A. Moralesvillagran et al., PROTECTION BY NMDA RECEPTOR ANTAGONISTS AGAINST SEIZURES INDUCED BY INTRACEREBRAL ADMINISTRATION OF 4-AMINOPYRIDINE, European journal of pharmacology, 305(1-3), 1996, pp. 87-93
The effects of NMDA receptor antagonists on the convulsant action of t
he administration of l-aminopyridine in the rat lateral cerebral ventr
icle (i.c.v. injection) and motor cerebral cortex (i.cx. injection) we
re studied. 4-Aminopyridine administration in both regions induced var
ious preconvulsive symptoms, such as salivation, tremors, chewing and
rearing, followed by continuous clonic convulsions and, only after i.c
.v. injection, running fits and generalized tonic convulsions. This be
havioral pattern appeared 5-9 min after administration of 4-aminopyrid
ine and persisted for 100-150 min. 4-Aminopyridine also generated epil
eptiform electroencephalographic (EEG) discharges characterized by iso
lated spikes, poly-spikes and spike-wave complexes, which began some s
econds after administration of the drug and were present for more than
2 h. The NMDA receptor antagonists -)-3-(2-carboxy-piperazi-4-yl)-pro
pyl-1-phosphonic acid (CPP), (+/-)-2-amino-7-phosphono-heptanoic acid
(AP7) and 0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen
maleate (MK-801) clearly protected against some of the behavioral alte
rations induced by i.c.v. 4-aminopyridine, particularly the tonic conv
ulsions, but were less effective against those produced by i.cx. 4-ami
nopyridine. These antagonists also delayed the appearance of EEG epile
ptiform discharges, reduced its amplitude, frequency and duration, and
blocked their propagation to other cortical regions after i.cx. 4-ami
nopyridine. These results, together with previous data showing that 4-
aminopyridine stimulates the release of glutamate in vivo, suggest tha
t an excessive glutamatergic neurotransmission involving NMDA receptor
s is implicated in 4-amino-pyridine-induced seizures.