Progesterone and Testosterone Modulate the Convulsant Actions of Pentylenetetrazol and Strychnine in Mice

Abstract

The influence of progesterone and testosterone on the incidence of seizures after administration of intraperitoneal pentylenetetrazol and subcutaneous strychnine was evaluated in mice. Pentylenetetrazol and strychnine were administered in doses that induced seizures in 40-50% of control mice in dioestrus (48 and 0.9 mg/kg, respectively). The percentage of seizures induced by pentylenetetrazol and strychnine was significantly lower in female mice in prooestrus/oestrus, when progesterone levels are high, than in dioestrus, when progesterone levels are low. Pretreatment of pentylenetetrazol-challenged mice with progesterone (250 microg/kg) increased the incidence of seizures in prooestrus/oestrus, without affecting seizures in dioestrus. The same pretreatment in strychnine-challenged mice also increased the incidence of seizures in prooestrus-dioestrus, but significantly reduced the incidence of seizures in dioestrus. In addition, progesterone pretreatment significantly increased the percentage of deaths induced by strychnine in prooestrus-oestrus, reducing deaths in dioestrus. Orchidectomized male mice had a significantly higher incidence of seizures after administration of pentylenetetrazol and strychnine than control mice. Administration of 11 daily doses of 250 microg/kg of testosterone to castrated mice significantly reduced the incidence of seizures induced by pentylenetetrazol. These results confirm the modulatory influence of reproductive steroids on the excitability of the central nervous system and the possible clinical importance of progesterone and testosterone in the management of partial epilepsy.

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

“…These results corroborate the reports that testosterone enhances the development of amygdala kindling seizures (Edwards et al, 1999; and lowers the threshold for electroshock seizures in rats (Woolley et al, 1961). However, these results are in contrast with two other studies that evaluated the neuroprotective actions of testosterone (Pesce et al, 2000;Frye et al, 2001a). It is likely that differences in the seizure model or the species used may have caused the discrepancies in the results.…”

“…The potential molecular pathways for the testosterone modulation of seizure activity are illustrated in Figure 3. Testosterone is known to produce both proconvulsant and anticonvulsant effects depending on the animal model and the seizure type (Werboff and Havlena, 1968;Thomas and McLean, 1991;Frye and Reed, 1998;Pesce et al, 2000;Mejias-Aponte et al, 2002). Both animal and clinical studies show that testosterone enhances seizure activity by metabolism to estrogens (Isojarvi et al, 1988;Thomas and Yang, 1991;Herzog et al, 1998;Edwards et al, 1999;El-Khayat et al, 2003).…”

“…On the contrary, testosterone and related androgens have protective effects against seizures induced by pentylenetetrazol and kainic acid (Schwartz-Giblin et al, 1989;Frye and Reed, 1998;Frye et al, 2001a;Reddy, 2004b). Moreover, studies in orchidectomized or castrated animals have shown that decreased testosterone is associated with higher incidence of seizures and replacement with testosterone attenuates seizures (Grigorian and Khudaverkian, 1970;Thomas and McLean, 1991;Pericic et al, 1996;Pesce et al, 2000). However, the precise mechanisms by which testosterone causes such bimodal effects on seizure susceptibility at the cellular level are unclear.…”

Seizure susceptibility in intact and ovariectomized female rats treated with the convulsant pilocarpine

“…Studies of ovariectomized rats treated with proestrous levels of estradiol also support the hypothesis that seizure susceptibility may be increased at proestrus (Edwards et al, 1999). However, proestrous rats may not always be more susceptible to seizures relative to rats examined at other times of the estrous cycle (Finn and Gee, 1994;Pesce et al, 2000;Wahnschaffe and Loscher, 1992), for reasons that presently remain unclear.…”

“…Numerous studies over the last few decades have identified sex and cycle-dependent differences in seizure susceptibility in rodents. These studies have used various methods to induce seizures, including kindling, electroshock, and chemoconvulsant administration Buterbaugh, 1989;Edwards et al, 1999;Finn and Gee, 1994;Hoffman et al, 2003;Hom and Buterbaugh, 1986;Hudson and Buterbaugh, 1991;Kalkbrenner and Standley, 2003;Matejovska et al, 1998;Nicoletti et al, 1985;Pericic and Bujas, 1997;Persinger et al, 1988;Pesce et al, 2000;Schwartz-Giblin et al, 1989;Slamberova and Vathy, 2000;Tan and Tan, 2001;Tominaga et al, 2001;Valente et al, 2002;Velisek et al, 1999;Wahnschaffe and Loscher, 1992;Woolley, 2000). However, these studies have failed to provide a clear picture of the relationship between ovarian hormone levels and seizure susceptibility.…”