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 / 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1049-1056 |
| Number of pages | 8 |
| Journal | Neuropharmacology |
| Volume | 35 |
| Issue number | 8 |
| DOIs | |
| State | Published - 1996 |
| Externally published | Yes |
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Keywords
- Kainic acid
- N-methyl-D-aspartate (NMDA)
- Neuroactive steroid
- Pilocarpine
- Seizure
- Status epilepticus
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Drug Discovery
- Pharmacology
Cite this
Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice. / Kokate, T. G.; Cohen, A. L.; Karp, E.; Rogawski, Michael A.
In: Neuropharmacology, Vol. 35, No. 8, 1996, p. 1049-1056.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice
AU - Kokate, T. G.
AU - Cohen, A. L.
AU - Karp, E.
AU - Rogawski, Michael A
PY - 1996
Y1 - 1996
N2 - 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 / 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.
AB - 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 / 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.
KW - Kainic acid
KW - N-methyl-D-aspartate (NMDA)
KW - Neuroactive steroid
KW - Pilocarpine
KW - Seizure
KW - Status epilepticus
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U2 - 10.1016/S0028-3908(96)00021-4
DO - 10.1016/S0028-3908(96)00021-4
M3 - Article
VL - 35
SP - 1049
EP - 1056
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
IS - 8
ER -