Effects of intraventricular locus coeruleus transplants on seizure severity in genetically epilepsy-prone rats following depletion of brain norepinephrine.

R W Clough,C Wang,P C Jobe,R A Browning,M A Statnick,M L Maring

doi:10.1155/np.1994.65

Abstract

Audiogenic seizures (AGS) in genetically epilepsy-prone rats (GEPR) of the moderateseizure substrain (GEPR-3s) were investigated to determine whether norepinephrine (NE) depletion induced by 6-hydroxydopalnine (6-OHDA) microinfusion into the locus coeruleus (LC) could alter the efficacy of intraventricular NE tissue grafts in promoting reductions in seizure severity in AGS. GEPR-3s were stereotaxically infused with 6-OHDA (4μg/side/rat), or vehicle into the region of the LC. Following 6-OHDA treatment all animals were subjected to 3 AGS tests. GEPR-3s seizure severities were increased in 39.5% of the animals after microinfusion of 6-OHDA into the region of the LC. Following the third AGS test, each rat was stereotaxicaily implanted with 17 gestational day rat fetal tissue obtained from the dorsal pons and containing the primordia of the LC or with tissue obtained from the neocortex or were sham-grafted. Subsequent to grafting, rats were subjected to 3 additional AGS tests. 53% (10/19) of 6-OHDA treated GEPRs showed a significant reduction in seizure severity following transplantation of fetal LC tissue. In contrast, only 20% (1/5) of GEPRs infused with saline rather than 6-OHDA showed, a reduction of seizure severity following fetal LC transplantation. NE content in the cortex and pons/medulla was decreased by 78% and 46% respectively following 6-OHDA microinfusion into the LC. Prominent grafts with numerous TH positive neurons and neurites were present within the third ventricle of grafted animals, while cortex grafts contained no TH immunostained structures. These findings suggest that the efficacy of fetal LC tissue to promote reductions in seizure severity in GEPRs is increased following depletion of central NE by microinfusion of 6-OHDA.

Highlights

Therapeutic potential in transplantation neurobiology is being explored in several animal models of neurological disorders including models of Parkinson’s disease/17,28,31,39/, Huntington’s disease /13,18/, Alzheimer’s disease /33,35/, and epilepsy /1,10,11,25/
Analysis of NE content in the cortex, an area of the brain which receives the majority of its noradrenergic terminals from the locus coeruleus (LC), revealed that 6-OHDA microinfusion into the LC caused a 78% reduction in cortical NE
In light of the remaining catecholamine cell groups in the brainstem, the 46% depletion following LC microinfusion of 6-OHDA appears to represent a rather large depletion of NE in those brainstem terminal fields which originate in LC neurons

Summary

Introduction

Therapeutic potential in transplantation neurobiology is being explored in several animal models of neurological disorders including models of Parkinson’s disease/17,28,31,39/, Huntington’s disease /13,18/, Alzheimer’s disease /33,35/, and epilepsy /1,10,11,25/. For Parkinson’s disease, progression of research on the potential beneficial effects of neurotransplantation has entered, perhaps prematurely /15,34/, the human clinical arena /24,26/. The hypothetical potential of neurotransplantation as a therapeutic approach to several neurological disorders is appreciable. Represents a natural animal model of epilepsy/19/. There are two independently derived strains of GEPR: GEPR-3s which consistently display an audiogenic seizure (AGS) score of 3, and GEPR-9s which consistently display an AGS score

Methods

Results

Conclusion