Protection from high pressure induced hyperexcitability by the AMPA/kainate receptor antagonists GYKI 52466 and LY 293558.
The neurophysiological effects of 2 novel AMPA/kainate receptor antagonists, GYKI 52466 and LY 293558, on the high pressure neurological syndrome have been investigated in the rat and baboon (GYKI 52466) and rat (LY 293558). Rats were exposed to increasing ambient pressures of helium and oxygen at 3 ATA/min, on one occasion each. GYKI 52466 at 20 mumol/kg i.v. immediately before, followed by 70 mumol/kg/hr i.v. during compression delayed tremor by 85% and myoclonus by 30%, compared with control vehicle, and no side effects were observed. Seizure activity was not affected by any of the doses used. LY 293558 at 36 mumol/kg i.p. delayed tremor and myoclonus (44% and 12%), LY 293558 72 mumol/kg additionally delayed seizure activity (21%). Side effects, principally tranquilization at the higher dose, were also noted. Six baboons were exposed to a maximum pressure of 91 ATA at 0.3 ATA/min, in the same environment, on two occasions. One exposure was treated with an i.v. infusion of GYKI 52466 15.2 mumol/kg/hr, the other with the same volume of control vehicle. Limb and face tremor and myoclonus were delayed and the severity of signs reduced. No seizures were observed in the drug treated group before 91 ATA. EEG changes associated with exposure to pressure were not affected. It is concluded that antagonism at the AMPA/kainate receptor by GYKI 52466 and LY 293558 beneficially alters HPNS signs but in a manner which is dependent on both the drug and species being studied.
Pearce
P C
PC
Anaesthesia/HPNS group, MRC Clinical Research Centre, Harrow, Middlesex, U.K.
Maclean
C J
CJ
Shergill
H K
HK
Ward
E M
EM
Halsey
M J
MJ
Tindley
G
G
Pearson
J
J
Meldrum
B S
BS
D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006610:High Pressure Neurological Syndrome / Q000517:prevention & control*; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009207:Myoclonus / Q000517:prevention & control; D010215:Papio; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014202:Tremor / Q000517:prevention & control
D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D013777:Tetrazoles; C061950:GYKI 52466; C082309:tezampanel