Nerve growth factor attenuates hippocampal cholinergic deficits and operant learning impairment in rats with entorhinal cortex lesions

Abstract

In the present study we investigated whether continuous intraventricular nerve growth factor (NGF) infusion could ameliorate hippocampal cholinergic deficits and learning impairment following entorhinal cortex lesions. Rats with such lesions received continuous intraventricular infusions of NGF or vehicle. Unlesioned rats with a sham operation were studied as controls. After learning sessions, a dialysis probe was implanted in the CA3 hippocampal region. In addition, brain sections were stained for synaptophysin immunoreactivity. In rats undergoing surgical procedures similar to those in the behavioral study, brains were processed for acetylcholinesterase (AChE) histochemistry. NGF-treated rats showed partial amelioration of lesion-associated hippocampal acetylcholine (ACh) efflux deficits and fixed-interval schedule learning impairment compared with vehicle-treated rats. Histochemical, immunohistologic, and microdensitometric analyses confirmed greater density of AChE-positive fibers and synaptophysin immunoreactivity in CA3, in NGF-treated rats relative to vehicle-treated rats, although not as great as in sham-operation rats, indicating partial recovery in NGF-treated rats. These results suggest that enhanced performance of the learning task with NGF treatment was related to improved hippocampal cholinergic function: specifically, increased cholinergic neurotransmission resulting from NGF effects on cholinergic neurons and presynaptic terminals.

Transplantation of NGF-Gene-Modified Bone Marrow Stromal Cells into a Rat Model of Alzheimer’ Disease

“…Thus, the observation that nerve growth factor (NGF) is able to rescue injured cholinergic neurons opened a new horizon for the possible use of NGF in AD treatment (Hartikka and Hefti 1988). NGF, as a crucial trophic factor for neuronal survival in both the peripheral and the central nervous system (CNS), has been documented for many years (Barde 1989(Barde , 1990Shimode et al 2003;Ramirez et al 2003). Consistent with its action on the cholinergic system, NGF also can enhance functional restoration in animals with cholinergic lesions and has been proposed to be useful in human AD patients (Zou et al 2002;Niewiadomska et al 2002;Tuszynski 2000;Ruberti et al 2000;Klein et al 2000).…”