Modulation of Sensory Inputs and Ectopic Presence of Schwann Cells Depend upon the Route and Duration of Nerve Growth Factor Administration

Abstract

Nerve growth factor (NGF) ameliorates deficits in models of cholinergic hypofunction. However, notable adverse effects of intracerebroventricular (ICV) infusion of NGF include weight loss, Schwann cell hyperplasia (SCH), and aberrant sensory and sympathetic sprouting. In order to maintain efficacy on the cholinergic basal forebrain (CBF) and minimize these detrimental effects, intraparenchymal NGF infusion was compared with ICV administration to assess morphological and functional measures. NGF was delivered intraparenchymally (Intra-NGF) or intracerebroventricularly (ICV-NGF) for 3 and 6 months. Hypertrophy of cholinergic nucleus basalis neurons at 3 and 6 months was not different between both routes of administration, indicating similar efficacy for the CBF. SCH surrounding the medulla was observed in both Intra- and ICV-NGF animals due to the widespread distribution of NGF from the infusion site. The thickness of SCH reached a plateau at 3 months in ICV-NGF animals, while further proliferation occurred in Intra-NGF animals. More importantly, ectopic Schwann cells and aberrant sensory and sympathetic sprouting within the medulla oblongata were found solely in ICV-NGF animals. Differential changes in sensory processing were evident by an exaggerated response to acoustic stimuli in Intra-NGF animals and a decrease in thermal pain threshold in ICV-NGF-treated animals. Intra-NGF treatment did not produce the reduction in body weight exhibited by ICV-NGF-treated rats. These results indicate that different routes of NGF administration are identically efficacious for CBF neurons, but differentially modulate behaviors and structures leading to distinct profiles of adverse effects. Thus, current trophic factor delivery methods require further refinement to abolish detrimental effects.