REDUCTION OF ESTRADIOL AND NOT INCREASED DIHYDROTESTEOSTERONE BY LETROZOLE IS RESPONSIBLE FOR ITS PROTECTIVE EFFECTS AGAINST PENTYLENETETRAZOLE-INDUCED KINDLING IN MICE

D Vohora, D Rashid. Hamdard University, New Delhi, India

Neurosteroids, such as testosterone and their metabolites, are known to modulate neuronal excitability (1, 2). The enzymes regulating the metabolism of these neurosteroids, thus, may be targeted as a novel strategy for the development of new antiepileptic drugs. The present work targeted two such enzymes i,e aromatase and 5α-reductase in order to explore the potential of letrozole (an aromatase inhibitor, AI) on pentylenetetrazole (PTZ)-induced kindling in mice and the ability of finasteride (a 5α-reductase inhibitor) to modulate any such effects. PTZ (30 mg/kg, i.p.), when administered once every two days (for a total of 24 doses) induced kindling in Swiss albino mice. Letrozole (1 mg/kg, p.o.), administered prior to PTZ, significantly reduced the % incidence of kindling (p<0.001, Fisher’s exact test), delayed mean onset time of seizures (p<0.001, ANOVA followed by Bonferroni multiple comparison test) and reduced seizure severity score (p<0.05, Kruskal Wallis ANOVA by ranks followed by multiple comparison test). This is, to the best of our knowledge, the first experimental report of an AI on seizures in mice. Letrozole reduced the levels of plasma 17β-estradiol after induction of kindling (p<0.05, ANOVA followed by Tukey Kramer test). The concurrent administration of finasteride and letrozole produced effects similar to letrozole in PTZ-kindling and on estradiol levels. This implies that the ability of letrozole to redirect the synthesis of dihydrotestosterone (DHT) and 5α -androstanediol from testosterone doesn’t appear to play a significant role in the protective effects of letrozole against PTZ kindling. Letrozole, however, increased the levels of 5α-DHT in mice plasma (p<0.05, ANOVA followed by Tukey Kramer test). The AIs, thus, may be exploited for inhibiting the synthesis of proconvulsant (17β-estradiol) and/or redirecting the synthesis of anticonvulsant (DHT and 5α-androstanediol) neurosteroids. They hold a great promise for use in epilepsy especially in patients also suffering from breast cancer or testosterone deficiency. However, our results are preliminary and any extrapolation to humans requires careful and rigorous experimentation.

Acknowledgement:

This study is supported by grant from University Grants Commission under its Special Assistance Programme.

References:

(1) Wooley CS (2000). Epilepsia 41:510-515

(2) Reddy DS (2004). Neuroreport 15:515-518.