SEIZURES AND HIPPOCAMPAL DAMAGE PRODUCED BY DENDROTOXIN-K IN RATS IS PREVENTED BY THE 21-AMINOSTEROID U-74389G

The epileptogenic and neurodegenerative effects of dendrotoxin K (DTx- K), from Dendroaspis polylepis, a specific blocker of a noninactivatin g, voltage-sensitive K+ channel, were studied after focal injection in to one dorsal hippocampus in rats pretreated with the 21-aminosteroid U-74389G, a scavenger of free oxygen radicals. Administration of 35 pm ol DTx-K elicited in all of the treated animals (n = 6) motor seizures and bilateral electrocortical (ECoG) discharges after a latent period of approximately 5 min. At 24 h, histological examination of brain (n = 6) coronal sections (10 mu m; n = 6 per brain) detected bilateral d amage to the hippocampal formation. Quantitation of damage revealed si gnificant bilateral neuronal cell loss in the CA1 and CA4 pyramidal ce ll layer and dentate gyrus granule cell layer relative to the correspo nding brain regions of rats (n = 6) injected with bovine serum albumin (300 ng), which per se was ineffective in all respects. DTx-K (35 pmo l) also caused a significant loss of CA3 pyramidal neurons ipsilateral to the site of toxin injection. Systemic (i.p.) administration of U-7 4389G (5 mg/kg given 30 min beforehand) delayed the onset of motor and ECoG seizures and reduced the number of epileptogenic discharges typi cally observed in rats receiving an injection of DTx-K (35 pmol) alone . Similarly, this treatment prevented the damage inflicted to the hipp ocampus by the toxin and in no instance was significant neuronal loss observed. At variance with these results, pretreatment with U-74389G ( up to 10 mg/kg i.p.) failed to prevent seizures and CA1 hippocampal da mage evoked by intrahippocampal injection of alpha-DTx (35 pmol), a DT x-K homologue which preferentially inhibits a slowly inactivating, vol tage-dependent K+ conductance in nerve cells. In conclusion, the prese nt data support a role for free oxygen radicals in mediating hippocamp al damage induced by DTx-K, but not alpha-DTx, and confirm the origina l deduction that these DTx homologues are complementary neurobiologica l tools to study mechanisms of seizures and neuronal death. (C) 1997 A cademic Press.