Drugs acting on amino acid neurotransmitters.
The most potent agents currently available for suppressing myoclonic activity in animals and humans act to enhance GABA-mediated inhibition and/or to diminish amino acid-induced excitation. Postsynaptic GABA-mediated inhibition plays an important role at the cortical level, diminishing the effect of augmented afferent activity and preventing pathologically enhanced output. Enhancement of GABAergic inhibition, principally at the cortical level but also at lower levels, by clonazepam and by valproate appears to be a predominant element in their antimyoclonic action. Studies in various animal models, including photically induced myoclonus in the baboon, P papio, indicate the value of other approaches to enhancing GABA-mediated inhibition. Among such approaches meriting evaluation in humans are inhibition of GABA-transaminase activity by gamma-vinyl GABA and action at some of the benzodiazepine receptors to enhance the action of GABA, as by the novel anticonvulsant beta-carbolines. Excitatory transmission mediated by dicarboxylic amino acids appears to play a role in myoclonus, especially at the spinal level, but also in the brainstem, cerebellum, basal ganglia, and cortex. Among various novel agents that act at the postsynaptic receptor site to antagonize such excitation, those specifically blocking excitation induced by aspartate and/or NMDA prevent myoclonic activity in a wide range of animal models. Further research is required before such agents can be evaluated in humans.
Meldrum
B S
BS
D000161:Acoustic Stimulation; D000596:Amino Acids / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003975:Diazepam / Q000494:pharmacology; D004594:Electrophysiology; D018756:GABA Antagonists; D005998:Glycine / Q000037:antagonists & inhibitors; D006801:Humans; D000860:Hypoxia / Q000150:complications; D007093:Imidazoles / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D009118:Muscimol / Q000494:pharmacology; D009207:Myoclonus / Q000209:etiology / Q000503:physiopathology*; D018377:Neurotransmitter Agents / Q000502:physiology*; D010215:Papio; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000503:physiopathology; D014635:Valproic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000596:Amino Acids; D018756:GABA Antagonists; D007093:Imidazoles; D007555:Isoxazoles; D018377:Neurotransmitter Agents; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; C005954:imidazoleacetic acid; C015542:gaboxadol; D003975:Diazepam; D005998:Glycine