A combined cobalt and C-14 2-deoxyglucose approach to antiepileptic drug assessment.
The cobalt model of epilepsy, in combination with the C-14 2-deoxyglucose (2-DG) autoradiographic technique, was used to assess the effects of phenytoin (PHT) and ethosuximide (ESM), two antiepileptic drugs, and ketamine (KET), a drug with anticonvulsant properties, on brain activity. Nine days after the unilateral insertion of a cobalt rod into visual cortex, the nondrugged control rats showed the usual hypermetabolic regions of putative epileptogenic tissue both adjacent to the necrotic cortical cobalt rod implant zone and more distally in the connecting thalamus. PHT and ESM, given a single injections immediately before the 2-DG uptake and clearing period, diminished glucose uptake in the cobalt-induced hypermetabolic "patches" as well as in normal tissue. However, both drugs decreased 2-DG uptake more in the thalamic patches, than in the less hypermetabolic cortical patches, where the drug-induced depression in glucose metabolism was the same as for normal tissue. These findings suggest that PHT and ESM, regardless of their actions on cell receptors and membrane conductances, are ultimately of therapeutic value because more active nervous tissue (such as epileptic tissue) is more vulnerable to the depressing effects of these drugs than is less active tissue. KET, in contrast to PHT and ESM, did not depress metabolic activity throughout the brain generally and even clearly increased it in limbic system structures. Also in contrast to PHT and SEM, KET diminished activity in the cobalt-induced patches without reducing it in the normal tissue of the homotopic control regions. The more selective depressing action of KET, an N-methyl-D-aspartate (NMDA) antagonist, may be related to the role NMDA receptors play in supporting strong nervous activity. The discussion emphasizes the usefulness of a combined cobalt/2-DG approach to antiepileptic drug assessment.
Krenz
N R
NR
Psychology Department, University of Calgary, Alberta, Canada.
Cooper
R M
RM
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000963:Antimetabolites / Q000008:administration & dosage; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects; D003035:Cobalt / Q000008:administration & dosage; D003847:Deoxyglucose / Q000008:administration & dosage; D004343:Drug Implants; D004827:Epilepsy / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D005013:Ethosuximide / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D010672:Phenytoin / Q000494:pharmacology; D051381:Rats; D013788:Thalamus / Q000033:anatomy & histology / Q000502:physiology; D014793:Visual Cortex / Q000033:anatomy & histology / Q000378:metabolism / Q000502:physiology
D000927:Anticonvulsants; D000963:Antimetabolites; D004343:Drug Implants; D003035:Cobalt; D005013:Ethosuximide; D010672:Phenytoin; D007649:Ketamine; D003847:Deoxyglucose