Pramod Kumari Mediratta

Evaluation of immunomodulatory potential of Ocimum sanctum seed oil and its possible mechanism of action

The present study investigates the effect of Ocimum sanctum seed oil (OSSO) on some immunological parameters in both non-stressed and stressed animals. An attempt has also been made to explore the possible mechanism of immunomodulatory activity. OSSO (3 ml/kg, ip) produced a significant increase in anti-sheep red blood cells (SRBC) antibody titre and a decrease in percentage histamine release from peritoneal mast cells of sensitized rats (humoral immune responses), and decrease in footpad thickness and percentage leucocyte migration inhibition (LMI) (cell-mediated immune responses). Restraint stress (RS) produced a significant reduction in the anti-SRBC antibody titre, foot pad thickness and percentage LMI (% LMI). The effects of RS on humoral as well as cell-mediated immune responses were effectively attenuated by pretreating the animals with OSSO. Co-administration of diazepam (1 mg/kg, sc), a benzodiazepine (BZD), with OSSO (1 ml/kg, ip) enhanced the effect of OSSO on RS-induced changes in both humoral and cell-mediated immune responses. Further, flumazenil (5 mg/kg, ip), a central BZD receptor antagonist inhibited the immunomodulatory action of OSSO on RS-induced immune responsiveness. Thus, OSSO appears to modulate both humoral and cell-mediated immune responsiveness and these immunomodulatory effects may be mediated by GABAergic pathways.

Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice

Cognitive impairment is frequently observed in epileptic patients. It has been seen that not only epilepsy but antiepileptic drugs also impair cognitive functions. The present study was undertaken to assess the effect of three anticonvulsants viz. lamotrigine (5mg/kg, p.o.), oxcarbazepine (15mg/kg, p.o.) and topiramate (10mg/kg, p.o.) on cognitive function and oxidative stress during pentylenetetrazole (PTZ)-kindling in mice. Kindling was induced by the administration of PTZ (25mg/kg, i.p.) on every alternate day till 5 weeks. Cognition was assessed after the development of kindling. Elevated plus maze (EPM) and passive avoidance response (PAR) tests were carried out after 24h and 48h of the last PTZ administration. After completion of behavioural tests malondialdehyde (MDA), glutathione levels, superoxide dismutase and catalase activity were measured as an indicator of oxidative stress. The results of the present study indicate that topiramate (10mg/kg) administration to kindled animals increased transfer latency and decreased step-down latency in EPM and PAR tests, respectively. However, lamotrigine and oxcarbazepine did not alter the two parameters. Topiramate administration to kindled as well as non-kindled animals has shown increase in MDA and decrease in glutathione levels. Lamotrigine and oxcarbazepine did not show significant alteration in oxidative stress parameters. To conclude, long term administration of topiramate impairs cognitive functions during experimental epilepsy while lamotrigine and oxcarbazepine are safer.

Curcumin has anticonvulsant activity on increasing current electroshock seizures in mice

Epilepsy is one of the most common serious disorders of the brain. Several experimental studies have reported neuroprotective and antioxidant activity of certain natural products like curcumin, an active ingredient of turmeric. The present study was designed to explore the effect of acute administration of curcumin at doses 50, 100 and 200 mg/kg, orally (p.o.) and its chronic (× 21 days) administration in 100 mg/kg, p.o. on increasing current electroshock (ICES) test, elevated plus maze and actophotometer in mice. Curcumin in a dose of 100 mg/kg significantly increased the seizure threshold in ICES test on both acute and chronic administration. The same dose of 100 mg/kg on acute administration showed anxiogenic effect on elevated plus maze and actophotometer test. However, this anxiogenic effect of curcumin disappeared on chronic administration. These results suggest that curcumin appears to possess anticonvulsant activity in mice. Copyright

Protective effect of N-acetylcysteine on bisphenol A-induced cognitive dysfunction and oxidative stress in rats

Bisphenol A (BPA) is commonly used as a monomer in polycarbonate plastics. The present study was designed to investigate the effect of BPA on cognitive functions and oxidative stress in the brain tissue of rats and if co-administration of N-acetylcysteine (NAC), an antioxidant, can modulate the effect of BPA on cognitive functions and prevent any possible oxidative stress. The BPA was administered per orally (p.o) in two doses 2 and 20 μg/kg for 28 days. Cognitive functions were assessed using step-down latency (SDL) on a passive avoidance apparatus and spatial navigation task on Morris water maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and reduced glutathione (GSH) levels. A significant reduction in SDL, and prolongation of latency in spatial navigation task were observed in BPA (2 and 20 μg/kg) treated group as compared to control group. The co-administration of NAC (100 mg/kg, p.o) antagonized the effect of BPA on SDL and spatial navigation test. NAC treatment also attenuated the BPA-induced increased MDA levels and decreased GSH levels in brain. Results of the present study show that NAC has potential to reverse cognitive dysfunction and oxidative stress induced by BPA exposure in rats.

Substitute of animals in drug research: An approach towards fulfillment of 4R′s

The preclinical studies for drug screening involve the use of animals which is very time consuming and expensive and at times leads to suffering of the used organism. Animal right activists around the world are increasingly opposing the use of animals. This has forced the researchers to find ways to not only decrease the time involved in drug screening procedures but also decrease the number of animals used and also increase the humane care of animals. To fulfill this goal a number of new in vitro techniques have been devised which are called ‘Alternatives’ or ‘Substitutes’ for use of animals in research involving drugs. These ‘Alternatives’ are defined as the adjuncts which help to decrease the use as well as the number of animals in biomedical research. Russell and Burch have defined these alternatives by three Rs - Reduction, Refinement and Replacement. These alternative strategies include physico-chemical methods and techniques utilizing tissue culture, microbiological system, stem cells, DNA chips, micro fluidics, computer analysis models, epidemiological surveys and plant-tissue based materials. The advantages of these alternatives include the decrease in the number of animals used, ability to obtain the results quickly, reduction in the costs and flexibility to control the variables of the experiment. However these techniques are not glittering gold and have their own shortcomings. The disadvantages include the lack of an appropriate alternative to study the whole animals metabolic response, inability to study transplant models and idiosyncratic responses and inability to study the bodys handling of drugs and its subsequent metabolites. None-the-less these aalternative methods to certain extent help to reduce the number of animals required for research. But such alternatives cannot eliminate the need for animals in research completely. Even though no animal model is a complete set of replica for a process within a human body, the intact animal does provide a better model of the complex interaction of the physiological processes.

Modulation of pentylenetetrazole-induced kindling and oxidative stress by curcumin in mice

Epilepsy is a chronic neurological disorder affecting 1% population worldwide. A number of experimental studies have reported anticonvulsant, neuroprotective and antioxidant activity of certain natural products like curcumin, an active ingredient of turmeric. The present study was designed to explore the effect of acute administration of curcumin at doses 50, 100 and 200 mg/kg, orally (p.o.) pentylenetetrazole-induced kindling in mice. Further two oxidative stress markers viz., malondialdehyde (MDA) and glutathione were estimated in brain tissues of rodents. Curcumin (50, 100 and 200 mg/kg, p.o.) dose dependently suppressed the progression of kindling in mice. In addition, the increased levels of MDA and glutathione were also reduced by curcumin in kindled animals. These results suggest that curcumin appears to possess protective activity against kindling in mice.

On the mechanism of anticonvulsant effect of tramadol in mice

The present study was conducted to examine the effects of tramadol, an atypical opioid on convulsive behaviour in maximal electroshock (MES) seizure test on mice. Moreover, an attempt was also made to investigate the role of possible receptor mechanisms involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 sec). Seizure severity was determined by (1) the duration of tonic hindlimb extensor (THE) phase and by (2) mortality due to electroconvulsions. Intraperitoneal (i.p.) administration of tramadol dose-dependently (10-50 mg/kg) decreased the duration of THE phase of MES. The anticonvulsant effect of tramadol was antagonized by the opioid antagonists, naloxone in high dose, and MR2266, a selective kappa antagonist but not by naltrindole, a delta opioid antagonist. Coadministration of either gamma-aminobutyric acid (GABA)-ergic drugs (diazepam, GABA, muscimol and baclofen) or N-methyl-D-aspartate (NMDA) receptor antagonist, MK801 with tramadol augmented the anticonvulsant effect of the latter drug. By contrast, flumazenil, a central benzodiazepine (BZD) receptor antagonist, counteracted the diazepam-induced facilitation of anti-MES effect of tramadol. Similarly, delta-aminovaleric acid (DAVA), a GABAB receptor antagonist, abolished the facilitatory effect of baclofen, a GABAB agonist on anti-MES action of tramadol. These BZD-GABAergic antagonists, flumazenil or DAVA, on their own also antagonized the anti-MES effect of tramadol administered alone. No significant effect on mortality was observed in any of the studied groups. Taken together, the current results have demonstrated a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), GABAA-BZD receptors system, GABAB receptors and NMDA channel involvement in the antielectroshock effect of tramadol in mice.

Studies on the anticonvulsant effect of U50488H on maximal electroshock seizure in mice

The present study was designed to investigate the effect of U50488H, a prototype non-peptide kappa opioid agonist on convulsive behaviour using a maximal electroshock (MES) seizure test in mice. An attempt was also made to explore the role of possible receptors involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 s). Seizure severity was evaluated by means of two parameters, i.e., (1). duration of tonic hindlimb extensor phase and (2). mortality due to convulsions. Intraperitoneal (i.p.) administration of U50488H dose dependently (5-20 mg/kg) decreased the hindlimb extensor phase of MES. The anticonvulsant effect of U50488H was attenuated by the general opioid antagonist, naloxone at a high dose, and by MR2266, a selective kappa antagonist, but not by naltrindole, a delta antagonist. Coadministration of gamma-aminobutyric acid (GABA)ergic drugs (diazepam, GABA, muscimol, and baclofen) and the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with U50488H augmented the anticonvulsant effect of the latter drug in mice. On the other hand, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the protective effect of diazepam and similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, blocked the protective effect of baclofen, a GABA(B) agonist on the anti-MES action of U50488H. These BZD-GABAergic antagonists, namely, flumazenil or DAVA, on their own also counteracted the anti-electroshock seizure effect of U50488H given alone. However, mortality was not significantly altered in any of the above animal groups. Taken together, the findings have shown a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), NMDA channel, GABA(A)-BZD-chloride channel complex, and GABA(B) receptors in the anticonvulsant action of U50488H.

Effect of Carbamazepine and Lamotrigine on Cognitive Function and Oxidative Stress in Brain during Chemical Epileptogenesis in Rats

The present study assessed the effect of carbamazepine and lamotrigine on cognitive function and oxidative stress in brain during chemically induced epileptogenesis in rats. Epileptogenesis was induced by administration of pentylenetetrazole (30 mg/kg, s.c.) on alternate days (three times/week) for 9-11 weeks or until stage 4 of seizure score was achieved. The neurobehavioural parameters used for cognitive assessment were step-down latency in continuous avoidance apparatus and transfer latency in elevated plus maze test paradigm. Carbamazepine and lamotrigine were administered intraperitoneally in doses of 60 mg/kg and 25 mg/kg, respectively, according to the groups, once a day for 11 weeks. Oxidative stress was assessed in isolated homogenized whole brain samples and estimated for the levels of malondialdehyde, reduced glutathione, catalase and superoxide dismutase. The results showed that lamotrigine did not produce any change in cognitive function, while carbamazepine produced cognitive dysfunction. Cognitive decline seen in the carbamazepine-treated pentylenetetrazole-kindled group was also associated with increased oxidative stress. Lamotrigine treatment had no effect on oxidative stress parameters alone, while it significantly decreased oxidative stress in the pentylenetetrazole-kindled group as compared to the pentylenetetrazole-kindled carbamazepine-treated group.

Liposomal formulation of curcumin attenuates seizures in different experimental models of epilepsy in mice

Contemporary research indicates promising anticonvulsant effect of curcumin. However, its poor oral bioavailability is a major hindrance toward its pharmacological action. Thus, this study was carried out to evaluate the acute effect of liposome‐entrapped curcumin on increasing current electroshock seizures (ICES) test, pentylenetetrazole (PTZ)‐induced seizures, and status epilepticus in mice. Liposome‐entrapped curcumin in doses 25 and 50 mg/kg demonstrated significant increase in seizure threshold current and latency to myoclonic and generalized seizures in ICES test and PTZ‐induced seizures, respectively. Similarly, liposomal‐entrapped curcumin also increased the latency to the onset and decreased the duration of seizures during status epilepticus in mice. To conclude, liposomal‐entrapped curcumin possesses anticonvulsant activity against status epilepticus in mice.