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Perampanel Inhibition Of Ampa Receptor Currents In Cultured Hippocampal Neurons, Chao-Yin Chen, Lucas Matt, Johannes Hell, Michael Rogawski
Perampanel Inhibition Of Ampa Receptor Currents In Cultured Hippocampal Neurons, Chao-Yin Chen, Lucas Matt, Johannes Hell, Michael Rogawski
Michael A. Rogawski
Perampanel is an aryl substituted 2-pyridone AMPA receptor antagonist that was recently approved as a treatment for epilepsy. The drug potently inhibits AMPA receptor responses but the mode of block has not been characterized. Here the action of perampanel on AMPA receptors was investigated by whole-cell voltage-clamp recording in cultured rat hippocampal neurons. Perampanel caused a slow (τ~1 s at 3 µM), concentration-dependent inhibition of AMPA receptor currents evoked by AMPA and kainate. The rates of block and unblock of AMPA receptor currents were 1.5×105 M−1 s−1 and 0.58 s−1, respectively. Perampanel did not affect NMDA receptor currents. The extent …
Anticonvulsant Potencies Of The Enantiomers Of The Neurosteroids Androsterone And Etiocholanolone Exceed Those Of The Natural Forms, Dorota Zolkowska, Ashish Dhir, Kathiresan Krishnan, Douglas F. Covey, Michael A. Rogawski
Anticonvulsant Potencies Of The Enantiomers Of The Neurosteroids Androsterone And Etiocholanolone Exceed Those Of The Natural Forms, Dorota Zolkowska, Ashish Dhir, Kathiresan Krishnan, Douglas F. Covey, Michael A. Rogawski
Michael A. Rogawski
RATIONALE: Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABA-A receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5β,3α-A, the unnatural enantiomers are more potent at GABA-A receptors than the natural forms. OBJECTIVES: The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5β,3α-A with their enantiomers in mouse seizure models. METHODS: Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 …
Neuroactive Steroids For The Treatment Of Status Epilepticus, Michael Rogawski, Carlos Loya, Kiran Reddy, Dorota Zolkowski, Christoph Lossin
Neuroactive Steroids For The Treatment Of Status Epilepticus, Michael Rogawski, Carlos Loya, Kiran Reddy, Dorota Zolkowski, Christoph Lossin
Michael A. Rogawski
Benzodiazepines are the current first-line standard-of-care treatment for status epilepticus but fail to terminate seizures in about one third of cases. Synaptic GABA-A receptors, which mediate phasic inhibition in central circuits, are the molecular target of benzodiazepines. As status epilepticus progresses, these receptors are internalized and become functionally inactivated, conferring benzodiazepine resistance, which is believed to be a major cause of treatment failure. GABA-A receptor positive allosteric modulator neuroactive steroids, such as allopregnanolone, also potentiate synaptic GABA-A receptors, but in addition they enhance extrasynaptic GABA-A receptors that mediate tonic inhibition. Extrasynaptic GABA-A receptors are not internalized, and desensitization of these …