathic pain and improve the health of patients.

Conditioning-induced cardioprotection: Aging as a confounding factor.

The aging process induces a plethora of changes in the body including alterations in hormonal regulation and metabolism in various organs including the heart. Aging is associated with marked increase in the vulnerability of the heart to ischemia-reperfusion injury. Furthermore, it significantly hampers the development of adaptive response to various forms of conditioning stimuli (pre/post/remote conditioning). Aging significantly impairs the activation of signaling pathways that mediate preconditioning-induced cardioprotection. It possibly impairs the uptake and release of adenosine, decreases the number of adenosine transporter sites and down-regulates the transcription of adenosine receptors in the myocardium to attenuate adenosine-mediated cardioprotection. Furthermore, aging decreases the expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) and subsequent transcription of catalase enzyme which subsequently increases the oxidative stress and decreases the responsiveness to preconditioning stimuli in the senescent diabetic hearts. In addition, in the aged rat hearts, the conditioning stimulus fails to phosphorylate Akt kinase that is required for mediating cardioprotective signaling in the heart. Moreover, aging increases the concentration of Na+ and K+, connexin expression and caveolin abundance in the myocardium and increases the susceptibility to ischemia-reperfusion injury. In addition, aging also reduces the responsiveness to conditioning stimuli possibly due to reduced kinase signaling and reduced STAT-3 phosphorylation. However, aging is associated with an increase in MKP-1 phosphorylation, which dephosphorylates (deactivates) mitogen activated protein kinase that is involved in cardioprotective signaling. The present review describes aging as one of the major confounding factors in attenuating remote ischemic preconditioning-induced cardioprotection along with the possible mechanisms.

Clinical evidence and mechanisms of growth factors in idiopathic and diabetes-induced carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is an entrapment neuropathy caused by compression and irritation of the median nerve, which travels through the carpal tunnel in the wrist. Increased fibrosis is a hallmark of the development and pathology of CTS. Different growth factors have been demonstrated to play a potential role in the development of CTS. Studies have described an increase in the expression of growth factors, including Transforming Growth Factor (TGF-ß), Vascular Endothelial Growth Factor (VEGF) and interleukins (growth factors for immune and inflammatory cells) in SSCT (sub-synovial connective tissue) in CTS patients. Additionally, SSCT fibrosis is also marked by increased activation of canonical TGF-ß second messenger Smads, increased expression of downstream fibrotic mediators such as connective tissue growth factor (CTGF), increased production of collagen type I, II, III and IV, and decreased expression of matrix metalloproteinases. Anti-fibrotic such as anti-TGF treatment may prove beneficial in idiopathic patients, however, anti VEGF therapy can be successful in the diabetic CTS patients. The present review describes the clinical evidence stating the role of different growth factors in the development of fibrosis in idiopathic and diabetes induced CTS.

Pharmacological investigations on mast cell stabilizer and histamine receptor antagonists in vincristine-induced neuropathic pain.

The present study was designed to investigate the role of mast cells and mast cell-derived histamine in vincristine-induced neuropathic pain. Neuropathic pain was induced by administration of vincristine (100 µg/kg, i.p.) over a period of 10 days, with a break of 2 days, and pain behavioural estimations including pin prick, hot plate and acetone spray tests were performed to assess mechanical and heat hyperalgesia and cold allodynia, respectively, on days 0, 14 and 28. Mast cell stabilizer, sodium cromoglycate, H1 receptor antagonist promethazine and H2 receptor antagonist ranitidine were administered over a period of 12 days. Administration of vincristine resulted in significant development of heat and mechanical hyperalgesia as well as cold allodynia. Furthermore, the pain observed was markedly elevated on the 28th day in comparison to the 14th day. Administration of sodium cromoglycate, promethazine and ranitidine significantly reduced mechanical and heat hyperalgesia and cold allodynia. However, the pain-attenuating effects of ranitidine were significantly less as compared to sodium cromoglycate and promethazine, which suggests that H1 receptors play a more important role than H2 receptors in vincristine-induced neuropathic pain. It may be concluded that vincristine may degranulate mast cells to release inflammatory mediators, particularly histamine which may act through H1 (primarily H1) and H2 receptors to induce neuropathic pain.

Neuropathic pain attenuating effects of perampanel in an experimental model of chronic constriction injury in rats.

The present study explores the pain attenuating effect of perampanel, AMPA receptor antagonist, in chronic constriction injury-induced neuropathic pain. Chronic Constriction Injury was performed by putting four loose ligatures around the sciatic nerve. Pain was assessed by determining mechanical hyperalgesia, cold allodynia and heat hyperalgesia on 7th and 14th day post surgery. Perampanel (3mg and 6mg/kg, p.o.) was administered 30min before pain assessment test on 14th day post-surgery. CCI led to significant development of pain and peak symptoms were observed on 14th day. Perampanel significantly attenuated CCI-induced mechanical hyperalgesia, cold allodynia and heat hyperalgesia, at different time intervals 30, 60, 90, 120min, with more substantial effect observed at dose of 6mg/kgNaloxone was administered in CCI subjected rats before perampanel treatment to explore the potential role of opioids in anti-nociceptive effects of perampanel. Naloxone decreased the pain attenuating effects of perampanel significantly, indicating a critical role of opioid system in anti-nociceptive potential of perampanel. Perampanel has pain attenuating potential in CCI-induced neuropathic pain, which may be due to partly mediated through the opioid system.

Anti-stress effects of a GSK-3ß inhibitor, AR-A014418, in immobilization stress of variable duration in mice.

BACKGROUND: The present study was designed to explore the anti-stress role of AR-A014418, a selective glycogen synthase kinase-3ß inhibitor (GSK-3ß), on changes provoked by immobilization stress of varying duration. METHODS: Acute stress of varying degree was induced by subjecting mice to immobilization stress of short duration (30 min) or long duration (120 min). Thereafter, these animals were exposed to the same stressor for 5 days to induce stress adaptation. The behavioral alterations were assessed using an actophotometer, a hole-board, and the open field and social interaction tests. The serum corticosterone levels were assessed as markers of the hypothalamic-pituitary-adrenal (HPA) axis activity. The levels of total GSK-3ß and p-GSK-3ß-S9 were determined in the prefrontal cortex. RESULTS: A single exposure to short or long immobilization stress produced behavioral and biochemical changes and the levels of p-GSK-3ß-S9 decreased without affecting the total GSK-3ß levels in the brain. However, repeated exposure to both short and long stress reversed the behavioral and biochemical changes along with the normalization of p-GSK-3ß-S9 levels. The administration of AR-A014418, a selective GSK-3ß inhibitor, diminished acute stress-induced behavioral and biochemical changes. Furthermore, AR-A014418 normalized acute stress-induced alterations in p-GSK-3ß-S9 levels without changing total GSK-3ß levels. CONCLUSIONS: Our study suggests that acute stress-induced decrease in p-GSK-3ß-S9 levels in the brain contributes to the development of behavioral and biochemical alterations and the normalization of GSK-3ß signaling may contribute to stress adaptive behavior in mice which have been subjected to repeated immobilization stress.

Exploring the Role of TRPV and CGRP in Adenosine Preconditioning and Remote Hind Limb Preconditioning-Induced Cardioprotection in Rats.

The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mechanisms by which protection occurs still remain to be explored. Therefore, the present study was designed to investigate the role of TRPV and CGRP in adenosine and remote preconditioning-induced cardioprotection, using sumatriptan, a CGRP release inhibitor and ruthenium red, a TRPV inhibitor, in rats. For remote preconditioning, a pressure cuff was tied around the hind limb of the rat and was inflated with air up to 150 mmHg to produce ischemia in the hind limb and during reperfusion pressure was released. Four cycles of ischemia and reperfusion, each consisting of 5 min of inflation and 5 min of deflation of pressure cuff were used to produce remote limb preconditioning. An ex vivo Langendorff's isolated rat heart model was used to induce ischemia reperfusion injury by 30 min of global ischemia followed by 120 min of reperfusion. RIPC demonstrated a significant decrease in ischemia reperfusion-induced significant myocardial injury in terms of increase in LDH, CK, infarct size and decrease in LVDP, +dp/dtmax and -dp/dtmin. Moreover, pharmacological preconditioning with adenosine produced cardioprotective effects in a similar manner to RIPC. Pretreatment with sumatriptan, a CGRP release blocker, abolished RIPC and adenosine preconditioning-induced cardioprotective effects. Administration of ruthenium red, a TRPV inhibitor, also abolished adenosine preconditioning-induced cardioprotection. It may be proposed that the cardioprotective effects of adenosine and remote preconditioning are possibly mediated through activation of a TRPV channels and consequent, release of CGRP.