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 μmol/kg i.v. immediately before, followed by 70 μmol/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 μmol kg i.p. delayed tremor and myoclonus (44% and 12%), LY 293558 72 μimol kg additionally delayed seizure activity (21%). Side effects, principally tranquillization 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 15.2μmol/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.