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 mg/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 mg/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.Several investigations have shown a relationship between reproductive steroids and central nervous system excitability. The active metabolite of progesterone, allopregnanolone, is a neurosteroid which exhibits hypnotic, anxiolytic and anticonvulsant actions (Bitran et al. 1991(Bitran et al. & 1995Galli et al. 1996;Korneyev & Costa 1996;Wilson & Biscardi 1997). Allopregnanolone exhibits potent inhibitory actions in the central nervous system, acting on the GABA-benzodiazepine-chloride channel macromolecular complex by an allosteric interaction with the GABA A receptor, with potentiation of the chloride channel current (Schumacher & Baulieu 1995;Rupprecht et al. 1996;Brot et al. 1997; Kellog et al. 1998). Neurosteroids are also synthetized within the central and peripheral nervous systems, mainly by glial cells (Schumacher & Baulieu 1995). Testosterone has more inconsistent actions, since it is metabolized to oestradiol, which can exacerbate seizures, and dihydrotestosterone, which inhibits NMDA-type glutamate transmission and may have antiseizure effects (Herzog 1999a). On the other hand, ovarian steroids modify the behavioural response to activation of the benzodiazepine receptor, reducing withdrawal anxiety and hyperactivity in mice (Bitran & Dowd 1996;Reddy & Kulkarni 1997). The number of seizures occurring during the benzodiazepine withdrawal syndrome is significantly less in prooestrus-oestrus, where p...

Risk Factors for Survival in a University Hospital Population of Dogs with Epilepsy

“…The fact that a significantly higher proportion of neutered male dogs experienced cluster seizures compared to intact males might explain this finding. Whether testosterone possesses pro‐ or anticonvulsive properties is an ongoing subject of investigation . A seizure protective effect, through modulation of the GABA receptor driven by testosterone‐derived neurosteroid 3α‐androstanediol, has however been suggested in some in vivo rodent studies …”

Four types of traditional Chinese medicine inducing epileptic seizures

“…10 In addition, it has been claimed that strychnine can induce convulsions, and some researchers have used the kindling model to show that specific medicines are able to modulate convulsant actions. 11,12 Previous research has confirmed that the mechanism in nux vomica-induced epileptic seizures are related to the mechanisms underlying the effects of brucine and strychnine. Strychnine and brucine have been found to compete with the inhibitory neurotransmitter glycine, leading to epileptic seizures.…”

Androgens and Adult Neurogenesis in the Hippocampus

“…In epilepsy, androgens can influence seizure susceptibility in males. 159–163 In males with epilepsy, lower levels of free testosterone and sexual dysfunction can be observed 164 but the directionality of this effect and whether treatments for epilepsy compound this relationship are not clear. 164 , 165 However, in animal studies, castrated rodents are more susceptible to pentylenetetrazol, picrotoxin, and perforant pathway stimulation-induced seizures compared with intact males, and testosterone administration decreases seizure activity in castrated males.…”

“… 164 , 165 However, in animal studies, castrated rodents are more susceptible to pentylenetetrazol, picrotoxin, and perforant pathway stimulation-induced seizures compared with intact males, and testosterone administration decreases seizure activity in castrated males. 159–161 There is also evidence to suggest that the testosterone metabolite 3α-diol is protective against gamma-aminobutyric acid (GABA) A receptor antagonist-induced seizures in male mice, 162 , 163 which is interesting as 3α-diol has a weak affinity for ARs. 41 However, the relationship between sex steroid hormones and epilepsy has proven difficult to discern as various factors such as experimental conditions and biological variability can greatly influence study outcomes (reviewed in Scharfman and MacLusky 166 ).…”