Synergistic Amelioration of Letrozole-induced Polycystic Ovary Syndrome in Rats: A Therapeutic Approach with Apple Cider Vinegar and Metformin Combination.

The present study was conducted to evaluate the combination effect of apple cider vinegar (ACV) and metformin against letrozole-induced polycystic ovary syndrome (PCOS). Female Wistar rats were administered letrozole (1 mg/kg/day, p.o) for 21 days, except for the control group of animals. On the 22nd day, PCOS-induced animals were segregated into 4 groups and administered with CMC, ACV, metformin, and a combination of ACV and metformin, respectively. The treatments were continued for 15 days, and on the 36th day, all the animals were sacrificed for biochemical (blood glucose, lipid profile), hormonal (sex hormones and adiponectin), and pro-inflammatory mediator estimations in blood samples. The ovarian tissue samples were used for oxidative stress parameters and histological alterations. The PCOS control animals showed a significant alteration in the estrous cycle. The administration of letrozole resulted in the alteration of hormonal balance and elevation of body weights, glycemic state, lipid profile, pro-inflammatory mediators in serum, and oxidative stress in ovarian samples. Individual treatment groups and combination treatment groups reversed the letrozole-induced alterations in PCOS animals, and more promising results were observed with combination therapy than with individual treatment groups. Further, the therapeutic potential of the combination treatment group was also confirmed by the histological observations in the ovarian samples. The study showed that the combination of ACV and metformin significantly alleviated letrozole-induced PCOS complications in rats. This might have been achieved by mitigating the hormonal imbalance, pro-inflammatory, hyperglycemic, and hyperlipidemic states in serum, and oxidative stress in the ovary samples.

Elevated Plus Maze for Assessment of Anxiety and Memory in Rodents.

The elevated plus maze is the most widely used paradigm to evaluate anxiety-associated behavioral alterations in rodent models of central nervous system (CNS) disorders. Unconditioned aversive behavior for open and elevated areas is a measure of anxiety and can be assessed by the plus maze. Plus maze consists of perpendicularly arranged open arms and closed arms crossed in the middle with a central platform. Rodents are allowed to explore the maze between the open and closed arms. The number of entries and time spent in the open arms and the closed arms are used as indicators for the anxiety nature of the animals. Transfer latency is a memory indicator that measures the amount of time it takes to move an animal from an open arm to a closed arm. This chapter describes the pretest conditions, materials required, and protocol for the conductance and evaluating the results for the anxiety and cognition-related behavior in rodents.

Tetramethylpyrazine contributes to the neuroprotection in a rodent epileptic model of pentylenetetrazole-induced kindling.

OBJECTIVES: In this study, tetramethylpyrazine (TMP) was evaluated for its therapeutic potential as an alternative therapy for epileptogenesis and its associated comorbidities in rats. METHODS: The sub-convulsant dose of pentylenetetrazole (PTZ) (35 mg/kg, intraperitoneally) was injected on alternative days to produce kindling for 32 days and observed for seizure score percent of kindled animals in each group. After kindling, the animals were evaluated in models of anxiety, memory and predictive of depression. The neuroprotective effect of TMP was assessed by estimating the biochemical parameters in the cortex and hippocampus of the brain. Histopathological alterations were also observed in the cortex and hippocampus (CA1, CA3 and DG). KEY FINDINGS: The administration of TMP reduced the seizure score and percentage of kindled animals dose-dependently. Furthermore, TMP significantly improved the behavioural parameters measured in the predictive models of depression but not in the anxiety and cognitive performances of the animals. The oxidative-nitrosative stress, excitotoxicity, neuroinflammation and histological alterations in the brain induced by PTZ were significantly mitigated by administering the TMP high dose of 60 mg/kg. CONCLUSION: In conclusion, the TMP attenuated the depression behaviour in the PTZ-induced kindled rats, and reduced the oxidative-nitrosative stress, excitotoxicity, neuroinflammation and histological alterations of the brain.

A prognostic study on the effect of post-traumatic stress disorder on cerebral ischaemia reperfusion-induced stroke.

OBJECTIVES: Previous studies have been established that persons who experienced a stroke are soon likely to develop several anxiety disorders. In which one of the major anxiety disorders is Post-traumatic Stress Disorder (PTSD). Yet, the likelihood of PTSD in conjunction with cerebral stroke has not been well described. Hence, we evaluated the impact of PTSD on cerebral stroke in rodents subjected to single prolonged stress (SPS) and bilateral common carotid artery occlusion (BCCAo), respectively. METHODS: The relation between PTSD and cerebral stroke is evaluated by performing behavioural, biochemical, histopathological, and brain lesion area measurement studies. RESULTS: Interestingly, SPS + BCCAo induction increased behavioural abnormalities like cognitive impairment and anxiety-like behaviour compared to SPS and BCCAo groups alone. Motor impairment was also observed in SPS + BCCAo rats compared to SPS rats, whereas no change with BCCAo rats. Furthermore, increased brain tissue MDA, acetylcholinesterase, and decreased SOD, catalase, and GSH were observed in SPS + BCCAo subjected rats compared to SPS and BCCAo rats alone. Additionally, SPS + BCCAo induction considerably increased the plasma corticosterone levels and caused severe neurotransmitter alterations. The SPS + BCCAo exposure significantly increased the brain lesion area in comparison with BCCAo rats. Moreover, severe histopathological alterations were observed in the hippocampus (CA1) of SPS + BCCAo rats compared to SPS and BCCAo rats alone. CONCLUSIONS: In conclusion, our study results suggested that SPS-induced PTSD may aggravate the BCCAo induced cerebral ischaemia-reperfusion injury.

Protective effects of duloxetine against chronic immobilisation stress-induced anxiety, depression, cognitive impairment and neurodegeneration in mice.

OBJECTIVES: This study aimed to evaluate the effect of duloxetine (10 and 20 mg/kg) against chronic immobilisation stress (CIS)-induced anxiety, depression, cognitive impairment and neurodegeneration in mice. METHODS: CIS, 2 h/10 days (11:00 AM-1:00 PM) was applied after 30 min of pretreatment with saline, duloxetine 10 mg/kg and 20 mg/kg to the respective groups of animals, except the control group. Animals were examined for physiological (body weight, locomotion and grip strength), psychological (memory impairment, anxiety and depression), neurochemical (GABA and glutamate), biochemical (MDA, catalase, glutathione, superoxide dismutase) and histopathological changes. KEY FINDINGS: CIS exposure revealed anxiety-like behaviour, depression-like behaviour, motor in-coordination and learning and memory impairment in mice. Besides, CIS induction decreased the antioxidant enzymes (GSH, SOD and catalase), GABA and the viable neuronal cell count, whereas CIS exposure significantly elevated the MDA, AChE activity and glutamate content in the cortex and hippocampus. Pretreatment with duloxetine10 and 20 mg/kg showed dose-dependent ameliorated effect against the CIS-induced alterations in mice. CONCLUSION: In conclusion, the results of this study demonstrated the protective effect of duloxetine against neuropsychiatric symptoms, memory impairment caused by CIS-induction through inhibition of oxidative stress, AChE activity and glutamate release.

COVID-19: molecular pathophysiology, genetic evolution and prospective therapeutics-a review.

The Covid-19 pandemic is highly contagious and has spread rapidly across the globe. To date there have been no specific treatment options available for this life-threatening disease. During this medical emergency, target-based drug repositioning/repurposing with a continuous monitoring and recording of results is an effective method for the treatment and drug discovery. This review summarizes the recent findings on COVID-19, its genomic organization, molecular evolution through phylogenetic analysis and has recapitulated the drug targets by analyzing the viral molecular machinery as drug targets and repurposing of most frequently used drugs worldwide and their therapeutic applications in COVID-19. Data from solidarity trials have shown that the treatment with Chloroquine, hydroxychloroquine and lopinavir-ritonavir had no effect in reducing the mortality rate and also had adverse side effects. Remdesivir, Favipiravir and Ribavirin might be a safer therapeutic option for COVID-19. Recent clinical trial has revealed that dexamethasone and convalescent plasma treatment can reduce mortality in patients with severe forms of COVID-19.

Coumarin-chalcone hybrids targeting insulin receptor: Design, synthesis, anti-diabetic activity, and molecular docking.

Four series of thirteen new coumarin-chalcone hybrids (DPCU 1-13, DPCT 1-13, DCCU 1-13 and DCCT 1-13) were designed and synthesized using Biginelli synthesis, Pechmann condensation, Acetylation, and Claisen-Schmidt reactions. Synthesized compounds were tested for insulin receptor in silico docking studies (PDB ID: 1IR3); DCCU 13 and DCCT 13 derivatives received the lowest docking score; Streptozocin (STZ) and Nicotinamide (NA) induced type II diabetes was tested for their anti-diabetic activity in rats. In vivo tests suggested that fasting blood glucose levels of animals treated with DCCU 13 (30 mg/kg body weight) and DCCT 13 (30 mg/kg body weight) were significantly and moderately suppressed, respectively, relative to fasting blood glucose levels of diabetic control animals. Similarly, therapy with DCCU 13 and DCCT 13 attenuated oxidative stress parameters such as lipid peroxidation (MDA), superoxide dismutase (SOD) and increased the glutathione (GSH) in the liver and pancreas in a dose-dependent manner. In comparison, therapy with DCCU 13 (30 mg/kg body weight) mitigated alterations in the histological architecture of the liver and pancreatic tissue. These results indicated that the hybrids DUUC 13 and DCCT 13 at 30 mg/kg had an anti-hyperglycemic and antioxidant impact on STZ + NA mediated type II diabetes in rats. Further detailed work could be required to determine the precise mode of action of the anti-diabetic behavior of hybrids.

Naringin in a combined therapy with phenytoin on pentylenetetrazole-induced kindling in rats.

Phenytoin (Dilantin) is an orally active, use-dependent voltage-gated sodium channel inhibitor and is a potent, economical, and widely used anticonvulsant agent. The objective of the present study was to investigate the effect of the combined treatment of naringin (40 mg/kg and 80 mg/kg) and phenytoin on prevention of seizure attacks, development of kindling, oxidative stress, cognitive impairment, and neurochemicals in the frontal cortex, temporal cortex, and hippocampus, and morphological changes in the hippocampus. Treatment with the high dose of naringin (80 mg/kg) along with phenytoin has shown to offer protection against seizures, development of kindling, and cognition enhancement through Y-maze test and improved % conditioned avoidance response (% CAR) through pole climbing test in pentylenetetrazole (PTZ)-induced kindling model. It has also been shown to improve neurochemical balance by elevating levels of Gamma amino butyric acid (GABA) and dopamine, decreasing levels of glutamate, oxidative biomarker (malondialdehyde (MDA)), and increasing levels of antioxidants (glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and total thiol and offered neuroprotection in the hippocampus. So, coadministration of naringin with phenytoin offers a potential treatment option for drug-resistant epilepsy and associated comorbidities. Interpretable research on flavonoids will support the clinical evidence for the recommendation of flavonoids as supplements with antiepileptic drugs (AEDs) for curtailing pharmacoresistant epilepsy and AED-associated comorbidities.

Neuroprotective activity of tetramethylpyrazine against 3-nitropropionic acid induced Huntington's disease-like symptoms in rats.

Huntington's disease (HD) is an autosomal neurodegenerative disease characterized by chorea, dystonia, motor ataxia, cognitive decline and psychiatric disorders with gradual loss of nerve cells and has no existing cure for the disease. In the present study, a mitochondrial toxin, 3-nitropropionic acid (3-NP) is used to induce HD like symptoms in rats. Tetramethylpyrazine is one of the active ingredients of Chuan Xiong which was reported to have neurotrophic and neuroprotective activities. The present study was designed to evaluate the role of TMP on 3-NP induced behavioral, biochemical, neurochemical, and histological alterations in the different regions of the brain. Animals were pretreated with normal saline/TMP for 7 days. From 8th day, the treatment groups were co-administered with 3-NP (10 mg/kg, i.p) and continued to the 21st day of the treatment protocol. At the end of the study, we found that the TMP improved all the behavioral performances of 3-NP induced neurotoxic rats, significantly. Further, oxidative stress parameters (lipid peroxidation, reduced glutathione, catalase, and superoxide dismutase), succinate dehydrogenase enzyme, and neurochemical (GABA and glutamate) estimations were done in the brain homogenate. In our study, the treatment with TMP ameliorated the 3-NP induced alterations, in the biochemical and neurochemical parameter in the brain homogenate, dose-dependently. The protective role of TMP further confirmed by measuring the lesion area with the 2,3,5-triphenyltetrazolium chloride staining of the brain slices and histopathological alteration in the hippocampus (CA1 and CA3) and striatal regions of the brain. Hence, the present findings suggest that the protective role of TMP against 3-NP induced behavioral, biochemical, neurochemical, and histological alterations in rats.

Effect of combination therapy with pramipexole and n-acetylcysteine on global cerebral ischemic reperfusion injury in rats.

OBJECTIVES: The study was intended to investigate the combined influence of two neuroprotective agents pramipexole and n-acetylcysteine on global cerebral ischemic reperfusion injury (GCIRI) model in rats. MATERIALS AND METHODS: GCIRI was induced by bilateral common carotid artery ligation (BCCA) in rats. Animals were divided into six groups. Groups I, II, and III received saline intraperitoneally (IP) (5 ml/kg/day, 0.9 % saline). The remaining groups IV, V, and VI were treated with n-acetylcysteine (NAC-150 mg/kg/day, IP), pramipexole (PPX-0.23 mg/kg/day, IP) alone and in combination, respectively. BCCA was done in all groups except in groups I (control) and II (sham control) of animals. The treatment was given for one week before the surgery and continued for two days after surgery. Subsequently, behavioral performances, biochemical estimations, proinflammatory cytokines, and histopathological evaluations were done. RESULTS: NAC, PPX, and combination treatment groups showed significant ameliorative effects on behavioral, biochemical, proinflammatory cytokines, and histopathological studies as compared with the BCCA group. Whereas, the combination group showed a significant difference in ameliorating the pathological changes of biochemical parameters and histopathological changes in comparison with the PPX alone treated group but not with the NAC alone group. CONCLUSION: The study concluded that in the combination treatment group the histopathological parameter improved and the oxidative stress parameters were mitigated significantly compared with the PPX alone treatment group but not with the NAC alone treatment group.