Intermittent vs Continuous Administration of Nerve Growth Factor to Injured Medial Septal Cholinergic Neurons in Rat Basal Forebrain

Authors

Kenneth E. Miller, Gregory E. Frierdich, Robert H. Dillard, Robert H. Soriano, Dikla G. Roufa

Abstract

Many medial septal neurons of the basal forebrain are dependent on nerve growth factor (NGF) from the hippocampus for survival and maintenance of a cholinergic phenotype. When deprived of their source of NGF by axotomy, medial septal neuronal cell bodies atrophy and lose their cholinergic markers. This is similar to what is observed in the basal forebrain during Alzheimer’s disease (AD). In the present study, medial septal neurons were axotomized in female rats by way of a fimbria/fornix lesion. For fourteen days following axotomy, varying NGF doses (1 - 250 μg/ml) were administered to the lateral cerebral ventricle with either mini-osmotic infusion or daily injection. The responsiveness of medial septal neurons was evaluated with choline acetyltransferase immunohistochemistry. Within the mini-osmotic pumps, NGF activity diminished greatly during the first five days of implantation, but increased dramatically in the CSF after five days of infusion. The responsiveness of medial septal neurons to NGF was dose dependent and the ED50 for NGF injection was determined to be 14.08 μg/ml compared to 27.60 μg/ml for NGF infusion. Intermittent injections at varying intervals were evaluated with 30 μg/ml NGF over a fourteen-day time period (2, 3, 6, or 12 injections). No differences occurred in the number of choline acetyltransferase neurons from rats that received weekly injections to those that received daily injections of NGF. NGF administration has been suggested as a therapy for AD. The results of these studies continue to highlight the need for NGF stability within the delivery system and AD patient CSF, the choice of delivery system, frequency of administration, and the NGF dose for maintaining basal forebrain cholinergic neurons during AD.