Involvement of a glutamergic mechanism in gamma-dendrotoxin-induced hippocampal neuronal cell loss in the rat.
The epileptogenic and neurodegenerative effects of gamma-dendrotoxin, from Dendroaspis angusticeps, a specific blocker of a non-inactivating, voltage-sensitive K+ channel, were studied after focal injection into one dorsal hippocampus in rats pretreated with CGP040116, a N-methyl-D-aspartate (NMDA) receptor antagonist, and in rats bearing a monolateral surgical lesion of the Schaffer collaterals whose terminals originate from CA3 pyramids and release glutamate in the CA1 hippocampal area. Administration of 35 pmol gamma-dendrotoxin elicited in all of the treated animals (n=8) bilateral EEG discharges and damage to the hippocampal formation. Quantitation of the damage revealed significant bilateral neuronal cell loss in the CA1, CA3 and CA4 pyramidal cell layers. The lowest dose (0.35 pmol; n=4) of the toxin used did not affect EEG activity and failed to cause significant hippocampal cell loss whereas the 3.5 pmol (n=6) dose caused EEG seizures and hippocampal cell loss limited to the CA1 area. Systematic intraperitoneal administration of CGP040116 (5mg/kg given 30 min. previously) delayed the onset of EEG seizures and reduced the number of epileptogenic discharges typically observed in rats receiving an injection of gamma-dendrotoxin (35 pmol) alone. Similarly, this treatment prevented the damage inflicted to the hippocampus by the toxin and in no instance was significant neuronal loss observed. Protection against seizures and hippocampal damage was also observed by a monolateral surgical lesion to the Schaffer collaterals. In conclusion, the present data suggest that an excitotoxic, glutamate-mediated, type of mechanism underlies seizures and hippocampal damage induced by gamma-dendrotoxin in rats.
Bagetta
Giacinto
G
Department of Pharmacobiology, University of Calabria at Cosenza, Rome, Italy. gbagett@tin.it
Palma
Ernesto
E
Piccirilli
Silvia
S
Del Duca
Claudio
C
Morrone
A Luigi
AL
Nappi
Guiseppe
G
Corasaniti
M Tiziana
MT
Dolly
J Oliver
JO
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000633:toxicity; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008297:Male; D009474:Neurons / Q000473:pathology*; D010455:Peptides / Q000633:toxicity*; D026902:Potassium Channel Blockers / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology
D004546:Elapid Venoms; D018691:Excitatory Amino Acid Antagonists; D010455:Peptides; D026902:Potassium Channel Blockers; C081639:dendrotoxin, gamma; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D018698:Glutamic Acid; D015763:2-Amino-5-phosphonovalerate