Photic and drug-induced epilepsy in the baboon ( Papio papio): The effects of isoniazid, thiosemicarbazide, pyridoxine and amino-oxyacetic acid

Abstract

1. 1. Drugs modifying γ-aminobutyric acid (GABA) metabolism have been administered intravenously to baboons ( Papio papio) manifesting a syndrome of photosensitive epilepsy. Myoclonic and seizure responses to intermittent light stimulation (ILS) have been observed before and after drug administration and compared with epileptic phenomena directly induced by the drugs. 2. 2. Isoniazid (INH), 65–80 mg/kg, increased the tendency to respond to ILS with generalized myoclonus or tonic-clonic seizures. ILS given 30–60 min after isoniazid 100 mg/kg induced seizures which commonly originated asymmetrically in the occipital cortex whereas in animals without drug treatment seizures usually originated in the fronto-rolandic cortex. Seizures occurred spontaneously ( i.e., in the absence of ILS) 7–70 min after isoniazid 130–150 mg/kg. Apart from changes associated with the seizures, no acute effects on behaviour were observed and there were no modifications in the background EEG rhythms. 3. 3. Enhanced responsiveness to ILS was observed 1–6 h after thiosemicarbazide (TSC), 4–5 mg/kg. Spontaneous seizures with very variable cortical points of origin were observed 1–4 h after thiosemicarbazide 7.5–10 mg/kg. After either TSC or INH it was possible to induce seizures with ILS repeatedly at intervals of a few minutes. 4. 4. Pyridoxine administered acutely in doses of 50–250 mg/kg did not diminish the tendency of photosensitive baboons to respond to ILS with generalized myoclonus. Thus the natural syndrome is not due to a dietary deficiency of pyridoxine or to a metabolic disorder leading to an abnormal requirement for pyridoxine. Pyridoxine, 150–300 mg/kg, given before isoniazid, did not modify its seizure-promoting effect. Pyridoxine, 200–250 mg/kg, completely blocked both the spontaneous and the ILS-induced seizures normally produced by thiosemicarbazide, 10 mg/kg. 5. 5. Amino-oxyacetic acid (AOAA) (5–15 mg/kg) had a marked protective effect against myoclonus induced by ILS. This effect began 30–40 min after AOAA administration and lasted up to 24 h. Spontaneous or ILS-induced cortical spikes or spikes and waves were not diminished by AOAA. A larger dose of AOAA (20 mg/kg) had a toxic effect, producing convulsions after 15–30 min. 6. 6. Drugs lowering brain GABA turnover (INH and TSC) enhance myoclonic responses to ILS and one which raises the brain GABA content (AOAA) blocks myoclonic responses. However, the occurrence of multiple seizures and the shift to an occipital point of origin for the seizures after INH and TSC suggest that it is unlikely that the same biochemical derangement is responsible for the photically-induced and drug-induced seizures. The persistence of spontaneous spikes and waves after AOAA suggests that this drug does not correct the primary abnormality but modifies its clinical expression.