title: Reduced estradiol synthesis by letrozole, an aromatase inhibitor, is protective against development of pentylenetetrazole-induced kindling in mice.
abstract: Neurosteroids, such as testosterone and their metabolites, are known to modulate neuronal excitability. The enzymes regulating the metabolism of these neurosteroids, thus, may be targeted as a noval 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) 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, delayed mean onset time of seizures and reduced seizure severity score. Letrozole reduced the levels of plasma 17β-estradiol after induction of kindling. The concurrent administration of finasteride and letrozole produced effects similar to letrozole on 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. The aromatase inhibitors, thus, may be exploited for inhibiting the synthesis of proconvulsant (17β-estradiol) and/or redirecting the synthesis of anticonvulsant (DHT and 5α-androstanediol) neurosteroids.
authors.affiliation: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, JamiaHamdard (Hamdard University), New Delhi, 110062, India.
authors.forename: Davood
authors.initials: D
authors.lastname: Rashid
authors.affiliation: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, JamiaHamdard (Hamdard University), New Delhi, 110062, India.
authors.forename: B P
authors.initials: BP
authors.lastname: Panda
authors.affiliation: Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of Pharmacy, JamiaHamdard (Hamdard University), New Delhi, 110062, India. Electronic address: divyavohora@hotmail.com.
authors.forename: Divya
authors.initials: D
authors.lastname: Vohora
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000096:biosynthesis*; D007696:Kindling, Neurologic / Q000187:drug effects*; D000077289:Letrozole; D008297:Male; D051379:Mice; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology*; D010433:Pentylenetetrazole / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D047072:Aromatase Inhibitors; D003292:Convulsants; D018377:Neurotransmitter Agents; D009570:Nitriles; D014230:Triazoles; D004958:Estradiol; D000077289:Letrozole; D010433:Pentylenetetrazole
keywords: 17β-estradiol; Dihydrotestosterone; Finasteride; Letrozole; PTZ kindling