Neuroprotective potential of topiramate, pregabalin and lacosamide combination in a rat model of acute SE and intractable epilepsy: Perspectives from electroencephalographic, neurobehavioral and regional degenerative analysis.

The lithium-pilocarpine model is commonly used to recapitulate characteristics of human intractable focal epilepsy. In the current study, we explored the impact of topiramate (TPM) alone and in combination with pregabalin and lacosamide administration for 6 weeks on the evolution of spontaneous recurrent seizures (SRS) and disease-modifying potential on associated neuropsychiatric comorbidities. In addition, redox impairments and neurodegeneration in hippocampus regions vulnerable to temporal lobe epilepsy (TLE) were assessed by cresyl violet staining. Results revealed that acute electrophysiological (EEG) profiling of the ASD cocktail markedly halted sharp ictogenic spikes as well as altered dynamics of brain wave oscillations thus validating the need for polytherapy vs. monotherapy. In TLE animals, pharmacological intervention for 6 weeks with topiramate 10 mg/kg in combination with PREG and LAC at the dose of 20 mg/kg exhibited marked protection from SRS incidence, improved body weight, offensive aggression, anxiety-like behavior, cognitive impairments, and depressive-like behavior (p < 0.05). Moreover, combination therapy impeded redox impairments as evidenced by decreased MDA and AchE levels and increased activity of antioxidant SOD, GSH enzymes. Furthermore, polytherapy rescued animals from SE-induced neurodegeneration with increased neuronal density in CA1, CA3c, CA3ab, hilus, and granular cell layer (GCL) of the dentate gyrus. In conclusion, early polytherapy with topiramate in combination with pregabalin and lacosamide prompted synergy and prevented epileptogenesis with associated psychological and neuropathologic alterations.

Neuroprotective Effect of Brivaracetam and Perampanel Combination on Electrographic Seizures and Behavior Anomalies in Pentylenetetrazole-Kindled Mice.

Pentylenetetrazole (PTZ)-induced kindling is a broadly used experimental model to study the anticonvulsive potential of new and existing chemical moieties with the aim of discovering drugs hindering seizure progression and associated neurological comorbidities. In the present study, the impact of brivaracetam (BRV) (10 and 20 mg/kg) as monotherapy as well as in combination with 0.25 mg/kg of perampanel (PRP) was investigated on seizure progression with simultaneous electroencephalographic changes in PTZ kindling mouse model. Subsequently, mice were experimentally analyzed for anxiety, cognition, and depression after which their brains were biochemically evaluated for oxidative stress. The outcomes demonstrated that BRV alone delayed the kindling process, but BRV + PRP combination significantly (p < 0.0001) protected the mice from seizures of higher severity and demonstrated an antikindling effect. The PTZ-kindled mice exhibited anxiety, memory impairment, and depression in behavioral tests, which were remarkably less (p < 0.001) in animals treated with drug combination (in a dose-dependent manner) as these mice explored central, illuminated, and exposed zones of open-field test, light/dark box, and elevated plus maze. Moreover, memory impairment was demonstrated by kindled mice, which was significantly (p < 0.001) protected by BRV + PRP as animal's spontaneous alteration, object discrimination, and step-through latencies were increased in various tests employed for the assessment of cognitive abilities. The brains of PTZ-kindled mice had increased malondialdehyde and reduced antioxidant enzymes while treatment with BRV + PRP combination prevented kindling-induced elevation in oxidative markers. The outcomes of this study demonstrate that combining the PRP at low dose augmented the antiseizure properties of BRV as both drugs when administered simultaneously hindered the process of kindling by reducing PTZ-induced excessive electrical activity and oxidative stress in the brain.

Investigating clinical pharmacokinetics of brivaracetam by using a pharmacokinetic modeling approach.

The development of technology and the processing speed of computing machines have facilitated the evaluation of advanced pharmacokinetic (PK) models, making modeling processes simple and faster. The present model aims to analyze the PK of brivaracetam (BRV) in healthy and diseased populations. A comprehensive literature review was conducted to incorporate the BRV plasma concentration data and its input parameters into PK-Sim software, leading to the creation of intravenous (IV) and oral models for both populations. The developed physiologically based pharmacokinetic (PBPK) model of BRV was then assessed using the visual predictive checks, mean observed/predicted ratios (Robs/pre), and average fold error for PK parameters including the maximum systemic concentration (Cmax), the area under the curve at time 0 to t (AUC0-∞), and drug clearance (CL). The PBPK model of BRV demonstrated that mean Robs/pre ratios of the PK parameters remained within the acceptable limits when assessed against a twofold error margin. Furthermore, model predictions were carried out to assess how AUC0-∞ is affected following the administration of BRV in individuals with varying degrees of liver cirrhosis, ranging from different child-pugh (CP) scores like A, B, and C. Moreover, dose adjustments were recommended by considering the variations in Cmax and CL in various kidney disease stages (mild to severe).

Correction: Zaman et al. Synthesis and Evaluation of Thiol-Conjugated Poloxamer and Its Pharmaceutical Applications. Pharmaceutics 2021, 13, 693.

In the original publication, there was a mistake in one author name, Mohammed Alasmari should be Mohammed S [...].

Ameliorative effect of Nyctanthes arbor-tristis L. by suppression of pentylenetetrazole-induced kindling in mice: An insight from EEG, neurobehavioral and in-silico studies.

Epilepsy is an abiding condition associated with recurrent seizure attacks along with associated neurological and psychological emanation owing to disparity of excitatory and inhibitory neurotransmission. The current study encompasses the assessment of the Nyctanthes arbor-tristis L. methanolic extract (Na.Cr) in the management of convulsive state and concomitant conditions owing to epilepsy. The latency of seizure incidence was assessed using pentylenetetrazol (PTZ) kindling models along with EEG in Na.Cr pretreated mice, trailed by behavior assessment (anxiety and memory), biochemical assay, histopathological alterations, chemical profiling through GCMS, and molecular docking. The chronic assessment of PTZ-induced kindled mice depicted salvation in a dose-related pattern and outcomes were noticeable with extract at 400 mg/kg. The extract at 400 mg/kg defends the progress of kindling seizures and associated EEG. Co-morbid conditions in mice emanating owing to epileptic outbreaks were validated by behavioral testing and the outcome depicted a noticeable defense related to anxiety (P<0.001) and cognitive deficit (P<0.001) at 400 mg/kg. The isolated brains were evaluated for oxidative stress and the outcome demonstrated a noticeable effect in a dose-dependent pattern. Treatment with Na.Cr. also preserved the brain from PTZ induced neuronal damage as indicated by histopathological analysis. Furthermore, the GCMS outcome predicted 28 compounds abundantly found in the plant. The results congregated in the current experiments deliver valued evidence about the defensive response apportioned by Na.Cr which might be due to decline in oxidative stress, AChE level, and GABAergic modulation. These activities may contribute to fundamental pharmacology and elucidate some mechanisms behind the activities of Nyctanthes arbor-tristis.

Exploring the pharmacokinetics of second-generation cephalosporin, cefaclor: a systematic review in healthy and diseased populations.

Cefaclor is a bactericidal antibiotic recommended for treating diverse types of infections. This review aims to comprehensively assess the pharmacokinetic (PK) data on cefaclor in humans.Google Scholar, PubMed, Cochrane Library, and EBSCO databases were systematically performed to identify all the relevant studies containing at least one reported PK parameter of cefaclor.Cefaclor shows the linear PK profile as the area under the plasma concentration-time curve from 0 to t (AUC0-t) and maximum plasma concentration (Cmax) increase in a dose-dependent manner. The AUC0-t of cefaclor in the rice diet was found to be higher than that of bread food, i.e. 19.9 ± 2.6 ug/ml.hr vs 15.4 ± 4 ug/ml.hr. The AUC in paediatrics during the fed state was significantly higher compared to that in adults. Patients with renal impairments showed a Cmax 2.2 times higher than that of normal subjects. A significant increase in Cmax was depicted among individuals following a vegetarian diet in comparison with the non-vegetarian diet. Moreover, cefaclor exhibits time-dependent killing above the minimum inhibitory concentration (MIC < 2 ug), favouring its use in treating infections caused by specific pathogens.This systematic review summarises all the reported PK parameters of cefaclor in healthy and diseased subjects in the literature. This data can help practitioners in adjusting cefaclor doses among different diseases and populations to avoid drug interactions and adverse effects.

A Comprehensive Physiologically Based Pharmacokinetic Model of Nadolol in Adults with Renal Disease and Pediatrics with Supraventricular Tachycardia.

Nadolol is a long-acting non-selective ß-adrenergic antagonist that helps treat angina and hypertension. The current study aimed to develop and validate the physiologically based pharmacokinetic model (PBPK) of nadolol in healthy adults, renal-compromised, and pediatric populations. A comprehensive PBPK model was established by utilizing a PK-Sim simulator. After establishing and validating the model in healthy adults, pathophysiological changes i.e., blood flow, hematocrit, and GFR that occur in renal failure were incorporated in the developed model, and the drug exposure was assessed through Box plots. The pediatric model was also developed and evaluated by considering the renal maturation process. The validation of the models was carried out by visual predictive checks, calculating predicted to observed (Rpre/obs) and the average fold error (AFE) of PK parameters i.e., the area under the concentration-time curve (AUC0-t), the maximum concentration in plasma (Cmax), and CL (clearance). The presented PBPK model successfully simulates the nadolol PK in healthy adults, renal-impaired, and pediatric populations, as the Rpre/obs values of all PK parameters fall within the acceptable range. The established PBPK model can be useful in nadolol dose optimization in patients with renal failure and children with supraventricular tachycardia.

A Systematic Critical Review of Clinical Pharmacokinetics of Torasemide.

PURPOSE: Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen. METHODS: Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178). RESULTS: A decrease in maximum plasma concentration (C max ) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration-time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC 0-∞ that is, 42.9 versus 8.091 mcg.h -1 .mL -1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC 0-∞ of torasemide, whereas losartan and empagliflozin did not. CONCLUSIONS: The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug-drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases.

Perampanel increases seizure threshold in pentylenetetrazole-kindled mice and improves behavioral dysfunctions by modifying mRNA expression levels of BDNF/TrkB and inflammatory markers.

Perampanel (PER), a novel 3rd-generation antiseizure drug that modulates altered post-synaptic glutamatergic storming by selectively inhibiting AMPA receptors, is recently approved to treat intractable forms of seizures. However, to date, presumably consequences of long-term PER therapy on the comorbid deleterious psychiatric disturbances and its correlation with neuroinflammatory parameters are not fully investigated in chronic models of epilepsy. Therefore, we investigated the real-time effect of PER on brain electroencephalographic (EEG) activity, behavioral alterations, redox balance, and relative mRNA expression in pentylenetetrazole (PTZ) induced kindling. Male BALB/c mice were pretreated with PER (0.125, 0.25, and 0.5 mg/kg) for 3 weeks and challenged with 11 injections of PTZ at the sub-threshold dose of 40 mg/kg every other day. vEEG from implanted cortical electrodes was monitored to elucidate seizure propagation and behavioral manifestations. Recorded EEG signals exhibited that PER 0.5 mg/kg pretreatment exceptionally impeded the onset of sharp epileptic spike-wave discharges and associated motor symptoms. Additionally, qEEG analysis showed that PER prevented alterations in absolute mean spectral power and reduced RMS amplitude of epileptogenic spikes vs PTZ control. Furthermore, our outcomes illustrated that PER dose-dependently attenuated PTZ-evoked anxiety-like behavior, memory deficits, and depressive-like behavior that was validated by a series of behavioral experiments. Moreover PER, significantly reduced lipid peroxidation, AChE, and increased levels of SOD and total thiol in the mice brain via AMPAR antagonism. Post-PTZ kindling provoked overstimulation of BDNF/TrkB signaling and increased release of pro-inflammatory cytokines that were reversed by PER with suppression of iNOS in brain immune cells. In conclusion, our findings highlight that PER might play an auspicious preventive role in the proepileptic transformation of brain circuits via suppression of BDNF/TrkB signaling and reduced transcriptional levels of neuroinflammatory markers leading to improvised epilepsy-induced neurobehavioral and neurochemical effects.

Therapeutic benefits of quercetin in traumatic brain injury model exposed to cigarette smoke.

Scientific evidences reported the deleterious effect of cigarette smoking or passive smoking on brain health particularly cognitive functions, blood-brain barrier (BBB) permeability, up-regulation of inflammatory cascades, and depletion of the antioxidant system. These combined effects become more progressive in the events of stroke, traumatic brain injury (TBI), and many other neurodegenerative diseases. In the current study, we investigated the long-term administered therapeutic potential of quercetin in ameliorating the deleterious neurobiological consequences of chronic tobacco smoke exposure in TBI mice. After exposure to 21 days of cigarette smoke and treatment with 50 mg/kg of quercetin, C57BL/6 mice were challenged for the induction of TBI by the weight drop method. Subsequently, a battery of behavioral tests and immunohistochemical analyses revealed the beneficial effect of quercetin on the locomotive and cognitive function of TBI + smoked group mice (p < 0.05 vs control sham). Immunohistochemistry analysis (Nrf2, HO-1, NFkB, caspase 3) demonstrated a marked protection after 21 days of quercetin treatment in the chronic tobacco smoking group possibly by up-regulation of antioxidant pathways, and decreased apoptosis. In conclusion, our findings support the therapeutic effectiveness of quercetin in partly protecting the central neurological functions that become aberrantly impaired in combined habitual cigarette-smoking individuals impacted with TBI.

Unveiling the potential of perampanel and pregabalin in addressing pentylenetetrazole-induced electrographic alterations and neurobehavioral anomalies.

Chemical kindling is broadly used experimental model to investigate novel treatments on the process of epileptogenesis and coexisting behavioral comorbidities. The current study aimed to investigate the low dose perampanel (PER) (0.125 and 0.5 mg/kg) and pregabalin (PG) (15 mg/kg) as standalone treatments and in combination on kindling-induced seizure progression with concurrent electroencephalographic alterations. Mice were subjected to pentylenetetrazole (PTZ)-induced kindling followed by neurobehavioral assessment for anxiety-like activity and cognitive deficit through behavioral experiments. The monotherapy with PER at 0.5 mg/kg and PG at 15 mg/kg delayed the kindling process but PRP+PG yielded pronounced benefits and hindered the development of seizures of higher severity. PER+PG combination relieved the animals from anxiety-like behavior in various employed anxiogenic tests. Furthermore, the kindling-associated cognitive deficit was protected by PER+PG combination as increased alteration behavior, discrimination index and latencies to enter the dark zone were noted in y-maze, object recognition and passive avoidance tests, respectively while shorter escape latencies were noted in water maze. The brain samples of kindled mice had elevated malondialdehyde and reduced catalase, superoxide dismutase and glutathione peroxidase enzymes while treatment with PER and PG combination shielded the mice from heightened kindling-associated oxidative stress. Overall, the findings of the present study illustrate that concurrent administration of PER and PG effectively hindered the process of epileptogenesis by protecting neuronal excitability and brain oxidative stress. The results predict the dominance of PER and PG combination over monotherapy which might serve as an effective novel combination to combat drug resistance and behavioral disorders in epileptic patients.

Protective effects of niacin following high fat rich diet: an in-vivo and in-silico study.

Niacin had long been understood as an antioxidant. There were reports that high fat diet (HFD) may cause psychological and physical impairments. The present study was aimed to experience the effect of Niacin on % growth rate, cumulative food intake, motor activity and anxiety profile, redox status, 5-HT metabolism and brain histopathology in rats. Rats were administered with Niacin at a dose of 50 mg/ml/kg body weight for 4 weeks following normal diet (ND) and HFD. Behavioral tests were performed after 4 weeks. Animals were sacrificed to collect brain samples. Biochemical, neurochemical and histopathological studies were performed. HFD increased food intake and body weight. The exploratory activity was reduced and anxiety like behavior was observed in HFD treated animals. Activity of antioxidant enzymes was decreased while oxidative stress marker and serotonin metabolism in the brain of rat were increased in HFD treated animals than ND fed rats. Morphology of the brain was also altered by HFD administration. Conversely, Niacin treated animals decreased food intake and % growth rate, increased exploratory activity, produced anxiolytic effects, decreased oxidative stress and increased antioxidant enzyme and 5-HT levels following HFD. Morphology of brain is also normalized by the treatment of Niacin following HFD. In-silico studies showed that Niacin has a potential binding affinity with degradative enzyme of 5-HT i.e. monoamine oxidase (MAO) A and B with an energy of ~ - 4.5 and - 5.0 kcal/mol respectively. In conclusion, the present study showed that Niacin enhanced motor activity, produced anxiolytic effect, and reduced oxidative stress, appetite, growth rate, increased antioxidant enzymes and normalized serotonin system and brain morphology following HFD intake. In-silico studies suggested that increase 5-HT was associated with the binding of MAO with Niacin subsequentially an inhibition of the degradation of monoamine. It is suggested that Niacin has a great antioxidant potential and could be a good therapy for the treatment of HFD induced obesity.

Demaghi, a polyherbal formulation, mitigates aluminum chloride-induced neurological impairment in mice: Insights from phytochemical analysis and behavioral assessment.

Herbal products have been very popular in Pakistan for their curative significance against various disorders. Demaghi (DEMG) is a widely used herbal product claimed to own natural substances having neuroprotective potential. The current study aims to scientifically validate the chemical composition as well as its neuroprotective claims of this widely used herbal tonic. The commercially available Demaghi product was chemically characterized for its phytocomposition. The mice were treated with two doses of Demaghi (DEMG 50 mg and 100 mg/kg/day), and the effects of its prolonged exposure on animal anxiety, memory, and depression were noted through a series of behavioral tests in the AlCl3-induced memory deficient mice model. Besides that, dissected brains were biochemically analyzed for oxidative stress markers and acetylcholinesterase activity, as well as histopathological changes. The study outcomes showed that DEMG (100 mg/kg/day) has prominent anti-anxiety effects, memory-enhancing properties, and anti-depressants effects observed in the AlCl3-induced memory-deficient mice model. Biochemical assays also showed a greater decrease in oxidative stress of tested animals treated with 100 mg/kg/day of DEMG. The histopathological analysis also revealed that administration of DEMG reduced the AlCl3-induced toxicity. UPLC-MS results revealed the presence of many phytoconstituents, which showed to support cholinergic signaling in in-silico studies. The current research validates the neurological benefits of Demaghi for memory-boosting properties. The phytocompounds present in Demaghi exert neuroprotective effects, possibly by enhancing the cholinergic neurotransmission and combating the neurotoxin-induced oxidative stress.

A systematic review on the clinical pharmacokinetics of vildagliptin in healthy and disease populations.

INTRODUCTION: Vildagliptin, a dipeptidyl peptidase-4 inhibitor, is indicated to cure type 2 diabetes mellitus (T2DM). This systematic literature search aims to assess the current knowledge about the clinical pharmacokinetics (PK) of vildagliptin to provide recommendations for clinical use to prevent the harmful effects of this drug. METHODS: The PubMed, Science Direct, EBSCO, Cochrane Central Register of Controlled Trials, and Google Scholar databases were screened for articles related to the clinical PK of vildagliptin using systematic search strategies. RESULTS: The literature search identified 2118 records, among which 28 were subsumed in this systematic review that fulfilled the inclusion standards. CONCLUSIONS: This systematic review can help dose optimization among critically ill patients (e.g. renal impairment) without exposing them to the drug's toxic effects.

Clinical pharmacokinetics of nebivolol: a systematic review.

Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC0-∞) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (Cmax) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher Cmax, AUC0-∞ and half-life (t1/2) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.

Physiologically Based Pharmacokinetic Model To Predict Metoprolol Disposition in Healthy and Disease Populations.

The evolution in the development of drugs has increased the popularity of physiologically based pharmacokinetic (PBPK) models. This study seeks to assess the PK of metoprolol in populations with healthy, chronic kidney disease (CKD), and acute myocardial infarction (AMI) conditions by developing and evaluating PBPK models. An extensive literature review for identifying and selecting plasma concentration vs time profile data and other drug-related parameters was undergone for their integration into the PK-Sim program followed by the development of intravenous, oral, and diseased models. The developed PBPK model of metoprolol was then evaluated using the visual predictive checks, mean observed/predicted ratios (Robs/pre), and average fold error for all PK parameters, i.e., the area under the curve (AUC), maximal plasma concentration, and clearance. The model evaluation depicted that none of the PK parameters were out of the allowed range (2-fold error) in the case of the mean Robs/pre ratios. The model anticipations were executed to determine the influence of diseases on unbound and total AUC after the application of metoprolol in healthy, moderate, and severe CKD. The dosage reductions were also suggested based on differences in unbound and total AUC in different stages of CKD. The developed PBPK models have successfully elaborated the PK changes of metoprolol occurring in healthy individuals and those with renal and heart diseases (CKD & AMI), which may be fruitful for dose optimization among diseased patients.

A physiologically based pharmacokinetic model of cefepime to predict its pharmacokinetics in healthy, pediatric and disease populations.

The physiologically based pharmacokinetic modeling (PBPK) approach can predict drug pharmacokinetics (PK) by combining changes in blood flow and pathophysiological alterations for developing drug-disease models. Cefepime hydrochloride is a parenteral cephalosporin that is used to treat pneumonia, sepsis, and febrile neutropenia, among other things. The current study sought to identify the factors that impact cefepime pharmacokinetics (PK) following dosing in healthy, diseased (CKD and obese), and pediatric populations. For model construction and simulation, the modeling tool PK-SIM was utilized. Estimating cefepime PK following intravenous (IV) application in healthy subjects served as the primary step in the model-building procedure. The prediction of cefepime PK in chronic kidney disease (CKD) and obese populations were performed after the integration of the relevant pathophysiological changes. Visual predictive checks and a comparison of the observed and predicted values of the PK parameters were used to verify the developed model. The results of the PK parameters were consistent with the reported clinical data in healthy subjects. The developed PBPK model successfully predicted cefepime PK as observed from the ratio of the observed and predicted PK parameters as they were within a two-fold error range.

Conocarpus lancifolius (Combretaceae): Pharmacological Effects, LC-ESI-MS/MS Profiling and In Silico Attributes.

In folklore medicine, Conocarpus lancifolius is used to treat various illnesses. The main objective of this study was a comprehensive investigation of Conocarpus lancifolius leaf aqueous extract (CLAE) for its antioxidant, cardioprotective, anxiolytic, antidepressant and memory-enhancing capabilities by using different in vitro, in vivo and in silico models. The in vitro experimentation revealed that CLAE consumed an ample amount of total phenolics (67.70 ± 0.15 µg GAE/mg) and flavonoids (47.54 ± 0.45 µg QE/mg) with stronger antiradical effects through DPPH (IC50 = 16.66 ± 0.42 µg/mL), TAC (77.33 ± 0.41 µg AAE/mg) and TRP (79.11 ± 0.67 µg GAE/mg) assays. The extract also displayed suitable acetylcholinesterase (AChE) inhibitory (IC50 = 110.13 ± 1.71 µg/mL) activity through a modified Ellman's method. The toxicology examination presented no mortality or any signs of clinical toxicity in both single-dose and repeated-dose tests. In line with the cardioprotective study, the pretreatment of CLAE was found to be effective in relieving the isoproterenol (ISO)-induced myocardial injury in rats by normalizing the heart weight index, serum cardiac biomarkers, lipid profile and various histopathological variations. In the noise-stress-induced model for behavior attributes, the results demonstrated that CLAE has the tendency to increase the time spent in the central zone and elevated open arms in the open field and elevated plus maze tests (examined for anxiety assessment), reduced periods of immobility in the forced swimming test (for depression) and improved recognition and working memory in the novel object recognition and Morris water maze tests, respectively. Moreover, the LC-ESI-MS/MS profiling predicted 53 phytocompounds in CLAE. The drug-likeness and ADMET analysis exhibited that the majority of the identified compounds have reasonable physicochemical and pharmacokinetic profiles. The co-expression of molecular docking and network analysis indicated that top-ranked CLAE phytoconstituents act efficiently against the key proteins and target multiple signaling pathways to exert its cardiovascular-protectant, anxiolytic, antidepressant and memory-enhancing activity. Hence, this artifact illustrates that the observed biological properties of CLAE elucidate its significance as a sustainable source of bioactive phytochemicals, which appears to be advantageous for pursuing further studies for the development of new therapeutic agents of desired interest.

Mitigation of behavioral deficits and cognitive impairment by antioxidant and neuromodulatory potential of Mukia madrespatana in D-galactose treated rats.

Plants and their parts have been extensively used for the therapeutic purposes such as aging due to their powerful antioxidative belongings. Presently, we intended to examine the consequence of fruit peel of Mukia madrespatana (M.M) on D-galactose (D-Gal) persuaded anxiety and/or depression profile, cognition and serotonin metabolism in rats. Animals were divided in to 4 groups (n = 6). (i) Water treated (ii) D-Gal treated (iii) M.M. treated (iv) D-Gal + M.M. treated. All the animals received their respective treatment for 4 weeks. D-Gal and M.M. fruit peel were given to animals with oral gavage with doses 300 mg/ml/kg/day and 2 g/kg/day respectively. After 4 weeks' behavioral analysis performed to evaluate anxiety and depression profile, cognitive function of animals. After that animals were sacrificed and whole brain removed for biochemical (redox status, degradative enzyme of acetylcholine), and neurochemical (serotonin metabolism) analysis. Results showed that administration of M.M. inhibited D-Gal-instigated anxious and depressive behaviors and improved cognition. Treatment of M.M. decreased MDA levels, AChE activity and increased antioxidant enzyme activity in D-Gal administered and control rats. Enhanced serotonin metabolism also decreased by M.M. in control and D-Gal administered rats. In conclusion, M.M. fruit peel has powerful antioxidative and neuromodulatory properties and due to this effect, it may be a good source of mitigation/treatment for aging induced behavioral and cognitive impairment.