Relief of experimental spasticity and anxiolytic/anticonvulsant actions of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline.
Spasticity is characterized by pathological overactivity in spinal stretch reflex circuits and may be associated with disturbances in excitatory amino acid-mediated transmission in the cord. A genetically determined syndrome of spasticity in the rat permits the quantitative evaluation of the antispastic effects of drugs by recording activity in the electromyogram (EMG) from a hind limb extensor muscle. In genetically spastic rats, systemic administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline (NBQX), normalized pathologically increased EMG activity, whereas the AMPA agonist, alpha-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionate (ATPA), exacerbated the EMG measures of spasticity. The reflex mechanisms in the spinal cord can be studied in mice using EMG recordings from the tibial muscle (Hoffmann reflex) or from the plantar foot muscle (flexor reflex) after electrical stimulation of the tibial nerve. Systemic and i.t. administration of NBQX blocked Hoffmann reflexes in mice, leaving flexor reflexes unchanged. ATPA enhanced Hoffmann, and had no effect on flexor reflexes. The effects of NBQX on spinal reflexes were seen in doses which do not affect locomotor activity, but show anxiolytic and some antiepileptic activity in rodents. These data suggest that the design of novel muscle relaxant drugs acting at the AMPA subtype of glutamate receptors may be feasible.
Turski
L
L
Research Laboratories of Schering AG, Berlin, Germany.
Jacobsen
P
P
Honoré
T
T
Stephens
D N
DN
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D004576:Electromyography; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007696:Kindling, Neurologic / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009128:Muscle Spasticity / Q000188:drug therapy*; D011810:Quinoxalines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D007051:Ibotenic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid