Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 36, Num. 1, 2004, pp. 42-43

Indian Journal of Pharmacology, Vol. 36, No. 1, Feb, 2004, pp. 42-43

Research Letter

The effect of a combination of sertraline with anticonvulsants on picrotoxin-induced convulsion and lipid peroxidation

A. N. Rizwan, A. Ali, K. K. Pillai, S. N. Pal*

Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi - 110062, India; and *World Health Organization, 1211 Geneva 27, Switzerland. E-mail: aliatif@rediffmail.com

Code Number: ph04012

Sir,

A rapid increase in our knowledge of the cellular theories of epileptogenesis has resulted in the development of the correlation between oxidative stress and epilepsy. Free radicals are involved in the pathogenesis of various diseases including epilepsy.¹ Chemoconvulsions are followed by the generation of free radicals that cause lipid peroxidation, which may subsequently cause neurodegeneration observed in certain types of human epilepsy.² Therefore, a drug that reduces seizure activity should also lower TBARS (Thiobarbituric acid reactive substances) levels.³ Reduction of TBARS levels compared to those by chemoconvulsants alone would also give an indication of the additional neuroprotective and/or antioxidant properties of the drug.

The coexistence of depression in epileptic patients makes it necessary to treat both the disorders (i.e. epilepsy and depression with antiepileptic and antidepressant drugs respectively) simultaneously. For this reason it has become necessary to evaluate the safety of these drugs upon co-administration.

In the present study we report the effect of picrotoxin (PTX; Sigma Chemicals Co. USA)-induced convulsions on lipid peroxidation (TBARS), and the modulation of TBARS levels by two known anticonvulsant drugs i.e. carbamazepine (CBZ; Novartis India Ltd.) and gabapentin (GBP; Intas Pharmaceuticals, India) when given alone and in combination with antidepressant sertraline (SERT; Unichem Labs Ltd., India). Convulsions were induced by a method similar to that described by Gupta et al.⁴ All drugs were dissolved/diluted in distilled water and were given in the volume of 10 ml/kg. Food was withdrawn 3 h before the administration of the drugs. Male albino mice were given 3.5 mg/kg picrotoxin subcutaneously, after suitable latency (4, 2.5 and 6 h after CBZ, GBP and SERT administration respectively) corresponding to the time of peak effect after oral administration of the test drug. Immediately after the administration of PTX, the animal was placed in the observational area. The severity of convulsions was carefully recorded using the scoring system 1-7: hyperlocomotion, piloerection=1; stunning, catatonic posture=2; clonic body tremors=3; prolonged clonic tremors=4; tonic forelimb convulsions followed by clonus=5; repetitive tonic forelimb convulsions followed by clonus=6; tonic extension of both forelimbs and hindlimbs followed by clonus=7. A mean cumulative score was calculated for each treatment group for comparisons and statistical analysis.

TBARS levels were determined in the serum by the method of Yagi.⁵ Samples were collected from the tail vein immediately after the observation of seizure pattern.

The project was undertaken with prior approval from the University Animal Ethics Committee. The results are presented as medians with 25 and 75 percentiles for seizure score and mean+SEM for TBARS. Data were analyzed using Kruskal-Wallis one-way ANOVA on ranks, followed by multiple comparison tests for seizure score whereas for TBARS, one-way ANOVA with Dunnett's test at 95% confidence level was employed. P<0.05 was considered significant.

The results summarized in the table showed that both CBZ and GBP offered significant protection (P<0.05) against PTX-induced convulsions. SERT significantly enhanced (P<0.05) the seizure severity. This is consistent with earlier findings that reported seizure aggravating the effects of selective serotonin reuptake inhibitors (SSRI).⁶ Co-treatment of anticonvulsants CBZ and GBP with SERT significantly attenuated the seizure protection by these drugs (P<0.05).

Picrotoxin increased the TBARS level to a significant extent (P<0.01) when compared with normal control (vehicle-treated group). This observation is in line with earlier reports¹,² suggesting the implication of oxidative stress in epilepsy. This may be attributed to the fact that enhanced lipid peroxidation can induce seizure activity by direct inactivation of glutamine synthase thereby permitting an abnormal buildup of excitatory neurotransmitter glutamic acid.⁷ Both GBP and CBZ significantly decreased (P<0.05) the serum TBARS concentration as compared to the PTX-treated group. SERT pretreatment resulted in a highly significant increase in serum TBARS when compared with normal control (P<0.01) as well as with PTX-treated group (P<0.05). This effect further substantiates the proconvulsive effect of SERT. A combination of CBZ+SERT and GBP+SERT showed TBARS levels almost equal to the PTX-treated group but the serum TBARS levels were significantly higher than the CBZ alone and GBP alone groups respectively. These findings correspond to the SERT potential of diminishing the anticonvulsant activities of CBZ and GBP.

Table 1

The management of epilepsy is a difficult task because of associated neuropsychiatric disorders among which depression being highly reported. Quite often epileptic patients have to be prescribed antidepressants along with anticonvulsants in order to treat the accompanying depression. SSRIs, especially SERT, is frequently given along with anticonvulsant drugs. However, the use of SERT in epileptics is questioned because of the proconvulsive effect of SSRI.⁶ The present study clearly demonstrates the proconvulsive and prooxidant activity of SERT when given in combination with CBZ and GBP. However, our findings are preliminary and further studies involving different oxidative stress parameters are needed for confirmation.

Acknowledgements

The authors are thankful to UGC for providing adequate funds for research.

Mr. Siraj Hussain (Vice Chancellor, Jamia Hamdard) is acknowledged for providing necessary facilities. We thank Mrs. Shaukat Shah (In-charge, Central Animal Facility, Jamia Hamdard) for providing animals in time and Mr. Mushtaque for his assistance in the experimental studies.

A. N. Rizwan, A. Ali, K. K. Pillai, S. N. Pal*

Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi - 110062, India; and *World Health Organization, 1211 Geneva 27, Switzerland. E-mail: aliatif@rediffmail.com

References

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2. Essman WB, Wollman SB. Free radicals, central nervous system processes and brain functions. In: Das DK, Essman WB, editors. Oxygen radicals: Systemic events and disease processes. Basel Karger; 1989. p. 172-91.
3. Wang JF, Azzam JE, Young LT. Valproate inhibits oxidative damage to lipid and protein in primary cultured rat cerebrocortical cells. Neuroscience 2003;116:485-9.
4. Gupta YK, Malhotra J, George B, Kulkarni SK. Methods and considerations for experimental evaluation of antiepileptic drugs. Indian J Physiol Pharmacol 1999;43:25-43.
5. Yagi K. A simple fluorometric assay for lipoperoxide in blood sample. Biochem Med 1976;15:212-6.
6. Verhoeven MAW. The serotonin syndrome; four case reports and a concise review of the literature. Eur J Psychiatry 1998;1:12-8.
7. Oliver CN, Starke-Reed PE, Stadtman ER, Lin GJ, Corney JM, Floyd RA. Oxidative damage to brain proteins, loss of glutamate synthetase activity and production of free radicals during ischaemia/reperfusion induced injury to gerbil brain. Proc Natl Acad Sci 1990;87:5144-7.

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