Benzyl alcohol suppresses seizures in two different animal models.

Introduction: We have been exploring the effects of dihydroprogesterone in female amygdala-kindled rats. For intraperitoneal (i.p.) time-response studies, we used a vehicle containing the common solvent, benzyl alcohol (BnOH). The vehicle containing BnOH was also tested alone as a control. Method and Results: Unexpectedly, it was found that the vehicle containing BnOH had clear-cut anti-seizure effects in the kindling model, with an ED50 of 100 mg/kg. In a follow-up study, dose- and time-response studies of i.p. BnOH were done in male mice in the maximal pentylenetetrazol (PTZ) model. BnOH suppressed PTZ seizures in a dose-dependent manner, with an ED50 of 300 mg/kg against hindlimb tonic extension. Effects were fully established at 5-min post injection and lasted for an hour. Conclusion: BnOH is not an inert solvent. It has clear-cut anti-seizure effects against both focal and generalized seizures.

Progesterone, 5a-dihydropogesterone and allopregnanolone's effects on seizures: A review of animal and clinical studies.

The anti-seizure effects of progesterone family compounds have long been known. Over the years, however, most studies have focused on progesterone and on its secondary metabolite allopregnanolone (ALLO), with less attention being paid to its primary metabolite 5a-dihydroprogesterone (DHP). Here we review animal and clinical studies related to the anti-seizure effects of progesterone and its 5a neuroactive metabolites, including DHP and ALLO. Progesterone and its reduced metabolites all have demonstrated seizure-suppression effects in animal models - except in models of absence seizures - with the common side effects of sedation and ataxia. Progesterone and ALLO have also shown anti-seizure effects in clinical trials. A large Phase III trial has revealed that female patients with premenstrual exacerbations of seizures benefit most from progesterone therapy. A liquid suspension of ALLO has also been tested in patients with supra-refractory status epilepticus with some success in a small phase II trial. ALLO's C3 methyl analog ganaxolone is under development as an anti-seizure drug. Progesterone's anti-seizure effects are mostly independent of its genomic receptors and are, in large part, due to its active metabolites. ALLO is a potent allosteric modulator of GABA receptors. Other membrane receptors are thought to be involved in the DHP's anti-seizure actions, but their exact nature is not yet known. Potential drawbacks to the development of progesterone family compounds as anti-seizure drug are their endocrine effects. These compounds might form a basis for the future development of novel anti-seizure drugs, however, with hormonal side effects being mitigated through rational drug design.

The anti-seizure effects of IV 5α-dihydroprogesterone on amygdala-kindled seizures in rats.

OBJECTIVE: The present study investigated the anti-seizure effects of 5α-dihydroprogesterone (DHP) in an animal model of human drug-resistant focal seizures with impaired awareness. DHP was administered via the intravenous (IV) route. METHODS: Female Wistar rats were implanted with an electrode in the right basolateral amygdala. They were then kindled to 15 stage 5 seizures, stability tested, and cannulated in the jugular vein. Multiple doses of IV DHP were tested against focal electrographic seizures and secondarily generalized convulsions. The time-course of DHP's action was also examined. RESULTS: The dose-response study, done at 5 min after injection, showed a dose-dependent suppression of both generalized and focal seizures, with an ED50 of 1.69 mg/kg for the generalized convulsive seizures and an ED50 of 3.48 mg/kg for the focal electrographic seizures. Ataxia, as rated by the Löscher ataxia scale, was also seen, with a TD50 of 3.57 mg/kg. The time-response study, done at the ED75 for focal seizure suppression, showed suppression of both generalized and focal seizures from immediately after injection to about 60 min post-injection. SIGNIFICANCE: DHP has demonstrated anti-seizure effects in a drug-resistant model of human focal seizures with impaired awareness. Its analogs might be developed as new anti-seizure drugs.