Divya Vohora

Seizures, antiepileptics, antioxidants and oxidative stress: an insight for researchers

Background: Neuronal hyperexcitability and excessive production of free radicals have been implicated in the pathogenesis of a considerable range of neurological disorders, including epilepsy. The high rate of oxidative metabolism, coupled with the low antioxidant defenses and the richness in polyunsaturated fatty acids, makes the brain highly vulnerable to free radical damage. The increased susceptibility of the brain to oxidative damage highlights the importance of understanding the role of oxidative stress in the pathophysiology of seizures. Objectives: The present review aims not only to address the link between mitochondrial dysfunction, oxidative stress and seizures, but also the modulation of the pro-oxidant/antioxidant balance following seizures and treatment with antioxidants and antiepileptic drugs. Methods: A literature review revealed that there are articles that address the role of oxidative stress and mitochondrial dysfunction in neurological disorders, including those involving different seizure models where the modulation of the pro-oxidant/antioxidant balance by seizures per se and by antioxidant agents is discussed. However, the critical role of oxidative stress in all seizure models is not uniform. Therefore, there is a need for a review article that will address all these issues together. Results/conclusions: The experimental and clinical data suggest a putative role of oxidative stress in the pathophysiology of certain seizure types. The pro-oxidant/antioxidant balance is not only modulated by seizures per se, but also by antiepileptic drugs. The ability of antioxidants for reducing the seizure manifestations and the accompanying biochemical changes (i.e., markers of oxidative stress) further supports a role of free radicals in seizures and highlights a possible role of antioxidants as adjuncts to antiepileptic drugs for better seizure control.

Protection from phenytoin-induced cognitive deficit by Bacopa monniera, a reputed Indian nootropic plant.

Many epileptic patients suffer from cognitive impairments; both the underlying pathology and antiepileptic drug therapy can cause such deficits. Phenytoin, one of the widely used anticonvulsants, is known to adversely affect cognitive function. A reputed Indian nootropic plant Bacopa monniera (BM) was evaluated alone and in combination with phenytoin for its effect on (a) passive-avoidance (PA) task; (b) maximal electroshock seizures; and (c) locomotor activity in mice. Phenytoin (PHT, 25 mg/kg po x 14 days) adversely affected cognitive function in the PA task. BM extract (40 mg/kg x 7 days), given along with phenytoin in the second week of the two-week regimen, significantly reversed PHT-induced impairment. Both acquisition and retention of memory showed improvement without affecting its anticonvulsant activity. The observed cognitive effects of PHT and BM were found to be independent of motor stimulation. The results provide evidence for potential corrective effect of BM in cognitive deficit associated with PHT therapy.

Evidence of the antiepileptic potential of amiloride with neuropharmacological benefits in rodent models of epilepsy and behavior

Sodium-hydrogen exchangers (NHEs) in the brain play a key role in regulating neuronal pH and, hence, modulate bioelectric and seizure activity. In this study, we investigated the anticonvulsant effect of amiloride (a NHE inhibitor) on increasing current electroshock (ICES) and pentylenetetrazole (PTZ)-induced seizures in mice. Further, the effect of amiloride on mood, memory, grip strength, and rotarod performance was also evaluated. The forced swimming test (FST) and spontaneous alternation behavior (SAB) models were employed to assess the effects on mood and memory, respectively. Amiloride produced a dose-dependent increase in seizure threshold in both rodent models of epilepsy. It was observed that amiloride reduced behavioral depression in the FST in mice. In addition, it resulted in memory improvement in the SAB model. Amiloride did not affect grip strength and rotarod performance, suggesting it is devoid of behavioral impairment. The results indicate the potential antiseizure activity of amiloride along with additional neurological advantages.

Histamine and selective H3-receptor ligands: a possible role in the mechanism and management of epilepsy

The interaction of selective histamine H3-receptor agonist R(alpha)-methyl-histamine (RAMH) and antagonist thioperamide (THP) with some antiepileptic drugs [AED; phenytoin (PHT), carbamazepine (CBZ), sodium valproate (SVP), and gabapentin (GBP)] was studied on seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in mice. It was found that subeffective dose of THP in combination with the subeffective doses of PHT and GBP provided protection against MES and/or PTZ-induced seizures. Further, RAMH reversed the protection afforded by either PHT or GBP on MES and/or PTZ seizures. In another set of experiments, the histamine content was measured in the whole brain and in different brain regions including cerebral cortex, hypothalamus, brain stem and cerebellum following convulsant (MES and PTZ) and AED treatment. It was seen that while MES exhibited a tendency to enhance brain histamine levels, PTZ showed the opposite effect. AEDs either increased (PHT and GBP) or decreased (SVP) brain histamine content in different regions to varying degrees. The results indicate a role for histamine in seizures and in the action of AEDs and suggest that selective H3-receptor antagonists may prove to be of value as adjuncts to conventional AEDs.

Thioperamide, a selective histamine H3 receptor antagonist, protects against PTZ-induced seizures in mice

The effect of selective histamine H3-receptor antagonist thioperamide was studied on PTZ-induced seizures in mice. Thioperamide significantly protected clonic seizures induced by PTZ in a dose-dependent manner. The effect of thioperamide was completely countered by pretreatment with R (alpha)-methylhistamine (RAMH), a selective H3-receptor agonist suggesting that the observed effect of thioperamide was elicited by histamine H3-receptors. RAMH alone did not significantly modify PTZ seizures. The findings are consistent with a role for the histaminergic neuronal system in seizures and suggest that H3-receptors may play an important role in modulating clonic seizures induced by PTZ in mice.

Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

The central histaminergic actions are mediated by H1, H2, H3 and H4 receptors. The histamine H3 receptor regulates the release of histamine and a number of other neurotransmitters and thereby plays a role in cognitive and homeostatic processes. Elevated histamine levels suppress seizure activities and appear to confer neuroprotection. The H3 receptors have a number of enigmatic features like constitutive activity, interspecies variation, distinct ligand binding affinities and differential distribution of prototypic splice variants in the CNS. Furthermore, this Gi/Go‐protein‐coupled receptor modulates several intracellular signalling pathways whose involvement in epilepsy and neurotoxicity are yet to be ascertained and hence represent an attractive target in the search for new anti‐epileptogenic drugs. So far, H3 receptor antagonists/inverse agonists have garnered a great deal of interest in view of their promising therapeutic properties in various CNS disorders including epilepsy and related neurotoxicity. However, a number of experiments have yielded opposing effects. This article reviews recent works that have provided evidence for diverse mechanisms of antiepileptic and neuroprotective effects that were observed in various experimental models both in vitro and in vivo. The likely reasons for the apparent disparities arising from the literature are also discussed with the aim of establishing a more reliable basis for the future use of H3 receptor antagonists, thus improving their utility in epilepsy and associated neurotoxicity.

Amiloride protects against pentylenetetrazole-induced kindling in mice

1 This study was performed to investigate whether or not amiloride, a sodium–hydrogen exchanger (NHE) inhibitor, can protect against seizure development of pentylenetetrazole (PTZ)‐induced kindling in mice. 2 Kindling was induced by once every 2 days treatment with PTZ (25 mg kg−1 i.p.) for 5 weeks. Challenge experiments were carried out after 15 or 30 days of last treatment with PTZ. 3 Administration of amiloride (2 h before PTZ, in doses of 0.65 and 1.3 mg kg−1, p.o.) significantly prolonged the onset of kindling and reduced the incidence and severity of seizures in a dose‐dependent manner. The effect of amiloride on the incidence of PTZ‐induced seizures was evident even after 15 or 30 days of last treatment. 4 The results indicate a protective role for amiloride against PTZ‐induced kindling in mice. The possibility of mediation of such effects by NHE inhibition is discussed.

Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse

Histamine H3 receptor (H3R) antagonists/inverse agonists possess potential to treat diverse disease states of the central nervous system (CNS). Cognitive dysfunction and motor impairments are the hallmark of multifarious neurodegenerative and/or psychiatric disorders. This review presents the various neurobiological/neurochemical evidences available so far following H3R antagonists in the pathophysiology of Alzheimers disease (AD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and drug abuse each of which is accompanied by deficits of some aspects of cognitive and/or motor functions. Whether the H3R inverse agonism modulates the neurochemical basis underlying the disease condition or affects only the cognitive/motor component of the disease process is discussed with the aim to provide a rationale for their use in diverse disease states that are interlinked and are accompanied by some common motor, cognitive and attentional deficits.

Effect of thioperamide on oxidative stress markers in middle cerebral artery occlusion model of focal cerebral ischemia in rats

In view of the recent evidence for the involvement of histamine in cerebral ischemia, the present study evaluated the effect of thioperamide (THP), a selective histamine H3-receptor antagonist, on middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia in rats. The rats were subjected to 2 h of MCAO followed by 22 h reperfusion after which the grip strength, locomotor activity and spontaneous alternation performance were assessed. Animals were then killed and oxidative stress markers were estimated in the whole brain. An elevation of thiobarbituric acid reactive substance (TBARS) and a reduction in glutathione (GSH) and antioxidant enzymes, such as glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD), was observed following MCAO, the last two being statistically insignificant. Pretreatment with THP (5.5 mg/kg i.p. and 11 mg/kg i.p.) significantly reversed the MCAO-induced increase in TBARS, but could not reverse the other parameters. Paradoxically, it further reduced the levels of GPx, GR and SOD. No significant changes were observed in the catalase levels and in the grip strength and spontaneous alternation behavior of rats. Locomotor activity was reduced slightly, but reversed on pretreatment with THP. The dual effect of THP on oxidative stress requires further investigation and raises doubts on its possible use in cerebral ischemia.

Antipsychotic-like profile of thioperamide, a selective H3-receptor antagonist in mice.

Experimental and clinical evidence points to a role of central histaminergic system in the pathogenesis of schizophrenia. The present study was designed to study the effect of histamine H3‐receptor ligands on neuroleptic‐induced catalepsy, apomorphine‐induced climbing behavior and amphetamine‐induced locomotor activities in mice. Catalepsy was induced by haloperidol (2 mg/kg p.o.), while apomorphine (1.5 mg/kg s.c.) and amphetamine (2 mg/kg s.c.) were used for studying climbing behavior and locomotor activities, respectively. (R)‐α‐methylhistamine (RAMH) (5 μg i.c.v.) and thioperamide (THP) (15 mg/kg i.p.), per se did not cause catalepsy. Administration of THP (3.75, 7.5 and 15 mg/kg i.p.) 1 h prior to haloperidol resulted in a dose‐dependent increase in the catalepsy times (P < 0.05). However, pretreatment with RAMH significantly reversed such an effect of THP (15 mg/kg i.p.). RAMH per se showed significant reduction in locomotor time, distance traveled and average speed but THP (15 mg/kg i.p.) per se had no effect on these parameters. On amphetamine‐induced hyperactivity, THP (3.75 and 7.5 mg/kg i.p.) reduced locomotor time, distance traveled and average speed (P < 0.05). Pretreatment with RAMH (5 μg i.c.v.) could partially reverse such effects of THP (3.75 mg/kg i.p.). Climbing behavior induced by apomorphine was reduced in animals treated with THP. Such an effect was, however, reversed in presence of RAMH. THP exhibited an antipsychotic‐like profile by potentiating haloperidol‐induced catalepsy, reducing amphetamine‐induced hyperactivity and reducing apomorphine‐induced climbing in mice. Such effects of THP were reversed by RAMH indicating the involvement of histamine H3‐receptors. Findings suggest a potential for H3‐receptor antagonists in improving the refractory cases of schizophrenia.