Differential neuroprotective effects of the NMDA receptor-associated glycine site partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and D-cycloserine in lithium-pilocarpine status epilepticus.
The status epilepticus (SE) induced in rats by lithium-pilocarpine (Li-pilo) shares many common features with soman-induced SE including a glutamatergic phase that is inhibited by NMDA antagonists. The present study determined whether 1-aminocyclopropanecarboxylic acid (ACPC) or D-cycloserine (DCS), both partial agonists of the strychnine-insensitive glycine site on the NMDA receptor ionophore complex, exerted anticonvulsant or neuroprotectant activity in Li-pilo SE. ACPC or DCS were administered either immediately following pilocarpine (exposure treatment) or 5 min after the onset of SE as determined by ECoG activity. SE was allowed to proceed for 3 h before termination with propofol. The rats were sacrificed 24 h following pilocarpine administration. Neither drug had an effect on the latency to seizure onset or the duration of seizure activity. ACPC administered 5 min after SE onset produced significant neuroprotection in cortical regions, amygdala and CA1 of the hippocampus. In contrast, when administered as exposure treatment ACPC enhanced the neural damage in the thalamus and CA3 of the hippocampus suggesting the neuropathology in those regions is mediated by a different subset of NMDA receptors. DCS had no neuroprotectant activity in Li-pilo SE but exacerbated neuronal damage in the thalamus. Neither drug affected the cholinergic convulsions but both had differential effects on neural damage. This suggests that the SE-induced seizure activity and subsequent neuronal damage involve independent mechanisms.
College of Pharmacy, 1 University of New Mexico, Albuquerque, NM 87131-0001, USA. bonfire@unm.edu
Steven L
SL
Peterson
Rebecca S
RS
Purvis
James W
JW
Griffith
D000598:Amino Acids, Cyclic / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D001921:Brain / Q000473:pathology; D003523:Cycloserine / Q000494:pharmacology*; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D008094:Lithium; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D013226:Status Epilepticus / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology
D000598:Amino Acids, Cyclic; D000963:Antimetabolites; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D010862:Pilocarpine; C023863:1-aminocyclopropane-1-carboxylic acid; D003523:Cycloserine; D008094:Lithium