Investigation of novel antiepileptic drugs in animal seizure models is carried out as a complement to studies on the interaction of these drugs with ion channels in in vitro systems. The anticonvulsant activities of a series of 2,3-benzodiazepine noncompetitive non-NMDA (AMPA/kainate) excitatory amino acid antagonist was characterized in the maximal electroshock (MES) test and for protection against kainate-induced seizures. The rank order of potencies of the compounds in vivo corresponded with their in vitro potencies, supporting the view that the anticonvulsant activity is related to blockade of non-NMDA receptors. Noncompetitive AMPA/kainate antagonists, such as the 2,3- benzodiazepine analogs may offer advantages over competitive antagonists in certain seizure types, especially those associated with high synaptic levels of glutamate. Endogenous metabolites of certain steroid hormones (neurosteroids) can modulate the excitability of central nervous system neurons via direct actions on GABAA receptors. The ability of a series of isomeric metabolites of progesterone and deoxycorticosterone (3- hydroxy preg-nane-20-ones and 3-hydroxy pregnane-21-ol-20-ones) to enhance GABA-evoked chloride currents in cultured hippocampal neurons was compared with their abilities to protect against pentylenetetrazol (PTZ)- induced seizures in mice. Progesterone metabolites with 3-hydroxy in the alpha-position and 5-H in the alpha- or beta-configuration were highly effective at potentiating GABA-evoked Cl- current and also showed potent anticonvulsant activity in the PTZ test. The corresponding metabolites with hydroxyl groups in the 3beta- position were considerably less potent in enhancing GABA responses and were inactive in the PTZ test. All neurosteroids failed to protect against tonic hindlimb extension in the MES test. At higher doses, neurosteroids effective in the PTZ test also produced motor impairment. Relative motor toxicity was lower (higher protective index) for compounds with the 5alpha- configuration than for their corresponding 5beta-epimers. Certain naturally occurring neurosteroid isomers are highly effective anticonvulsants and this activity is correlated with their ability to potentiate GABAA receptor responses. Although toxicity (sedation) may be an impediment to the clinical use of neurosteroids in seizure therapy, there is variation among analogs in the extent to which toxicity is produced at anticonvulsant doses suggesting that some neurosteroids could have utility as anticonvulsant agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002877-02
Application #
3760355
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Gasior, Maciej; Tang, Rebecca; Rogawski, Michael A (2013) Long-lasting attenuation of amygdala-kindled seizures after convection-enhanced delivery of botulinum neurotoxins a and B into the amygdala in rats. J Pharmacol Exp Ther 346:528-34
Reddy, Doodipala S; Rogawski, Michael A (2010) Neurosteroids as endogenous regulators of seizure susceptibility and use in the treatment of epilepsy. Epilepsia 51:84
Gasior, Maciej; White, Natalie A; Rogawski, Michael A (2007) Prolonged attenuation of amygdala-kindled seizure measures in rats by convection-enhanced delivery of the N-type calcium channel antagonists omega-conotoxin GVIA and omega-conotoxin MVIIA. J Pharmacol Exp Ther 323:458-68
Meldrum, Brian S; Rogawski, Michael A (2007) Molecular targets for antiepileptic drug development. Neurotherapeutics 4:18-61
Hartman, Adam L; Gasior, Maciej; Vining, Eileen P G et al. (2007) The neuropharmacology of the ketogenic diet. Pediatr Neurol 36:281-92
Rogawski, Michael A (2006) Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 69:273-94
Gasior, Maciej; Rogawski, Michael A; Hartman, Adam L (2006) Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol 17:431-9
Rogawski, Michael A (2006) Molecular targets versus models for new antiepileptic drug discovery. Epilepsy Res 68:22-8
Biagini, Giuseppe; Baldelli, Enrica; Longo, Daniela et al. (2006) Endogenous neurosteroids modulate epileptogenesis in a model of temporal lobe epilepsy. Exp Neurol 201:519-24
Kaminski, Rafal M; Marini, Herbert; Ortinski, Pavel I et al. (2006) The pheromone androstenol (5 alpha-androst-16-en-3 alpha-ol) is a neurosteroid positive modulator of GABAA receptors. J Pharmacol Exp Ther 317:694-703

Showing the most recent 10 out of 37 publications