Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice

https://doi.org/10.1016/S0028-3908(96)00021-4Get rights and content

Abstract

Several structurally related metabolites of progesterone (3α-hydroxy pregnane-20-ones) and deoxycorticosterone (3α-hydroxy pregnane-21-diol-20-ones) and their 3β-epimers were evaluated for protective activity against pilocarpine-, kainic acid- and N-methyl-D-aspartate (NMDA)-induced seizures in mice. Steroids with the 3-hydroxy group in the α-position and 5-H in the α- or β-configurations were highly effective in protecting against pilocarpine (416 mg/kg, s.c.)-induced limbic motor seizures and status epilepticus (ED50 values, 7.0–18.7 mg/kg, i.p.). The corresponding epimers with the 3-hydroxy group in the β-position were also effective but less potent (ED50 values, 33.8-63.5, i.p.). Although the neuroactive steroids were considerably less potent than the benzodiazepine clonazepam in protecting against pilocarpine seizures, steroids with the 5α,3α-configuration had comparable or higher protective index values (TD50 for motor impairment -4- ED50 for seizure protection) than clonazepam, indicating that some neuroactive steroids may have lower relative toxicity. Steroids with the 5α,3α- or 5β,3α-configurations also produced a dose-dependent delay in the onset of limbic seizures induced by kainic acid (32 mg/kg, s.c.), but did not completely protect against the seizures. However, when a second dose of the steroid was administered 1 hr after the first dose, complete protection from the kainic acid-induced limbic seizures and status epilepticus was obtained. The steroids also caused a dose-dependent delay in NMDA (257 mg/kg, s.c.)-induced lethality, but did not completely protect against NMDA seizures or lethality. We conclude that neuroactive steroids are highly effective in protecting against pilocarpine- and kainic acid-induced seizures and status epilepticus in mice, and may be of utility in the treatment of some forms of status epilepticus in humans. Published by Elsevier Science Ltd.

References (25)

  • L.S. Chin et al.

    Status epilepticus controlled by althesin infusion

    Anaesth. Intensive Care

    (1979)
  • K.W. Gee et al.

    Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action

    J. Pharmacol. exp. Ther.

    (1988)
  • Cited by (144)

    • The interactions between reproductive hormones and epilepsy

      2021, Handbook of Clinical Neurology
      Citation Excerpt :

      The amygdala, in particular, can be parceled into two distinct cytoarchitectonic functional divisions that exert opposing modulatory influences on the hypothalamic regulation of pituitary gonadotropin secretion (Kaada, 1972; Herzog, 1989). The temporolimbic system also shows sensitive electrophysiologic responses to the feedback of neuroactive reproductive steroids (Fig. 11.5) (Herzog, 1989; Wong and Moss, 1992; Kokate et al., 1996). The potential role of epilepsy in the development of reproductive endocrine disorders has gained support from findings which suggest that the laterality and focality of the epilepsy may be associated with different specific types of reproductive endocrine disorders (Herzog, 1993; Gerendai and Halasz, 1997; Friedman et al., 2000; Herzog et al., 2003a,b; Kalinin and Zheleznova, 2007) and that altered neuroendocrine regulation may be a pathophysiologic mechanism (Fig. 11.6) (Bilo et al., 1991; Herzog et al., 2003a).

    • Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA-A receptor-mediated tonic inhibition in the hippocampus

      2019, Neuropharmacology
      Citation Excerpt :

      Neurosteroids modulate GABA-A receptors primarily via allosteric potentiation of GABA at nanomolar concentrations and through direct activation of the channel at micromolar concentrations (Hosie et al., 2007). AP has powerful antiseizure activity (Kokate et al., 1996; Kaminski et al., 2003; Kaminski et al., 2004; Carver et al., 2016; Reddy and Estes, 2016). Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one, GX), a synthetic analog of AP, is designed to treat epilepsy and related seizure conditions.

    View all citing articles on Scopus
    View full text