Serotonergic mechanisms in the 6-Hz psychomotor seizures in mice.

Serotonin (5-hydroxytrytamine (5-HT)) plays an important role in experimental seizures. Recently, we reported the depletion of 5-HT by parachlorophynylalanine (PCPA) in whole brain to enhance 6-Hz psychomotor seizures in mice. In the present work, we investigated the effect of 5-HT depletion in cortex and hippocampus, brain regions relevant for epilepsy, on behavioral and ultra-structural changes following 6-Hz psychomotor seizures in mice. In addition, we studied the effect of sodium valproate (SVP) on behavioral, biochemical, and ultra-structural effects induced by 6 Hz. Behavioral changes induced by 6 Hz stimulation were characterized as the increased duration of Straub's tail, stun position, twitching of vibrissae, forelimb clonus, and increased rearing and grooming. PCPA administration further enhanced while SVP reduced these behaviors in mice. The 6-Hz psychomotor seizure induced ultra-structural changes in both cortex and hippocampus in mice treated with PCPA. Furthermore, PCPA administrations followed by 6Hz-induced seizures were accompanied by reduced hippocampal and cortical 5-HT. SVP attenuated the PCPA-induced ultra-structural changes and alterations of 5-HT content in the mouse brain. The study suggests the involvement of 5-HT in the 6 Hz psychomotor seizures and in the mechanisms of action of SVP against such seizures in mice.

Raloxifene protects against seizures and neurodegeneration in a mouse model mimicking epilepsy in postmenopausal woman.

Epilepsy in menopausal women presents several challenges in the treatment including an increased risk of seizures due to hormone replacement therapy. We investigated the hypothesis if raloxifene, a selective oestrogen receptor modulator, could be employed to prevent behavioural seizures and morphological alterations in a mouse model mimicking epilepsy in postmenopausal women. Female mice were made ovotoxic by treatment with 4-vinylcyclohexene diepoxide (VCD) to mimic a postmenopausal state. They were then subjected to kainic acid (KA)-induced seizures and neurotoxicity, as assessed by microscopic examination of hippocampus, relevant to human temporal lobe epilepsy. VCD administration (for 15days followed by a drug-free period of 30days) induced ovotoxicity in mice as evidenced by reduced number of primary ovarian follicles. This was accompanied by a 62.4% reduction in serum oestradiol levels. The bone mineral density of ovotoxic mice, however, remained unaffected. Raloxifene (8mg/kg) reduced the seizure severity score in both normal and ovotoxic mice and protected against degeneration induced by KA in the CA3, CA1 sub-fields and hilus of the DG. Hippocampal TGF-ß3 levels were not affected by any of the treatments. We show the potential protective role of raloxifene in preventing seizures and neuronal damage in a mouse model mimicking epilepsy in postmenopausal women which was found unrelated to hippocampal TGF-ß3. Raloxifene might represent a novel therapeutic option for postmenopausal temporal lobe epileptic woman.

Comparative effect of antihypertensive therapy on blood glucose level in hypertensive patients in an Indian population.

Hypertensive patients have higher prevalence of insulin resistance and are at increased risk of developing type 2 diabetes mellitus (DM). There is scarcity of data on the relationship between antihypertensive therapies and glycaemic control in Indian population. Thus, the present study was designed to investigate such association among Indian population in a University teaching hospital.The study was carried out on 177 hypertensive patients (with new onset of diabetes or without diabetes) visiting the OPD of medicine department at Majeedia hospital, New Delhi. The drug history of hypertensive patients and blood glucose levels following 1-5 yrs of antihypertensive therapy were recorded.The gender distribution of hypertensive patients reveals a higher percentage of incidences in males (53.7%) as compared to females (46.3%). Hypertensive patient without DM on beta blockers and on thiazide shows higher incidence of impaired glucose tolerance (IGT) (17.5%, 18.5%) and DM (10%, 11%) as compared to patient receiving other antihypertensive therapy. While in patients of new onset diabetes the incidence was higher with ß-blockers (56.2%) than with thiazides (31.3%) followed by calcium channel blockers (CCBs) (12.5%). There was proportionate increase in incidence with the duration of therapy (3-5 years). None of the patients who were on ACE inhibitors or on angiotensin receptor blockers (ARBs) reported any incidence of IGT or DM.To conclude, ß-blockers and thiazides increases the risk of type 2 diabetes mellitus with long term antihypertensive therapy requiring regular monitoring. CCBs have lowered risks while ACE inhibitors and ARBs are relatively free of such metabolic adverse effects.

Effect of escitalopram on cardiomyopathy-induced anxiety in mice.

The present study was aimed to evaluate the effect of escitalopram on anxiety following doxorubicin (DOX)-induced cardiomyopathy, a rodent model for heart failure (HF), in mice. The study was carried out in Swiss albino mice. DOX was used at a dose of 10 mg/kg intravenously. Escitalopram was administered at the doses of 10 and 20 mg/kg orally for 7 days pre- and 7 days post-DOX. Anxiety was measured on day 8 and on day 14 using elevated plus maze and Vogel's conflict test. On day 14, serum lactate dehydrogenase (LDH) was estimated. The mice were then killed and their hearts were dissected out for the estimation of malondialdehyde (MDA) and for the transmission electron microscopic (TEM) studies. Our results showed that the DOX administration induced cardiomyopathy in mice. This was evidenced by the increased levels of serum LDH and tissue MDA and was also confirmed by TEM. Escitalopram (20 mg/kg) not only reversed the anxiety-like effects induced by DOX but also DOX-induced increase in LDH and MDA as well as the morphological alterations induced by DOX in TEM studies. Escitalopram, thus, appears to be a good candidate for alleviating anxiety in patients with HF.

Combination therapy of piperine and phenytoin in maximal electroshock induced seizures in mice: isobolographic and biochemical analysis.

The present study was aimed to characterize the anticonvulsant effects of piperine in combination with well established antiepileptic drug (AED) phenytoin, in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of phenytoin with piperine at the fixed-ratio of 1:1 from the MES test with respect to long-term memory and skeletal muscular strength were evaluated along with free plasma concentration of piperine and phenytoin. Parameters of oxidative stress (glutathione, malondialdehyde), brain serotonin and serum calcium levels were also determined to probe the mechanism involved in the interaction. Test of parallelism revealed that 2 drugs were associated with non-parallel dose response effects, hence only one fixed ratio combination (1:1) was evaluated which displayed additive interaction between the 2 drugs with a slight tendency towards superadditivity. Free plasma concentrations of piperine and phenytoin revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratio of 1:1. In combination, neither long-term memory nor skeletal muscular strength was impaired. Analysis of biochemical parameters showed that the piperine alone or in combination with phenytoin successfully reversed the parameters of oxidative stress and increased brain serotonin levels as compared to MES group. However, no significant alteration in the serum calcium levels was observed by any treatment. In conclusion, the combination displayed additive interaction and slight tendency towards synergistic potential with protection towards side effects associated with AED therapy and is worthy of consideration for further investigations.

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 H(1) , H(2) , H(3) and H(4) receptors. The histamine H(3) 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 H(3) 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, H(3) 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 H(3) receptor antagonists, thus improving their utility in epilepsy and associated neurotoxicity.

Evaluation of venlafaxine on glucose homeostasis and oxidative stress in diabetic mice.

Depression occurs frequently with diabetes affecting the quality of life. All major classes of antidepressants have been shown to have a direct pharmacologic effect on metabolic function, which further worsens glycemic control. There were no reports on the effects of venlafaxine on glucose levels and oxidative stress in diabetic animals. The present study evaluated the effects of venlafaxine (8 and 16 mg/kg per d) on glucose homeostasis along with oxidative stress in brain in diabetic mice (streptozotocin (STZ), 40 mg/kg per d for 5 days). We observed that 21 days of administration of venlafaxine (8 and 16 mg/kg per d) in diabetic mice significantly enhanced swimming in normal and STZ-treated mice with a corresponding reduction in immobility. No significant difference in blood glucose levels was observed in diabetic and normal mice following venlafaxine treatment. Venlafaxine (16 mg/kg) reversed STZ-induced elevated thiobarbituric acid reactive substance (TBARS) levels and also restored the glutathione (GSH) levels in diabetic mice. Venlafaxine (8 and 16 mg/kg) per se does not produce any significant effect in normal animals. The results indicate a dose-dependent antidepressant action of venlafaxine in diabetes-induced depressive mice. Furthermore, the blood glucose levels were not significantly altered in normal and diabetic mice. In addition, venlafaxine exhibited a decrease in TBARS and elevation in GSH levels in mice brain. Venlafaxine drug treatment appears to be safer for depression associated with diabetes.

Effect of medroxyprogesterone on development of pentylenetetrazole-induced kindling in mice.

In the present study, the effect of medroxyprogesterone (MPA) is evaluated for its effect on pentylenetetrazole (PTZ) kindling model of epileptogenesis in mice followed by evaluation on kindling-induced changes in cognitive and motor functions. To explore whether the effects are mediated via progesterone receptors, a selective antagonist of progesterone (mifepristone, MIF) was also taken. Kindling was induced by once every 2 days treatment with PTZ (25 mg/kg, i.p.) for 5 weeks. The seizure severity during induction of kindling and % incidence of animals kindled at the end of 5 weeks were recorded. The motor function was assessed using a grip strength meter, whereas spatial memory was assessed in a cross maze. MPA (5 and 10 mg/kg, i.p.) significantly reduced the seizure severity scores and produced a significant decrease in the incidence of animals kindled at the end of 5 weeks (P<0.01). A higher efficacy was observed against male mice as compared with females following MPA. MIF neither reduced nor delayed the development of PTZ-induced kindling in mice. Also, it couldn't reverse the antiepileptogenic effects of MPA. On grip strength test (GST) and spontaneous alternation behavior (SAB), a significant decline in GST and % alternation was observed in kindled mice which was reversed by pre-treatment with MPA. MIF, however, could reverse only the reduced % alternation and not grip strength (GS) in PTZ-kindled animals. The study shows that MPA has antiepileptogenic effects against development of PTZ-induced kindling in mice that may not be mediated via progesterone receptors.

Beneficial interaction between clobenpropit and pyridoxine in prevention of electroshock-induced seizures in mice: lack of histaminergic mechanisms.

Clobenpropit, an H( 3) receptor antagonist, has been reported to modulate both the release of neurotransmitters and also the activity of histidine decarboxylase (HDC). Therefore, a decarboxylase-positive modulator, namely pyridoxine, was taken for interaction studies with clobenpropit in the electroshock (ES) model of seizures in mice and subsequent changes in brain histamine levels were estimated. A significant inhibition of ES-induced seizures was seen after the simultaneous use of clobenpropit and pyridoxine. No significant effects were evident on the brain histamine levels following this combination. The combination of clobenpropit with pyridoxine appears to exhibit beneficial pharmacodynamic interaction for the prevention of ES-induced seizures, which might not be mediated by the histaminergic mechanisms.

Recent advances in adjunctive therapy for epilepsy: focus on sodium channel blockers as third-generation antiepileptic drugs.

Voltage-gated sodium channel blockers like phenytoin and carbamazepine have long been used in the treatment of epilepsy. Brain sodium channels continue to be an important target of many newer second-generation (fosphenytoin, oxcarbazepine, lamotrigine, felbamate, topiramate, zonisamide) and third-generation (eslicarbazepine, brivaracetam, carisbamate, fluorofelbamate, elpetrigine, lacosamide, rufinamide, safinamide, vinpocetine) antiepileptic drugs (AEDs). Some of the newer drugs show either state-dependent antiepileptic action or sodium channel subtype selectivity, although most agents do not differentiate between these channel subtypes. The present review highlights the preclinical and clinical efficacy, pharmacokinetics, drug interactions and adverse event profiles. It also addresses AED selection of sodium channel blockers that constitutes the third generation of AEDs.

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.

Seizures and sodium hydrogen exchangers: potential of sodium hydrogen exchanger inhibitors as novel anticonvulsants.

Advances in the understanding of mechanisms underlying the pathophysiology of epilepsy have led to the identification of sodium hydrogen exchanger (NHE) as one of the possible targets for future antiepileptic drugs (AEDs). There are indicators from several experimental studies that NHE inhibitors could be of significant value as potential anticonvulsants. Various in-vitro reports (brain slices) have suggested anticonvulsant potential of these agents. Recently we provided the in-vivo data on anticonvulsant efficacy of amiloride (an NHE inhibitor) in different animal models of seizure and epilepsy. In addition to blocking NHE, these agents are known to affect other traditional targets like voltage-gated Na(+) channels, Ca(2+) channels, glutamate concentration, etc. Thus NHE inhibitors may represent a novel class of AEDs and surely deserve more scientific attention. In this review, we focus on the role of NHE in epilepsy and provide the experimental evidence available so far on the effect of NHE inhibitors in various animal models.

Anticonvulsant effect of amiloride in pentetrazole-induced status epilepticus in mice.

Inhibition of sodium hydrogen exchangers (NHE) has been shown to diminish seizure activity in various in vitro and in vivo models of epilepsy. In the present study, we examined the effect of amiloride, a sodium hydrogen exchanger inhibitor, against pentetrazole (PTZ)-induced status epilepticus (SE). The study was conducted in mice and status epilepticus was induced by administering ip 50 mg/kg of phenytoin followed 2 hour later by PTZ, 100 mg/kg sc. Amiloride produced dose-dependent protection against PTZ-induced SE.

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.

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.

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.

NORADRENERGIC MECHANISMS IN THE PROCONVULSANT EFFECTS OF BUSPIRONE.

The effect of buspirone on the protection of chemically and electrically-induced seizures by anticonvulsant drugs was studied in mice. We found antagonism to the protective action of sodium valproate (300 mg/kg, po), carbamazepine (420 mg/kg, po) and phenytoin (23.2 mg/kg, po) against picrotoxin (3.5 mg/kg, ip) and maximal electroshock (54 mA, 0.2s) induced seizures by BUS (20 mg/kg, po) and a reversal of such antagonism by pretreatment with clonidine (1 mg/kg, po). The effects appear to be elicited through central α2 adrenoceptor mechanisms.