Antagonism of kainic acid lesions in the mouse hippocampus by U-54494A and U-50488H.
A morphometric study of kainic acid- (KA) induced lesions was designed for the study of the interaction of the diamines U-5449A and U-50488H with excitatory amino acids, and the dose-response relationship thereof. IC50S determined for binding at the kappa receptor and other opioid receptors demonstrated the lack of kappa activity of U-54494A, a structurally related analog of U-50488H. Both opiate kappa receptor related anticonvulsant diamines were tested for their ability to protect the mouse hippocampus from the cytopathological changes induced by KA in neurons and glia. The damage observed with i.c.v. KA in mouse was restricted to neurons of the CA3 pyramidal region and glia of the hippocampus. It involved massive cell loss and shrunken neurons with dark cytoplasm and nuclei. Groups treated with combinations of KA and U-54494A or U-50488H showed scarce damage, but patches of necrotic changes were still observed. Control animals treated with saline (i.c.v.) and U-54494A (s.c.) or U-50488H (s.c.) did not suffer any noticeable alterations of the polymorphic layers of the hippocampal formation. Image analysis of the CA3 area of the hippocampus was used to quantitate the vacuolization induced by KA lesions in the control and treated groups. By this method, both U-54494A and U-50488H were shown to protect this area in a dose-related fashion as evidenced by reduced vacuolization. The anticonvulsant properties of these compounds may result in the antagonism of the excitotoxic lesions. More specifically, the ability of these diamines to block depolarization-induced influxes of Ca++ may protect the CA3 cells from the cytotoxic effects of persistent depolarization.
Camacho Ochoa
M
M
CNS Research, Upjohn Company, Kalamazoo, MI 49001.
Jackson
T A
TA
Aaron
C S
CS
Lahti
R A
RA
Strain
G M
GM
Von Voigtlander
P F
PF
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007276:Injections, Intraventricular; D007608:Kainic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D014617:Vacuoles / Q000187:drug effects
D000927:Anticonvulsants; D011759:Pyrrolidines; D011957:Receptors, Opioid; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C054216:U 54494A; D007608:Kainic Acid