Effects of Intraventricular Locus Coeruleus Transplants on Seizure Severity in Genetically Epilepsy-Prone Rats Following Depletion of Brain Norepinephrine

摘要

Audiogenic seizures (AGS) in geneticallyepilepsy-prone rats (GEPR) of the moderateseizuresubstrain (GEPR-3s) were investigatedto determine whether norepinephrine (NE)depletion induced by 6-hydroxydopalnine (6-OHDA)microinfusion into the locus coeruleus(LC) could alter the efficacy of intraventricularNE tissue grafts in promoting reductions inseizure severity in AGS. GEPR-3s werestereotaxically infused with 6-OHDA(4μg/side/rat), or vehicle into the region of theLC. Following 6-OHDA treatment all animalswere subjected to 3 AGS tests. GEPR-3s seizureseverities were increased in 39.5% of theanimals after microinfusion of 6-OHDA into theregion of the LC. Following the third AGS test,each rat was stereotaxicaily implanted with 17gestational day rat fetal tissue obtained from thedorsal pons and containing the primordia of theLC or with tissue obtained from the neocortexor were sham-grafted. Subsequent to grafting,rats were subjected to 3 additional AGS tests.53% (10/19) of 6-OHDA treated GEPRs showeda significant reduction in seizure severityfollowing transplantation of fetal LC tissue. Incontrast, only 20% (1/5) of GEPRs infused withsaline rather than 6-OHDA showed, a reductionof seizure severity following fetal LCtransplantation. NE content in the cortex andpons/medulla was decreased by 78% and 46%respectively following 6-OHDA microinfusioninto the LC. Prominent grafts with numerousTH positive neurons and neurites were presentwithin the third ventricle of grafted animals,while cortex grafts contained no THimmunostained structures. These findingssuggest that the efficacy of fetal LC tissue topromote reductions in seizure severity in GEPRsis increased following depletion of central NE bymicroinfusion of 6-OHDA.