Induction of memory and cortical cholinergic neurochemical recovery with combine fetal transplantation and GM1 treatments in rats with lesions of the NBM

Abstract

Sixty-four Sprague-Dawley rats received ibotenic-acid-induced unilateral nucleus basalis of Meynert (nbM) lesions; 10 additional animals served as sham controls. Eight to ten days later, subjects with lesions received either fetal cholinergic transplants implanted within the ipsilateral (relative to the lesion) frontal cortex or control transplant surgeries. Lesioned animals with and without transplants were then treated with GM1 (20 mg/kg, i.p.) for either 0, 1 or 10 days and were then trained and tested for 72-hour retention of passive avoidance. Results indicated that the lesion produced a significant impairment on this task. Transplant therapy combined with GM1 for 10 days yielded a significant reversal of this deficit. GM1 injections continued once per week for 4 weeks for half the lesioned animals in the transplant and no-transplant 10-day conditions. During a 6-month period, all subjects were assessed on two additional memory tasks (complex spatial discrimination and delayed spatial alternation). In general, there was no indication of a lesion, transplant, GM1, or transplant X GM1 effect on these tasks. Approximately 7.5 months after transplants, subjects were sacrificed and their frontal cortices examined for choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activity. Only lesioned subjects with transplants which were given sustained GM1 treatment (i.e., 10 days plus weekly injections for 4 weeks) showed significant attenuations of lesion-induced CAT and AChE depletions. These data suggest that a combined treatment strategy of fetal transplant plus GM1 is capable of reversing nbM lesion-induced memory and neurochemical deficits in an animal model of the cholinergic deficits in Alzheimer's disease.