Tanveer Singh

Neuroprotective effect of Allium cepa L. in aluminium chloride induced neurotoxicity.

The present study was envisaged to investigate the neuroprotective potential of Allium cepa (A. cepa) in aluminium chloride induced neurotoxicity. Aluminium chloride (50 mg/kg/day) was administered orally in mice supplemented with different doses of A. cepa hydroethanolic extract for a period of 60 days. Various behavioural, biochemical and histopathological parameters were estimated in aluminium exposed animals. Chronic aluminium administration resulted in significant motor incoordination and memory deficits, which were also endorsed biochemically as there was increased oxidative stress as well as elevated acetylcholinesterase (AChE) and aluminium levels in the brain. Supplementation with A. cepa in aluminium exposed animals significantly improved muscle coordination and memory deficits as well as reduced oxidative stress, AChE and decreased abnormal aluminium deposition in the brain. Histopathologically, there was marked deterioration visualized as decreased vacuolated cytoplasm as well as decreased pyramidal cells in the hippocampal area of mice brain which were found to be reversed with A. cepa supplementation. Administration of BADGE (PPARγ antagonist) in aluminium exposed animals reversed the neuroprotective potential of A. cepa as assessed with various behavioural, biochemical, neurochemical and histopathological estimations. In conclusion, finding of this study suggested significant neuroprotective potential of A. cepa in aluminium induced neurotoxicity. Further, the role of PPARγ receptor agonism has also been suggested as a putative neuroprotective mechanism of A. cepa, which needs further studies for confirmation.

Revealing pharmacodynamics of medicinal plants using in silico approach: A case study with wet lab validation

BACKGROUND Exploration of therapeutic mechanism is an integral part of medicinal plant based drug discovery for better understanding of pharmacological behavior of these agents. But, its study using conventional hit and trial wet laboratory experiments proves to be very tedious, time consuming and expensive, thus encouraging development of in silico techniques. Hence, an in silico technique has been devised using a computer software Prediction of Activity Spectra for Substances (PASS) to study pharmacodynamics of medicinal plants. The technique has been presented with a case study using Ficus religiosa L. (Moraceae) in which its anticonvulsant mechanism has been elucidated with PASS and further validated experimentally. METHODS Pentylenetetrazol (PTZ)-induced convulsion test was used to study the anticonvulsant effect of standardized bark extract of F. religiosa. Thereafter, structure of all the reported bioactive metabolites in the bark was subjected to PASS software to obtain biological activity spectrum of each compound. The mechanism signifying anticonvulsant effect was selected from the spectrum and was further validated using in vitro test. RESULTS AND DISCUSSION The extract showed significant anticonvulsant effect in PTZ test. PASS analysis showed a high activity score for GABA aminotransferase (GABA-AT) inhibitory effect of the bioactive metabolites present in the bark. In vitro GABA-AT enzyme assay results were in concordance with the predicted mechanism by PASS for the observed anticonvulsant effect, as the extract showed potent inhibition of the enzyme. The results of present study showed the in silico technique to be useful for elucidation of unknown therapeutic mechanisms of medicinal plants.

Adjuvant indoleamine 2,3-dioxygenase enzyme inhibition for comprehensive management of epilepsy and comorbid depression

Epilepsy is one of the major neurological disorders frequently associated with psychiatric disorders such as depression. Alteration of tryptophan metabolism towards kynurenine pathway may be one of the plausible reasons for association of depression in epilepsy. Hence, this study was envisaged to evaluate the dose dependent inhibition of indoleamine 2,3-dioxygenase (IDO) enzyme (responsible for shifting tryptophan metabolism) employing minocycline with valproic acid for comprehensive management of epilepsy and comorbid depression. Kindling was induced in male swiss albino mice by administration of pentylenetetrazole subconvulsive dose (35mg/kg, i.p.) at an interval of 48±2h. Kindled animals were treated with saline, valproate (300mg/kg/day i.p.), valproate in combination with different doses of minocycline (10mg/kg; 20mg/kg; 40mg/kg)/day i.p. and minocycline per se (40mg/kg/day i.p.) for 15 days. Except naïve, all the groups were challenged with pentylenetetrazole (35mg/kg i.p.) on day 5, 10, and 15 to evaluate the seizure severity score. Depression was evaluated in all experimental groups using tail suspension and forced swim test on days 1, 5, 10 and 15, 2h after pentylenetetrazole challenge. Results suggested that saline treated kindled animals were significantly associated with depression. Chronic valproate treatment significantly reduced seizure severity score but unable to ameliorate the associated depression. Minocycline supplementation with valproic acid dose dependently ameliorated depression associated with epilepsy. Neurochemical and biochemical findings also supported the behavioural findings of the study. Thus, our results suggested that supplementation of IDO enzyme inhibitors with valproic acid could be explored further for comprehensive management of epilepsy and associated depression.

Evidence in support of using a neurochemistry approach to identify therapy for both epilepsy and associated depression

The present study aimed to develop a neurochemistry-based single or adjuvant therapy approach for comprehensive management of epilepsy and associated depression employing pentylenetetrazole-kindled animals. Kindling was induced in two-month-old male Swiss albino mice by administering a subconvulsant pentylenetetrazole dose (35mg/kg, i.p.) at an interval of 48±2h. These kindled animals were treated with saline and sodium valproate (300mg/kg/day, i.p.) for 15days. Except for the naïve group, all other groups were challenged with pentylenetetrazole (35mg/kg, i.p.) on days 5, 10, and 15 to evaluate the seizure severity. Depression was evaluated in all experimental groups after normalization of locomotor activity, using tail suspension and forced swim test on days 1, 5, 10, and 15. Four hours after behavioral evaluations on day 15, all animals were euthanized to collect their serum and discrete brain parts. Corticosterone levels were estimated in all the experimental groups as a marker of a dysregulated hypothalamus pituitary adrenal axis. Neurochemical alterations (norepinephrine, dopamine, tryptophan, kynurenine, serotonin, glutamate, GABA, and total nitrate levels) were also estimated in the cortical and hippocampal areas of the mouse brain. Results revealed that saline-treated kindled animals were associated with significant depression and altered neurochemical milieu in comparison with naïve animals. Chronic valproate treatment in kindled animals significantly reduced seizure severity score bud did not ameliorate associated depression or completely restore altered biochemical and neurochemical milieu. Based on the observation of neurochemical changes in all the groups, we propose that restoration of altered neurochemical milieu, elevated indoleamine 2,3-dioxygenase enzyme activity, and corticosterone levels using pharmacological tools with/out valproic acid may be explored for management of both epilepsy and comorbid depression.

Adjuvant neuronal nitric oxide synthase inhibition for combined treatment of epilepsy and comorbid depression

BACKGROUND Elevated nitric oxide (NO) levels in the brain have been apparently associated with depression in kindled animals. Owing to the major role of neuronal nitric oxide synthase (nNOS) in brain and ineffectiveness of antiepileptic drugs (AEDs) in restoring nitrosative stress, the present study was envisaged to evaluate the adjuvant nNOS inhibitor, 7-nitroindazole (7-NI) with valproic acid for combined treatment of epilepsy and associated depression. METHODS Pentylenetetrazole kindled animals associated with depression were treated with vehicle, valproate (300mg/kg/day ip), valproate with 7-NI (10mg/kg; 20mg/kg; 40mg/kg)/day ip and 7-NI (40mg/kg/day ip) for 15days. Except naïve, all groups were challenged with pentylenetetrazole (35mg/kg ip) on days 5, 10, and 15 to evaluate seizure severity. Depression was evaluated in all experimental groups using the tail suspension and forced swim test on days 1, 5, 10 and 15. On day 15, biochemical (corticosterone levels) and neurochemical (serotonin, kynurenine, tryptophan, glutamate, GABA, nitrite levels) estimations were carried out in cortical and hippocampal area of mice brain. RESULTS Vehicle treated kindled animals were significantly associated with depression. Chronic valproate treatment in kindled animals significantly reduced seizure severity, but could not reverse associated depression. 7-NI per se treatment in kindled animals was also reported unable to restore the associated depression completely. However, 7-NI supplementation with valproate significantly reduced seizure severity score and completely ameliorated depression with restoration of altered biochemical and neurochemical milieu. CONCLUSION Adjuvant nNOS inhibition can be previewed as safe therapy with AEDs for the combined management of epilepsy and associated depression.

Adjuvant quercetin therapy for combined treatment of epilepsy and comorbid depression

ABSTRACT Epilepsy is one of the major neurological disorders frequently associated with psychiatric disorders such as depression. The predisposition of tryptophan metabolism towards kynurenine pathway has been reported as one of the plausible reasons for association of depression in epilepsy. Hence, this study was envisaged to evaluate the dose dependent inhibition of indoleamine 2,3‐dioxygenase (IDO) enzyme employing quercetin (screened employing in vitro method) with levetiracetam for combined management of epilepsy and comorbid depression. Kindling was induced in male swiss albino mice by administration of pentylenetetrazole subconvulsive doses (35 mg/kg, i.p.) at an interval of 48 ± 2 h. Kindled animals were treated with vehicle, levetiracetam (40 mg/kg/day i.p.) levetiracetam in combination with different doses of quercetin (10 mg/kg; 20 mg/kg; 40 mg/kg)/day/p.o. for 15 days. Except naïve, all the groups were challenged with pentylenetetrazole (35 mg/kg i.p.) on day 5, 10, and 15 to evaluate the seizure severity score. Depression was evaluated in all experimental groups using the tail suspension and sucrose preference test on days 1, 5, 10 and 15, 2 h after pentylenetetrazole challenge. Results suggested that vehicle treated kindled animals were significantly associated with depression. Chronic levetiracetam treatment significantly reduced seizure severity score, but further worsened the associated depression. Quercetin supplementation with levetiracetam dose dependently ameliorated depression associated with epilepsy. Neurochemical and biochemical findings also supported the behavioural findings of the study. Thus, our results suggested that supplementation of quercetin with levetiracetam could be explored further for combined treatment of epilepsy and comorbid depression. Graphical abstract Figure. No Caption available. HighlightsThe study explored the adjuvant role of quercetin with levetiracetam for combined treatment of epilepsy and depression.Neurochemical changes suggested altered tryptophan metabolism to be responsible for depression associated with epilepsy.Levetiracetam treatment decreased seizure severity and further worsened the comorbid depression.Adjuvant quercetin supplementation restored normal tryptophan and ameliorated comorbid depression.Quercetin supplementation with levetiracetam seems effective approach for combined management of epilepsy and depression.

Managing epilepsy-associated depression: Serotonin enhancers or serotonin producers?

Depression is one of the major psychiatric comorbidities having a major impact on the quality of life in people with epilepsy (PWE). Selective serotonin reuptake inhibitors (SSRIs) are considered as safest therapy for the treatment of depression in PWE. Although administration of SSRIs increases the synaptic serotonin levels, it decreases the overall serotonin synthesis in the brain. Long-term therapy with SSRIs has been reported to decrease serotonin synthesis, which may be the possible reason for lessening of their antidepressant effect over time as well as elevated seizure outcomes observed in PWE. Thus the present scenario warrants streamlined studies to explore the safety and efficacy of SSRIs as well as approaches beyond SSRIs for treatment of depression in epilepsy. In this review, we outline the approaches which may restore serotonin levels rather than a pseudo enhancement of serotonin with SSRIs. The potential of various anti-inflammatory approaches such as selective cyclooxygenase-2 inhibitors, inflammatory cytokine inhibitors, and indoleamine 2,3-dioxygenase inhibitors pertaining to their serotonin restoring effects is discussed as possible therapy for treatment of depression in epilepsy.

Relative Safety of Different Antidepressants for Treatment of Depression in Chronic Epileptic Animals Associated with Depression

Background and Purpose Depression is one of the major psychiatric comorbidities associated with epilepsy. The inconclusive results of antidepressants (ADs) regarding their safety in regard to convulsions have strongly contributed towards under treatment of depression in people with epilepsy (PWE). Thus, the present study was envisaged to assess the relative safety of four different classes of ADs regarding their convulsive potential in kindled/epileptic animals. Methods Kindling (an animal model to induce chronic epilepsy) was induced in male Swiss albino mice by administration of pentylenetetrazole subconvulsive doses (35 mg/kg, i.p.) at an interval of 48 ± 2 h for 42 days. The epileptic animals were treated with saline; imipramine (20 mg/kg/day i.p.); fluoxetine (20 mg/kg/day i.p.); venlafaxine (10 mg/kg/day i.p.) and mirtazapine (10 mg/kg/day i.p.) for 15 days. Except naive, animals were challenged with pentylenetetrazole subconvulsive dose (35 mg/kg, i.p.) on every 5th day to determine convulsion severity score, latency to first myoclonic jerk, latency to first tonic-clonic convulsions and numbers of tonic-clonic convulsions. Depression was also evaluated every 5th day employing tail suspension test 2 h after pentylenetetrazole subconvulsive dose. Results All ADs have been reported significant antidepressant potential however regarding their safety in regard to convulsions in epileptic animals, variable results are obtained. Chronic administration of venlafaxine and mirtazapine were found to have significant anticonvulsant effect in epileptic animals. The behavioral data was further corroborated by neurochemical findings. Conclusions The treatment with venlafaxine and mirtazapine can be considered safe for treatment of depression in epilepsy and may enhance anticonvulsant potential of antiepileptic drugs as an adjuvant therapy. However, pharmacokinetic studies are warranted before translating these findings in PWE.

Agmatine for combined treatment of epilepsy, depression and cognitive impairment in chronic epileptic animals

Epilepsy is fourth most common neurological disorders associated with depression and cognitive deficits. As per present scenario, none of the antiseizure drugs have been reported successful to have ameliorative effect on epilepsy associated depression and cognitive deficits. Thus, the study was envisioned to assess an ameliorative potential of agmatine on epilepsy and its efficacy and safety for management of associated depression and cognitive deficits. The animals were made epileptic employing pentylenetetrazole (35mg/kg i.p. every 48±2h) kindling model of epilepsy and subsequently were treated with vehicle, valproic acid (300mg/kg/day i.p.) and agmatine (2.5, 5, and 10mg/kg)/day/i.p. for 15days. Except naïve, all the groups were challenged with same pentylenetetrazole dose as employed during kindling on days 5, 10, and 15 to evaluate seizure severity. Two hours after seizure severity test, tail suspension test and passive shock avoidance paradigm was employed to evaluate depression and cognitive behavior respectively. Results suggested that epileptic animals were significantly associated with depression and cognitive impairment. Chronic valproate treatment significantly reduced seizure severity, but was found unable to mitigate depression and cognitive deficits. However, agmatine treatment dose dependently ameliorated seizure severity as well as associated depression and cognitive deficits. On 15th day, animals were euthanized and pertinent neurochemical estimations were carried out in cortical and hippocampal areas of the mice brain. Thus, study concluded that agmatine ameliorated seizure severity, depression and cognitive impairment in epileptic animals, possibly via restoring glutamate-GABA neurotransmission and serotonin synthesis with decreased nitrosative stress.

Neurochemical evidence based suggested therapy for safe management of epileptogenesis

Most of the clinically available antiepileptic drugs have only antiseizure effects and are reported unable to prevent epileptogenesis. In the past decade, several drugs underwent clinical trials for management of epileptogenesis, but none of the drugs tested was found effective. One of the major lacunas is availability of appropriate preclinical approaches to delineate mechanisms of epileptogenesis. Thus, the present study attempts to suggest a neurochemistry based approach for safe management of epileptogenesis. The altered neurochemical milieu in amygdala, cortex and hippocampus areas of the mice brain in naïve, kindled and kindling resistant animals has been delineated. The endogenous natural antiepileptogenic neurochemical defense mechanism observed in kindling resistant animals may uncover neurochemical mechanisms of epileptogenesis and in turn suggest us novel interventions for safe management of epileptogenesis. The kindling epileptogenesis was carried out in two month old male Swiss albino mice by administering subconvulsive pentylenetetrazole (35mg/kg; i.p.) at an interval of 48±2h for 42days. 2h after the last pentylenetetrazole injection, the animals were subjected to behavioral evaluations. Four hours after behavioral evaluation, all animals were euthanized and discrete parts of brain (amygdala, cortex and hippocampus) were harvested for neurochemical analysis. Results revealed that 60% of animals responded to kindling as observed with decreased seizure threshold, while the rest were found resistant. The kindled animals were found to be associated with anxiety, depression and cognitive impairment; while in kindling resistant animals no such behavioral deficits were observed. The neurochemical analysis revealed that in kindled animals altered glutamate-GABA neurotransmission, and decreased taurine, glycine, d-serine, monoamine levels with elevated indoleamine 2,3-dioxygenase activity were observed, which may be convicted for progression of kindling epileptogenesis. However, in kindling resistant animals elevated GABA, taurine, tryptophan, serotonin, glycine, and d-serine levels with decreased indoleamine 2,3-dioxygenase activity were observed as natural endogenous antiepileptogenic mechanisms, which may be foreseen as safe pharmacological targets for management of epileptogenesis.