Protective effect of olopatadine hydrochloride against LPS-induced acute lung injury: via targeting NF-κB signaling pathway.

BACKGROUND: Morbidity and mortality rates associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are high (30-40%). Nuclear factor-kappa B (NF-κB) is a transcription factor, associated with transcription of numerous cytokines leading to cytokine storm, and thereby, plays a major role in ALI/ARDS and in advanced COVID-19 syndrome. METHODS: Considering the role of NF-κB in ALI, cost-effective in silico approaches were utilized in the study to identify potential NF-κB inhibitor based on the docking and pharmacokinetic results. The identified compound was then pharmacologically validated in lipopolysaccharide (LPS) rodent model of acute lung injury. LPS induces ALI by altering alveolar membrane permeability, recruiting activated neutrophils and macrophages to the lungs, and compromising the alveolar membrane integrity and ultimately impairs the gaseous exchange. Furthermore, LPS exposure is associated with exaggerated production of various proinflammatory cytokines in lungs. RESULTS: Based on in silico studies Olopatadine Hydrochloride (Olo), an FDA-approved drug was found as a potential NF-κB inhibitor which has been reported for the first time, and considered further for the pharmacological validation. Intraperitoneal LPS administration resulted in ALI/ARDS by fulfilling 3 out of the 4 criteria described by ATS committee (2011) published workshop report. However, treatment with Olo attenuated LPS-induced elevation of proinflammatory markers (IL-6 and NF-κB), oxidative stress, neutrophil infiltration, edema, and damage in lungs. Histopathological studies also revealed that Olo treatment significantly ameliorated LPS-induced lung injury, thus conferring improvement in survival. Especially, the effects produced by Olo medium dose (1 mg/kg) were comparable to dexamethasone standard. CONCLUSION: In nutshell, inhibition of NF-κB pathway by Olo resulted in protection and reduced mortality in LPS- induced ALI and thus has potential to be used clinically to arrest disease progression in ALI/ARDS, since the drug is already in the market. However, the findings warrant further extensive studies, and also future studies can be planned to elucidate its role in COVID-19-associated ARDS or cytokine storm.

Sarcosine (glycine transporter inhibitor) attenuates behavioural and biochemical changes induced by ketamine, in the rat model of schizophrenia.

Schizophrenia is a neurological disorder that alters the behavior and affects the quality of life of a patient. It is characterized by hallucinations, disorganized behavior, cognitive dysfunction, hyperlocomotion, and loss of the reward system. Schizophrenia constitutes three symptoms' domains, viz. positive, negative and cognitive. Typical and atypical antipsychotics do not fully resolve all the symptoms' domains thus paving the way to the genesis of the glutamatergic hypothesis, i.e. N-methyl-D-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Positive modulation of NMDA receptors by enhancing co-agonist, glycine effect is proposed to produce a therapeutic effect in schizophrenia. Hence, sarcosine (N-methyl glycine), natural amino acid, and a glycine transporter inhibitor (GlyT-1) which also acts on NMDA receptors were used in the present study. The present study unravels the role of sarcosine in the attenuation of ketamine-induced three symptom domains in a rat model through modulation of oxidative stress, mitochondrial dysfunction, and neuroinflammatory pathways. The animal model of schizophrenia was established by injecting ketamine intraperitoneal (ip) at a 30 mg/kg dose for 10 consecutive days, after which sarcosine (300, 600 mg/kg, ip) as a treatment was given for 7 days followed by behavioral, biochemical, molecular, and histopathological analysis. It was revealed that sarcosine reversed ketamine-induced behavioral impairments. Moreover, sarcosine ameliorated oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation and showed protective effects in histopathological examination by hematoxylin and eosin staining. Hence, conclusively, sarcosine was regarded to attenuate the behavioural symptoms of schizophrenia by alleviating oxidative stress, neuroinflammation, and mitochondrial dysfunction established by the ketamine.

Anti-inflammatory effects of ellagic acid and vanillic acid against quinolinic acid-induced rat model of Huntington's disease by targeting IKK-NF-κB pathway.

Huntington disease (HD), an autosomal dominant neurodegenerative disorder characterized by involuntary choreatic movements with cognitive and behavioral disturbances. HD striatum has increased conversion of kynurenine to quinolinic acid (QA) which activates NMDA receptors leading to activation of microglia and increased levels of nuclear factor kappa B (NF-κB) leading to elevated transcription of inducible nitric oxide synthase (iNOS) and various cytokines causing neuronal death via neuroinflammation, oxidative stress, mitochondrial dysfunction and apoptosis. Therefore, inhibiting IKK-NF-κB pathway induced excitotoxicity, oxidative stress and neuroinflammation could be a potential intervention in slowing down the disease progression. QA injection intrastriatally (IS-QA) produce damage mimicking HD where neuroinflammation, oxidative stress and mitochondrial dysfunction play crucial role. Ellagic acid (EA) and vanillic acid (VA) are well reported to possess antioxidant and NF-κB inhibiting effect. Hence, in present study, rats administered IS-QA were treated with EA and VA for 21 days to explore their neuroprotective effects. Behavioral studies, biochemical estimations for oxidative stress and acetylcholinesterase assay were performed. Mitochondrial function was determined by estimating mitochondrial enzyme complexes; inflammatory markers like TNF-α, IL-6, NF-κB by ELISA and apoptosis by caspase-3 levels. Brain damage was determined by histopathology which revealed their neuroprotective effects. Various doses of EA and VA produced improved motor and cognitive functions, oxidative stress and neuroinflammation were also reduced and mitochondrial functioning was improved. In a nutshell, these results signify improved motor and cognitive functions by EA and VA in QA model of HD, along with declined oxidative stress, mitochondrial dysfunction and neuroinflammation.

Antidepressant-like effect of sodium orthovanadate in a mouse model of chronic unpredictable mild stress.

Depression is a psychiatric disorder characterized by low-esteem, anhedonia, social deficit, and lack of interest. Decreased brain-derived neurotrophic factor (BDNF) and impaired tropomyosin kinase B receptor (TrkB receptor) signaling are associated with depression. In our study, depressive-like behavior was induced in mice by chronic unpredictable mild stress (CUMS) model. Various behavioral tests like tail suspension test (TST), open field test (OFT), sucrose preference test (SPT); biochemical analyses for corticosterone, reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), nitric oxide (NO) and enzyme-linked immunosorbent assay (ELISA) for BDNF were performed. Body weight was measured every week. CUMS induced depressive-like behavior was found to be associated with increased oxidative stress in the brain and serum corticisterone with subsequent reduction of BDNF. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor already reported to elevate BDNF levels, was used as the test drug. Sodium orthovanadate (5 mg/kg, 10 mg/kg) and fluoxetine (FLX-10 mg/kg) was given to mice orally for 21days before 30 min of stress induction. The behavioral tests reflected depressive-like behavior in CUMS, which was attenuated by both SOV and fluoxetine. SOV at 10 mg/kg demonstrated significant results in the present study characterized by decreased malondialdehyde levels (MDA/LPO), NO levels, and increased GSH level and SOD activity in both the cortex and hippocampus. Besides, ELISA has revealed the significant elevation of BDNF levels in the treatment groups (SOV-5 mg/kg, 10 mg/kg and FLX-10 mg/kg) as compared to the disease group (CUMS). Therefore, the treatment with SOV appeared to reverse both oxidative and nitrosative stress. Decreased serum corticosterone levels observed with SOV (5 & 10 mg/kg), FLX-10 mg/kg, FLX (10 mg/kg) + SOV (5 mg/kg); and SOV-10 mg/kg per-se treatment and elevated BDNF level with SOV (5 & 10 mg/kg), FLX-10 mg/kg were associated with attenuation of depressive-like behavior. The findings of this preliminary study indicate that SOV has the potential to restore antidepressant-like effects or prevent stress-induced anhedonia and so further molecular mechanisms are warranted for clinical translation.

Safety profile of COVID-19 drugs in a real clinical setting.

PURPOSE: The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has affected millions all over the world and has been declared pandemic, as of 11 March 2020. In addition to the ongoing research and development of vaccines, there is still a dire need for safe and effective drugs for the control and treatment against the SARS-CoV-2 virus infection. Numerous repurposed drugs are under clinical investigations whose reported adverse events can raise worries about their safety. The aim of this review is to illuminate the associated adverse events related to the drugs used in a real COVID-19 setting along with their relevant mechanism(s). METHOD: Through a literature search conducted on PubMed and Google Scholar database, various adverse events suspected to be induced by eight drugs, including dexamethasone, hydroxychloroquine, chloroquine, remdesivir, favipiravir, lopinavir/ritonavir, ivermectin, and tocilizumab, administered in COVID-19 patients in clinical practice and studies were identified in 30 case reports, 3 case series, and 10 randomized clinical trials. RESULTS: Mild, moderate, or severe adverse events of numerous repurposed and investigational drugs caused by various factors and mechanisms were observed. Gastrointestinal side effects such as nausea, abdominal cramps, diarrhea, and vomiting were the most frequently followed by cardiovascular, cutaneous, and hepatic adverse events. Few other rare adverse drug reactions were also observed. CONCLUSION: In light of their ineffectiveness against COVID-19 as evident in large clinical studies, drugs including hydroxychloroquine, lopinavir/ritonavir, and ivermectin should neither be used routinely nor in clinical studies. While lack of sufficient data, it creates doubt regarding the reliability of chloroquine and favipiravir use in COVID-19 patients. Hence, these two drugs can only be used in clinical studies. In contrast, ample well-conducted studies have approved the use of remdesivir, tocilizumab, and dexamethasone under certain conditions in COVID-19 patients. Consequently, it is significant to establish a strong surveillance system in order to monitor the proper safety and toxicity profile of the potential anti-COVID-19 drugs with good clinical outcomes.

7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer's disease by reversing oxidative stress, mitochondrial dysfunction, and insulin resistance.

RATIONALE: Intracerebroventricular (ICV) streptozotocin (STZ) mimics sporadic Alzheimer's disease (SAD) characterized by tau pathology and neurodegeneration arising from oxidative stress, mitochondrial dysfunction, and insulin resistance. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid having antioxidant property interlinked with mitochondrial functioning and insulin actions. OBJECTIVES: To evaluate the neuroprotective and cognitive enhancement properties of 7,8-DHF in an ICV-STZ rat model of SAD. METHODS: ICV-STZ (3 mg/kg) was injected into male Wistar rats. Cognitive functions were evaluated by Morris water maze (MWM) and novel object recognition (NOR). 7,8-DHF (5 mg/kg, 10 mg/kg, and 20 mg/kg) and rivastigmine (2 mg/kg) were given orally for 21 days. Reduced glutathione (GSH), catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX), lipid peroxidation (LPO), protein carbonylation (PCO), and nitrite assays were performed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were determined. ELISA for the insulin-degrading enzyme (IDE) and p-tau was done. Histopathology was investigated by hematoxylin and eosin staining. RESULTS: 7,8-DHF treatment attenuated ICV-STZ-induced cognitive deficit in MWM and NOR. Moreover, in the cortex and hippocampus regions of the brain, GSH, catalase, SOD, GPX, LPO, PCO, and nitrite levels were reversed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were also normalized. IDE and p-tau protein were found to be significantly altered. 7,8-DHF provided protection from neuronal cell death examined in histopathology. CONCLUSIONS: Conclusively, 7,8-DHF was found to be neuroprotective in the ICV-STZ rat model by ameliorating oxidative stress, mitochondrial dysfunction, and insulin resistance, thereby improving cognitive functions evident with the behavioral results.

Neuroprotective effects of roflumilast against quinolinic acid-induced rat model of Huntington's disease through inhibition of NF-κB mediated neuroinflammatory markers and activation of cAMP/CREB/BDNF signaling pathway.

Huntington's disease (HD) is a progressive neurodegenerative and hyperkinetic movement disorder. Decreased activity of cAMP-responsive element-binding protein (CREB) is thought to contribute to the death of striatal medium spiny neurons in HD. The present study has been designed to explore the possible role of roflumilast against qunilonic acid (QA) induced neurotoxicity in rats intending to investigate whether it inhibits the neuroinflammatory response through activation of the cAMP/CREB/BDNF signaling pathway. QA was microinjected (200 nmol/2 µl, bilaterally) through the intrastriatal route in the stereotaxic apparatus. Roflumilast (0.5, 1, and 2 mg/kg, orally) once-daily treatment for 21 days significantly improved locomotor activity in actophotometer, motor coordination in rotarod, and impaired gait performance in narrow beam walk test. Moreover, roflumilast treatment significantly attenuated oxidative and nitrosative stress (p < 0.05) through attenuating lipid peroxidation nitrite concentration and enhancing reduced glutathione, superoxide dismutase, and catalase levels. Furthermore, roflumilast also significantly decreased elevated pro-inflammatory cytokines like TNF-α (p < 0.01), IL-6 (p < 0.01), IFN-γ (p < 0.05), NF-κB (p < 0.05) and significantly increased BDNF(p < 0.05) in the striatum and cortex of rat brain. The results further demonstrated that roflumilast effectively increased the gene expression of cAMP(p < 0.05), CREB(p < 0.05) and decreased the gene expression of PDE4 (p < 0.05) in qRT-PCR. These results conclusively depicted that roflumilast could be a potential candidate as an effective therapeutic agent in the management of HD through the cAMP/CREB/BDNF signaling pathway.

Sodium orthovanadate improves learning and memory in intracerebroventricular-streptozotocin rat model of Alzheimer's disease through modulation of brain insulin resistance induced tau pathology.

Sporadic Alzheimer's disease (sAD) is the most common type of dementia and progressive neurodegenerative disease. To establish the sAD model, intracerebroventricular (ICV) streptozotocin (STZ) at a dose of 3 mg/kg was administered bilaterally in rats on a stereotaxic apparatus. Behavioral tests such as Morris water maze (MWM), novel object recognition (NOR) and open field test were performed to evaluate cognitive and locomotor functions. Two treatment doses (5 mg/kg and 10 mg/kg) of sodium orthovanadate (SOV) and rivastigmine (2 mg/kg) were given orally to ICV-STZ induced rats for 21 days. Cortical and hippocampal tissues were dissected. Estimation of oxidative stress, mitochondrial dysfunction as complex I, II, III, IV activity, cholinergic function as acetylcholinesterase activity, ELISA for phosphorylated tau protein and insulin degrading enzyme (IDE), neuroinflammation as NF-κB gene expression and insulin signaling functioning as Q-RT-PCR for IR, IRS-1, PI3K, AKT, GSK-3ß gene expression were performed. Behavioral results with SOV and rivastigmine treatment revealed decreased escape latency and increased discrimination index in MWM and NOR respectively. Treatment results with SOV also demonstrated attenuation of oxidative imbalance, improved mitochondrial activity, and reversed IDE and tau pathology. SOV treatment upregulated gene expression of IR, IRS-1, PI3K, and AKT, and downregulated that of GSK-3ß. SOV results were compared with standard drug rivastigmine. Conclusively, the memory enhancement by SOV was mediated through oxidative balance, mitochondrial enzyme complex activation, and improved insulin signaling regulation. However, the primary mechanism of SOV remained attenuation of tau pathology by the upregulation of IRS-1/PI3K/AKT/GSK-3ß pathway and reversal of insulin resistance in terms of IDE. Hence, in sAD paradigm, SOV contributed to memory improvement evident with the findings of behavioral studies, which can further potentially have clinical significance in AD.

Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Its major pathological hallmarks, neurofibrillary tangles (NFT), and amyloid-ß plaques can result from dysfunctional insulin signaling. Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function, autophagy, oxidative stress, synaptic plasticity, and cognitive function. Insulin and its downstream signaling molecules are located majorly in the regions of cortex and hippocampus. The major molecules involved in impaired insulin signaling include IRS, PI3K, Akt, and GSK-3ß. Activation or inactivation of these major molecules through increased or decreased phosphorylation plays a role in insulin signaling abnormalities or insulin resistance. Insulin resistance, therefore, is considered as a major culprit in generating the hallmarks of AD arising from neuroinflammation and oxidative stress, etc. Moreover, caspases, Nrf2, and NF-κB influence this pathway in an indirect way. Various studies also suggest a strong link between Diabetes Mellitus and AD due to the impairment of insulin signaling pathway. Moreover, studies also depict a strong correlation of other neurodegenerative diseases such as Parkinson's disease and Huntington's disease with insulin resistance. Hence this review will provide an insight into the role of insulin signaling pathway and related molecules as therapeutic targets in AD and other neurodegenerative diseases.

Chromium picolinate attenuates cognitive deficit in ICV-STZ rat paradigm of sporadic Alzheimer's-like dementia via targeting neuroinflammatory and IRS-1/PI3K/AKT/GSK-3ß pathway.

Alzheimer's disease (AD) is prevalent in old age people and is one of the most common brain diseases. Brain insulin resistance, neuroinflammation, oxidative stress, and mitochondrial and cholinergic dysfunction are key features of the disease. In our study, streptozotocin (STZ) in a dose of 3 mg/kg was injected in male Wistar rats bilaterally through the intracerebroventricular (ICV) route on stereotaxic apparatus. Chromium picolinate (CrPic) was tested at doses of 1 mg/kg, 2 mg/kg, and 4 mg/kg, while rivastigmine (2 mg/kg) was used as reference standard drug. Cognitive dysfunction induced by STZ was assessed by behavioral tests like Morris water maze and novel object recognition test. Treatment with CrPic revealed attenuation of cognitive deficit. This was confirmed by behavioral tests, biochemical estimations of antioxidant enzymes, oxidative stress, nitrosative stress, and cholinergic and mitochondrial activity. CrPic did not change AchE activity significantly. STZ-induced neuroinflammation evident by increased TNF-α, IL-6, and CRP levels was also significantly decreased by CrPic. Dysfunctional insulin signaling after ICV-STZ was demonstrated by reduced IRS-1, PI3K, AKT, BDNF gene expression, and increased GSK-3ß, NF-κB gene expression with the help of qRT-PCR. CrPic treatment produced an improvement in insulin signaling revealed by increased gene expression of IRS-1, PI3-K, AKT, BDNF, and decreased gene expression of GSK-3ß and NF-κB. It was concluded that CrPic reversed AD pathology revealed by improved memory, reduced oxidative stress, neuroinflammation, mitochondrial dysfunction, and upregulated insulin signaling.

Pharmacological rewriting of fear memories: A beacon for post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a psychopathological response that develops after exposure to an extreme life-threatening traumatic event. Its prevalence ranges from 0.5% to 14.5% worldwide. Due to the complex pathophysiology of PTSD, currently available treatment approaches are associated with high chances of failure, thus further research to identify better pharmacotherapeutic approaches is needed. The traumatic event associated with fear memories plays an important role in the development of PTSD and could be considered as the main culprit. PTSD patient feels frightened in a safe environment as the memories of the traumatic event are revisited. Neurocircuit involving normal processing of fear memories get disturbed in PTSD hence making a fear memory to remain to dominate even after years of trauma. Persistence of fear memories could be explained by acquisition, re-(consolidation) and extinction triad as all of these processes have been widely explored in preclinical as well as clinical studies and set a therapeutic platform for fear memory associated disorders. This review focuses on neurocircuit and pathophysiology of PTSD in context to fear memories and pharmacological targeting of fear memory for the management of PTSD.

Co-treatment of piracetam with risperidone rescued extinction deficits in experimental paradigms of post-traumatic stress disorder by restoring the physiological alterations in cortex and hippocampus.

Pharmacotherapy and cognitive behavioral therapy, both fail to treat post-traumatic stress disorder (PTSD) in a considerable number of populations. The persistence of traumatic memories and deficit in extinction contributes to the failure of exposure therapy in PTSD. With the objective to enhance the outcomes of exposure therapy by targeting the extinction window using pharmacological agents in PTSD, the present study was aimed to explore the effect of piracetam, risperidone and their combinations in experimentally-induced PTSD-like phenotype in rats. Male SD rats were exposed to single prolonged stress model (SPS) for induction of PTSD-like behavioral changes. Piracetam, risperidone and their combination were used as therapeutic interventions while sertraline was used as a standard treatment for 14 days along with extinction training. Induction of PTSD-like behaviors were assessed in behavioral tests such as fear conditioning, elevated plus maze, social interaction test, and the marble burying test. Neurotransmitters (dopamine and serotonin and their metabolites), BDNF, proinflammatory cytokines (TNF-α, IL-6), caspase-3, and markers for oxidative stress were assessed in the hippocampus and cortex while corticosterone and nitrite levels were estimated in plasma. Our result indicated that the SPS paradigm efficiently induced PTSD-like phenotype in rats. Risperidone and piracetam were found to be effective alone, while their high dose combination, produced potentiating effect in reversing the extinction deficit, behavioral alterations, altered cortical and hippocampal BDNF, IL-6, TNF-α, caspase-3, oxidative stress markers, and neurotransmitter levels. Plasma corticosterone and nitrite levels were also found to be reversed in the combination treated groups. Our preliminary study suggests that piracetam, risperidone and their combination restored the physiological cascades in cortex and hippocampus along with successful suppression of fear memory and a symptom cluster of PTSD-like phenotype in rats. Hence they could be used as an effective adjunct to enhance the outcome of exposure therapy for the management of PTSD.

Alpha lipoic acid and metformin alleviates experimentally induced insulin resistance and cognitive deficit by modulation of TLR2 signalling.

BACKGROUND: Obesity is commonly found to be co-morbid with type 2 Diabetes Mellitus. In obese diabetic patients, TLR-2 receptor induced inflammation leads to the development of insulin resistance (IR). Furthermore, the IR is considered to be the most important cause for promoting cognitive decline which is evident in brain of patients with Alzheimer's disease related dementia (ADRD). METHODS: In this study, the effect of α-lipoic acid (ALA) has been examined in rodent model of zymosan induced insulin resistance and cognitive deficits, targeting at TLR-2 signalling. TLR-2 agonist, Zymosan initiates inflammatory cascade, resulting in IR and cognitive dysfunction. Zymosan (50 mg/kg ip) was given to mice on 1st, 8th, 15th and 22nd day to induce IR which was confirmed by hyperglycaemia, hyperinsulinemia, hyperlipidimea, increased glycated haemoglobin and HOMA-IR. Further the cognitive performance was assessed in Morris water maze revealing cognitive deficit in zymosan treated mice. RESULTS: Daily treatment with ALA for 28 days (50, 100, 200 mg/kg, ip) significantly improved insulin sensitivity and cognitive performance in mice by decreasing insulin resistance, corticosterone, IL-6 levels, acetylcholinesterase enzyme activity and oxidative stress in liver, cortex and hippocampus. ALA also increased adiponectin level and reduced body weight. Combination of ALA (100 mg/kg, ip) with metformin (100 mg/kg, ip) exhibited a potentiating effect in improving cognitive performance and insulin signalling. CONCLUSION: The findings of the study supported the hypothesis that TLR-2 induced inflammation leads to insulin resistance and cognitive impairment and provides an evidence for the therapeutic effect of ALA in IR and ADRD patients.

Synergistic action of ursolic acid and metformin in experimental model of insulin resistance and related behavioral alterations.

Chronic restraint stress (CRS) is known to cause metabolic and neurological complications in a number of ways. Prolonged exposure to stress evident by increased corticosterone level led to impaired altered insulin signaling and oxidative stress in mice, in the present study. Impaired insulin signaling or insulin resistance was characterized by hyperglycemia, hyperinsulinemia, hyperlipidemia, hypoadiponectinemia, increased glycosylated haemoglobin and HOMA-IR. It was also associated with increased proinflammatory cytokine TNF-α levels. CRS also caused significant increase in acetylcholinesterase activity and oxidative stress in brain along with cognitive impairment in behavioral test. Ursolic acid, metformin, gliclazide and their combinations when administered daily for 30 days significantly improved insulin sensitivity apart from behavioral and biochemical alterations in stressed mice. Treatment with drugs also decreased serum corticosterone and TNF-α levels. The findings of our study revealed that improvement in insulin sensitivity, learning and cognitive performance in stressed mice was attributed to attenuation of proinflammatory cytokines and oxidative stress. Moreover, combination of [Metformin (150 mg/kg) + Ursolic acid (10 mg/kg)] produced enhanced improvement in insulin sensitivity and cognitive impairment as compared to their individual effects, suggesting possibly the common mode of anti-inflammatory and antioxidant mechanisms.

Protective effect of losartan and ramipril against stress induced insulin resistance and related complications: Anti-inflammatory mechanisms.

Chronic restraint stress (CRS) is known to cause various behavioural and biochemical alterations, leading to several negative health outcomes. The present study was designed to explore the impact of inhibiting Renin angiotensin aldosterone system (RAAS) and inflammatory pathways in stress pathophysiology. In the present study, male LACA mice were subjected to restraint stress daily for 30 days. Losartan, nimesulide, ramipril, minocycline and their combinations were administered 45min prior to restraint stress daily and their effects were observed. Restraint stressed mice depicted depression like behavior along with increased oxidative stress markers in their brains. CRS induced insulin resistance depicted by hyperglycemia, hyperinsulinemia, hypercholesteremia, increased glycosylated hemoglobin and HOMA-IR. Besides, treatment with losartan, nimesulide, ramipril and minocycline significantly restored the behavioural and biochemical alterations and improved insulin sensitivity in stressed mice. Combination treatments synergistically reversed depression like behavior and decreased plasma glucose levels. Moreover they restored insulin levels, glycosylated hemoglobin levels and HOMA-IR values to the normal. This study signifies the synergistic effect of simultaneously blocking RAS and inflammatory pathways in stress pathophysiology.

Plausible anti-inflammatory mechanism of resveratrol and caffeic acid against chronic stress-induced insulin resistance in mice.

Stress is associated with many diseases and dysfunctions, such as depression, cardiovascular alterations, immunological function disorder, inflammation, obesity, and insulin resistance. Stress-induced inflammation is associated with the genesis of insulin resistance. Stress activates hypothalamic pituitary adrenal axis, Renin Angiotensin System pathway, and sympatho-adrenal system, all of which are involved in the production of cytokines, causing the negative downregulation of insulin signaling either by phosphorylating serine residues of IRS or by inhibiting the activity of Akt leading to insulin resistance. In this study, male LACA mice (20-30 g) were subjected to 2 h of chronic restraint stress daily for 30 days at variable time. Resveratrol, caffeic acid, glibenclamide, and their combinations were administered 45 min prior to restraint stress daily for 30 days and their anti-inflammatory effect was examined on CRS-induced behavioral, biochemical, and metabolic alterations. Induction of stress in mice was evident by increased corticosterone and decreased bodyweight. Chronic restraint stress for 30 days developed insulin resistance characterized by hyperglycemia, hyperinsulinemia, increased glycosylated haemoglobin (HbA1c), and homeostasis model assessment of insulin resistance index, hyperlipidemia, increased inflammatory cytokines, and TNF-α. Treatment with resveratrol, caffeic acid, and their combinations has attenuated stress-induced insulin resistance by reducing inflammation.

Animal models of insulin resistance: A review.

Insulin resistance can be seen as a molecular and genetic mystery, with a role in the pathophysiology of type 2 diabetes mellitus. It is a basis for a number of chronic diseases like hypertension, dyslipidemia, glucose intolerance, coronary heart disease, cerebral vascular disease along with T2DM, thus the key is to cure and prevent insulin resistance. Critical perspicacity into the etiology of insulin resistance have been gained by the use of animal models where insulin action has been modulated by various transgenic and non-transgenic models which is not possible in human studies. The following review comprises the pathophysiology involved in insulin resistance, various factors causing insulin resistance, their screening and various genetic and non-genetic animal models highlighting the pathological and metabolic characteristics of each.

Neuroprotective mechanism of losartan and its interaction with nimesulide against chronic fatigue stress.

Potential role of angiotensin-II and cyclooxygenase have been suggested in the pathophysiology of chronic fatigue stress. The present study has been designed to evaluate the neuroprotective effect of losartan and its interaction with nimesulide against chronic fatigue stress and related complications in mice. In the present study, male Laca mice (20-30 g) were subjected to running wheel activity test session (RWATS) for 6 min daily for 21 days. Losartan, nimesulide and their combinations were administered daily for 21 days, 45 min before being subjected to RWATS. Various behavioral and biochemical and neuroinflammatory mediators were assessed subsequently. 21 days RWATS treatment significantly decreased number of wheel rotations/6 min indicating fatigue stress like behaviors as compared to naive group. 21 days treatment with losartan (10 and 20 mg/kg, ip), nimesulide (5 and 10 mg/kg, po) and their combinations significantly improved behavior [increased number of wheel rotations, reversal of post-exercise fatigue, locomotor activity, antianxiety-like behavior (number of entries, latency to enter and time spent in mirror chamber), and memory performance (transfer latency in plus-maze performance task)], biochemical parameters (reduced serum corticosterone, brain lipid peroxidation, nitrite concentration, acetylcholinesterase activity, restored reduced glutathione levels and catalase activity) as compared to RWATS control. Besides, TNF-α, CRP levels were significantly attenuated by these drugs and their combinations as compared to control. The present study highlights the role of cyclooxygenase modulation in the neuroprotective effect of losartan against chronic fatigue stress-induced behavioral, biochemical and cellular alterations in mice.

Antidepressant-like action of the hydromethanolic flower extract of Tagetes erecta L. in mice and its possible mechanism of action.

OBJECTIVE: Tagetes erecta, the marigold, has commercial and ethnomedicinal use; however, reports concerning its efficacy for the treatment of depression are lacking. This study was carried out to elucidate the antidepressant effect of hydromethanolic flower extract of T. erecta. MATERIALS AND METHODS: Hydromethanolic extract of flowers of Tagetes erecta was subjected to preliminary phytochemical screening. The extract (12.5, 25, and 50 mg/kg, i.p.) was evaluated for antidepressant effect using forced swim test in mice. The mechanism of antidepressant action was further examined using different drugs and imipramine was used as standard drug. RESULTS: T. erecta significantly inhibited the immobility period in forced swim test in mice P<0.05). T. erecta (25 mg/kg, i.p.) enhanced the anti-immobility effect of antidepressant drugs like imipramine, fluoxetine, and p-chlorophenylalanine, an inhibitor of serotonin synthesis significantly attenuated its antidepressant effect. The antidepressant effect of T. erecta in the forced swim test was prevented by pretreatment with L-arginine and sildenafil, whereas pretreatment of mice with nitric oxide synthase inhibitors potentiated the action. Pentazocine, a high-affinity sigma receptor agonist, produced synergism with effective dose of T. erecta while progesterone, a sigma receptor antagonist, reversed the antidepressant effect of T. erecta. However, the locomotor activity was not affected at tested doses. CONCLUSIONS: Serotonergic, nitrergic pathway, and sigma receptors are possibly involved in mediating antidepressant action of T. erecta in mouse forced swim test.

Involvement of nitric oxide (NO) signalling pathway in the antidepressant activity of essential oil of Valeriana wallichii Patchouli alcohol chemotype.

Valeriana wallichii DC (Valerianaceae), popularly named as Indian valerian has been shown to exist as three chemotypes. The present study evaluated the antidepressant like effect of root essential oil of Valeriana wallichii patchouli alcohol chemotype in both acute and chronic treatment study using forced swim test (FST). Mice (n=6 per group) received 10, 20 and 40 mg/kg p.o. doses of test drug. Single administration of oil significantly inhibited the immobility period (57.6% and 46.9%) at doses 20 and 40 mg/kg respectively without changing the motor function (p<0.05). Similarly, daily administration of essential oil (20mg/kg) for 14 days significantly reduced the immobility period (69.9%) in FST (p<0.05). The neurotransmitter levels in mouse brain were estimated on day 14 after the behavioral study. Significant increase in the level of norepinephrine (29%) and serotonin (19%) (p<0.05) was found at 20mg/kg dose, while no change was observed at 10 and 40 mg/kg doses. The antidepressant-like effect of essential oil (20mg/kg) was prevented by pretreatment of mice with l-arginine (750 mg/kg i.p.) and sildenafil (5mg/kg i.p). On the contrary, pretreatment of mice with l-NAME (10mg/kg i.p.) or methylene blue (10mg/kg i.p.) potentiated the antidepressant action of essential oil (10mg/kg). Taken together, these findings demonstrated that nitric oxide pathway is involved in mediating antidepressant like effect of essential oil from this chemotype.