Effects of Ketoconazole on Oestrus Cycle and Convulsant Action of Pentylenetetrazol in Mice

Abstract

Abstract:The frequency of oestrus cycles in female mice was significantly reduced by the implantation of a pellet of subcutaneous ketoconazole (50 mg every 6 days). The effect was more pronounced after 22 days than after 13 days and it was probably related with the progressive reduction in steroid synthesis induced by the inhibition of key steroidogenic P450 cytochromes by the drug. In addition, the influence of ketoconazole on the incidence of seizures after the administration of intraperitoneal pentylenetetrazol was evaluated in female mice. Pentylenetetrazol produced a higher percentage of seizures during dioestrus than during oestrus. Pretreatment with ketoconazole significantly increased the percentage of animals with induced seizures in oestrus but not in dioestrus as compared to controls, probably through reduced progesterone levels. The reduced seizure threshold confirm the modulatory role exerted by progesterone on central nervous system excitability, and may be relevant in epileptic patients undergoing antifungal therapy.Several experimental investigations have shown that ketoconazole, an antifungal agent related to imidazol, inhibits testicular, ovarian and adrenal biosynthesis of steroids by inhibiting key steroidogenic cytochromes, namely P450ssc (side-chain cleavage enzyme that converts cholesterol to pregnenolone), P450-17a (17-a-hydroxilase) and P450arom (steroid aromatase) (Mason et al. 1987;Weber et al. 1993;Carlson et al. 1995;Cummings et al. 1997;Adams et al. 1998;Tsafriri et al., 1998). Consequently, progesterone, testosterone and oestrogen levels tend to be reduced during ketoconazole treatment. On the other hand, the relationship between reproductive steroids and central nervous system excitability has been clearly demonstrated. Hypnotic, anxiolytic and anticonvulsivant effects are mediated by an active metabolite of progesterone, the neurosteroid allopregnanolone (Bitran et al. 1991;Korneyev & Costa 1996). The inhibitory actions of the neurosteroid in the central nervous system are due to interaction with the GABA A receptor of the GABA-benzodiazepine-chloride channel macromolecular complex, resulting in potentiation of the chloride channel current (Rupprecht et al. 1996;Brot et al. 1997). Neurosteroids are also synthetized within the central and peripheral nervous systems, mainly by glial cells (Schumacher & Baulieu 1995). On the other hand, progesterone and testosterone modulate the excitability of the central nervous system, as assessed by behavioural effects related to the oestrus cycle during benzodiazepine withdrawal syndrome and by evaluating the convulsant actions of pentylenetetrazol and strychnine (Pesce et al. 1994(Pesce et al. , 1996(Pesce et al. & 2000.The present investigation was designed to study the effect of chronic administration of high doses of ketoconazole in the inhibition of progesterone biosynthesis as judged by alterations in the oestral cycle and in the convulsivant action of pentylenetetrazol. Material and MethodsCF/1 female mice (20-30 g) were used throughout...

Progestins in the Hippocampus of Female Rats Have Antiseizure Effects in a Pentylenetetrazole Seizure Model

“…Progesterone (P) and its 5α‐reduced metabolite, 5α‐pregnan‐3α‐ol‐20‐one (3α,5α‐THP), have demonstrated antiseizure effects in some, but not all, reports (1). First, endogenous variations exist in seizure susceptibility of women and rodents, such that seizures are typically decreased during phases of the cycle when progestin levels are high compared with when they are low (2–7). Second, P or 3α,5α‐THP administration to women with epilepsy, or to female rodents in seizure models, generally decreases ictal activity (8–16).…”