Rajesh Kumar Goel

Mechanisms pertaining to arsenic toxicity

Arsenic is an environmental pollutant and its contamination in the drinking water is considered as a serious worldwide environmental health threat. The chronic arsenic exposure is a cause of immense health distress as it accounts for the increased risk of various disorders such as cardiovascular abnormalities, diabetes mellitus, neurotoxicity, and nephrotoxicity. In addition, the exposure to arsenic has been suggested to affect the liver function and to induce hepatotoxicity. Moreover, few studies demonstrated the induction of carcinogenicity especially cancer of the skin, bladder, and lungs after the chronic exposure to arsenic. The present review addresses diverse mechanisms involved in the pathogenesis of arsenic-induced toxicity and end-organ damage.

Traditional uses, phytochemistry and pharmacology of Ficus religiosa: a review.

ETHNOPHARMACOLOGICAL RELEVANCE Ficus religiosa L. (Moraceae) has been extensively used in traditional medicine for a wide range of ailments of the central nervous system, endocrine system, gastrointestinal tract, reproductive system, respiratory system and infectious disorders. AIM OF THE REVIEW To comprehend the fragmented information available on the botany, traditional uses, phytochemistry, pharmacology and toxicology of F. religiosa to explore its therapeutic potential and future research opportunities. MATERIALS AND METHODS All the available information on F. religiosa was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar, Agricola and Web of Science) and a library search. RESULTS Ethnomedical uses of F. religiosa are recorded throughout South Asia, where it has been used for about 50 types of disorders. Phytochemical research had led to the isolation of phytosterols, amino acids, furanocoumarins, phenolic components, hydrocarbons, aliphatic alcohols, volatile components and few other classes of secondary metabolites from F. religiosa. Fresh plant materials, crude extracts and isolated components of F. religiosa showed a wide spectrum of in vitro and in vivo pharmacological activities like, antidiabetic, cognitive enhancer, wound healing, anticonvulsant, anti-inflammatory, analgesic, antimicrobial, antiviral, hypolipidemic, antioxidant, immunomodulatory, antiasthmatic, parasympathetic modulatory, esterogenic, antitumor, antiulcer, antianxiety, antihelmintic, endotheilin receptor antagonistic, apoptosis inducer and hypotensive. CONCLUSIONS F. religiosa emerged as a good source of traditional medicine for the treatment of asthma, diabetes, diarrhea, epilepsy, gastric problems, inflammatory disorders, infectious disorders and sexual disorders. Although many of the experimental studies validated its traditional medicinal uses, but employed uncharacterized crude extracts. Thus, it is difficult to reproduce the results and pinpoint the bioactive metabolite. Hence, there is a need of phytochemical standardization and bioactivity-guided identification of bioactive metabolites. The results of few pharmacological studies and bioactive metabolites already reported in F. religiosa warrant detailed investigation for its potential against cancer, cardiovascular disorders, neuroinflammatory disorders, neuropsychiatric disorders, oxidative stress related disorders and parasitic infections. The outcome of these studies will further expand the existing therapeutic potential of F. religiosa and provide a convincing support to its future clinical use in modern medicine.

Anticonvulsant effect of Ficus religiosa: role of serotonergic pathways.

ETHNOPHARMACOLOGICAL RELEVANCE Ficus religiosa (Moraceae) is reported to have numerous therapeutic utility in folk medicine. Among different biological activities on central nervous system, it has been reported to be used in ethnomedical treatment of epilepsy, which led us to further explore its anticonvulsant activity in various animal models of epilepsy. AIM OF THE STUDY To investigate anticonvulsant activity of methanolic extract of figs of Ficus religiosa in animal models and to determine its possible anticonvulsant mechanism. MATERIALS AND METHODS Anticonvulsant activity of figs extract (25, 50 and 100 mg/kg, i.p.) was studied in seizures induced by maximum electroshock (MES), picrotoxin and pentylenetetrazol (PTZ). Cyproheptadine, a nonselective (5HT(1/2)) serotonin antagonist (4 mg/kg, i.p.) was used to study the reversal of protective effect of extract in the above mentioned models. Acute toxicity, neurotoxicity and potentiation of pentobarbitone induced sleep by extract was also studied. RESULTS Extract showed no toxicity, potentiated pentobarbitone induced sleep and inhibited seizures induced by MES and picrotoxin in a dose dependent manner. Anticonvulsant effect of extract was comparable to clinically used antiepileptic drugs (phenytoin and diazepam). However, PTZ induced seizures were not inhibited. Animals pretreated with cyproheptadine showed inhibition of the anticonvulsant effect of extract. CONCLUSIONS These findings suggested that the methanolic extract of figs of Ficus religiosa had anticonvulsant activity against MES and picrotoxin induced convulsions, with no neurotoxic effect, in a dose dependent manner. Inhibition of the anticonvulsant effect of extract by cyproheptadine substantiates the involvement of serotonergic pathways for the anticonvulsant activity of extract.

Ameliorative effect of Curcumin on seizure severity, depression like behavior, learning and memory deficit in post-pentylenetetrazole-kindled mice

Epilepsy is a chronic neurological disorder and generally associated with certain psychiatric comorbidities. Among several comorbidities depressive behavior and cognitive impairment has been reported to be most debilitating comorbidity associated with epilepsy. This study was envisaged to evaluate the ameliorative effect of Curcumin on depression like behavior and cognitive impairment observed in pentylenetetrazole kindled animals. Male Swiss Albino mice were kindled with subconvulsive dose of pentylenetetrazole (35 mg/kg, i.p.). Successfully kindled animals were used in the study to observe the effect of different treatments. Treatment groups received phenytoin (30 mg/kg) and Curcumin (50, 100 and 200mg/kg) for 15 days. The animals were challenged with pentylenetetrazole (35 mg/kg, i.p.) on day 5, 10 and 15 and seizure severity score, immobility period, number of mistakes and step down latency were recorded. On 15th day, all the animals were sacrificed after behavioral evaluations and their brain was isolated and homogenized to estimate brain norepinephrine, serotonin, total nitrite level and acetylcholinesterase activity. Phenytoin treatment significantly improved the depressive like behavior along with its anticonvulsant effect, however was unable to improve memory impairment. Curcumin significantly attenuated seizure severity, depression like behavior and memory impairment in kindled animals, in dose dependent manner. These results were supported by the biochemical modulation of brain monoamine, nitrosative stress level and acetylcholinesterase activity. Thus present study concluded that Curcumin has the ameliorative effect on seizure severity, depression like behavior and memory impairment in pentylenetetrazole kindled mice, possibly via central monoaminergic modulation and inhibitory effect on nitrosative stress and acetylcholinesterase activity.

Dual protective effect of Passiflora incarnata in epilepsy and associated post-ictal depression

ETHNOPHARMACOLOGICAL RELEVANCE Passiflora incarnata L. (Passifloraceae) has been used for the treatment of epilepsy in several traditional systems of medicine. AIM OF THE STUDY The aerial parts of Passiflora incarnata contain multiple bioactive metabolites such as, flavonoids (like, chrysin that show CNS depressant activity by agonizing GABA-benzodiazepine receptor), amino acids (like, GABA), harmala alkaloids (reversible monoamine oxidase-A inhibitor), etc. In view of this, the present study was designed to investigate dual protective effect of the hydroethanolic extract of Passiflora incarnata in pentylenetetrazol (PTZ)-induced seizure and associated post-ictal depression. MATERIALS AND METHODS Different groups of mice were administered with repeated subconvulsive doses of PTZ (50mg/kg; i.p.) at an interval of 5 days for 15 days. From 5th to 15th day the animals in different groups were administered daily with varying doses of hydroethanolic extract of Passiflora incarnata (150, 300, and 600mg/kg; i.p.), diazepam (2mg/kg; i.p.) and vehicle. On every 5th day, after PTZ treatment, seizure severity (score) was noted. Following convulsive episodes the locomotor activity (using actophotometer) and immobility period (using forced swim test) were also determined. On 15th day after behavioral assessment, the brain serotonin and noradrenaline levels were determined using spectrofluorometric methods. RESULTS Treatment with the extract significantly (p<0.05) reduced the seizure severity and immobility period as compared to vehicle control, in a dose and time-dependent manner. Moreover, the extract treatment retained the serotonin and noradrenaline levels of the brain. CONCLUSIONS The results of present study concluded that the hydroethanolic extract of Passiflora incarnata suppress PTZ-induced seizures, and ameliorates its associated post-ictal depression, which has been found to be get worsened with the standard antiepileptic drug, diazepam.

Effect of saponin fraction from Ficus religiosa on memory deficit, and behavioral and biochemical impairments in pentylenetetrazol kindled mice.

In our previous study, the saponin-rich fraction (SRF) of adventitious root extract of Ficus religiosa L. (Moraceae) was shown to have an anticonvulsant effect in acute animal models of convulsions. The present study was envisaged to study the effect of SRF in the pentylenetetrazol (PTZ) kindling mouse model and its associated depression and cognition deficit. Treatment with the SRF (1, 2 and 4 mg/kg; i.p.) for 15 days in kindled mice significantly decreased seizure severity on days 5, 10 and 15 when challenged with PTZ (35 mg/kg; i.p.). Marked protection against kindling-associated depression was also observed on days 10 and 15 in the SRF-treated groups when tested using the tail-suspension test. However, the SRF treatment failed to protect kindling-associated learning and memory impairments in the passive shock avoidance paradigm. The observed behavioral effects were corroborated with modulation in the levels of noradrenaline, dopamine, serotonin, GABA and glutamate in discrete brain regions.

Gastroprotective effect of Acacia nilotica young seedless pod extract: Role of polyphenolic constituents

OBJECTIVE To systematically evaluate antiulcer potential of Acacia nilotica in different ulcer models in rats. METHODS Different extracts [ethanolic, 50% hydroethanolic (50:50), 70% hydroethanolic (70:30) and aqueous] of young seedless pods were examined in pylorus ligation induced gastric ulcers in rats. Various parameters like, volume of gastric acid secretion, pH, free acidity, total acidity, ulcer index, mucin content and antioxidant studies were determined and were compared between extract treated, standard and vehicle control following ulcer induction. The most active extract was also evaluated in swimming stress induced and NSAID induced gastric ulceration. RESULTS Among different extracts of young seedless pods only hydroethanolic extracts showed significant antiulcer activity in pyloric ligation induced ulceration. Even more the 70% hydroethanolic extract showed better protection as compared to 50% hydroethanolic extract. Further 70 % hydroethanolic extract also showed significant mucoprotection in swimming stress induced and nonsteroidal antiinflammatory drugs induced gastric ulceration. CONCLUSION The results of present study concluded that the hydroethanolic extract of young seedless pods of Acacia nilotica has antiulcer activity in pylorus ligation, swimming stress and NSAID induced rat ulcer models. The extract containing more amount of phenolic components show high antiulcer activity, indicating the phenolic component of the extract to be responsible for the activity of the extracts.

PASS assisted prediction and pharmacological evaluation of novel nicotinic analogs for nootropic activity in mice.

The aim of present study is to predict the probable nootropic activity of novel nicotine analogues with the help of computer program, PASS (prediction of activity spectra for substances) and evaluate the same. Two compounds from differently substituted pyridines were selected for synthesis and evaluation of nootropic activity based on their high probable activity (Pa) value predicted by PASS computer program. Evaluation of nootropic activity of compounds after acute and chronic treatment was done with transfer latency (TL) and step down latency (SDL) methods which showed significant nootropic activity. The effect on scopolamine induced amnesia was also observed along with their acetylcholine esterase inhibitory activity which also showed positive results which strengthened their efficacy as nootropic agents through involvement of cholinergic system. This nootropic effect was similar to the effect of nicotine and donepezil used as standard drugs. Muscle coordination and locomotor activity along with their addiction liability, safety and tolerability studies were also evaluated. These studies showed that these compounds are well tolerable and safe over a wide range of doses tested along with the absence of withdrawal effect which is present in nicotine due to its addiction liability. The study showed that these compounds are true nicotine analogs with desirable efficacy and safety profile for their use as effective nootropic agents.

Age dependent learning and memory deficit in Pentylenetetrazol kindled mice.

Epilepsy is a chronic neurological disorder and well documented to induce cognitive impairment. Further onset of epilepsy at different age levels have different effect on cognitive function. Kindling has been used to model clinical epilepsy to study different psychiatric and neurological changes associated with it. Only one study has been reported for age dependent learning deficit in kindled rats but till date no such study is available for mice. Therefore this study was envisaged to find out the correlation of age of mice with feasibility for induction and resistance to kindling and learning and memory deficits. In this study, kindling was induced by administration of subconvulsive dose of pentylenetetrazol (35 mg/kg; i.p.) on alternate days in mice of different age group (2, 6 and 12 month old). For the evaluation of short term, long term spatial and contextual fear memory Elevated Plus Maze and Passive Shock Avoidance Paradigm were used respectively. Induction of kindling significantly impaired learning and memory in different age group of mice as compared to their naïve. Kindling also affected the working and reference spatial memory, with function of age in kindled mice, and contextual fear memory in kindled mice, however not in age dependent manner. Thus the present study validated the existence of age dependent differences in learning and memory deficit and induction of kindling in mice. Results suggested suitability of 6 month old mice for long term neuropharmacological studies pertaining to epilepsy associated cognitive deficit with adequate memory deficit and insignificant resistance to kindling and mortality.

Anti-amnesic effect of Ficus religiosa in scopolamine-induced anterograde and retrograde amnesia.

Context: Ficus religiosa Linn (Moraceae) is a variety of fig tree. Its figs are known to contain a high serotonergic content, and modulation of serotonergic neurotransmission plays a crucial role in the pathogenesis of amnesia. Thus, the present study was envisaged. Objective: To investigate the effect of the methanol extract of figs of Ficus religiosa (FRFE) on scopolamine-induced anterograde and retrograde amnesia in mice. Materials and methods: Transfer latency (TL) to the preferred niche in the elevated plus-maze (EPM) and learning avoidance of passive behavior to avoid punishment in the modified passive avoidance paradigm (MPA) served as behavioral models for the assessment of memory. Scopolamine (1 mg/kg, i.p.) was administered before training for induction of anterograde amnesia and before retrieval for induction of retrograde amnesia in both models. TL in the EPM, step down latency (SDL), number of trials, and number of mistakes in the MPA were determined in vehicle control, FRFE treated (10, 50, and 100 mg/kg, i.p.), and standard groups (piracetam 200 mg/kg, i.p.). Cyproheptadine, a non-selective 5-HT1/2 blocker (4 mg/kg, i.p.), was administered along with the FRFE to investigate the involvement of serotonergic pathways in the anti-amnesic effect of FRFE. Results and discussion: FRFE resulted in a significant improvement of memory, as its treatment attenuated the scopolamine-induced anterograde and retrograde amnesia dose-dependently. Further, cyproheptadine pretreatment significantly reversed the anti-amnesic effect of FRFE. Conclusion: FRFE has anti-amnesic activity against scopolamine-induced amnesia, in a dose-dependent manner. Inhibition of the anti-amnesic effect of FRFE by cyproheptadine substantiates the involvement of serotonergic pathways for its activity.