Rescue of lesioned septal cholinergic neurons by nerve growth factor: specificity and requirement for chronic treatment

Abstract

We earlier reported that chronic intraventricular injections of NGF into adult rats with partial transection of the fimbria prevent the lesion-induced disappearance of cholinergic neurons in the medial septal nucleus and the diagonal band of Broca (Hefti, 1986). The present study assessed the specificity and treatment requirements of this effect of NGF. Immunohistochemical visualization of NGF receptors (NGF-R) revealed that these molecules are selectively located in forebrain cholinergic neurons of unlesioned brains. Fimbrial transection resulted in transient accumulation of NGF-R in proximal stumps of lesioned axons but failed to induce the expression of NGF-R by other cells in the septal area or near the lesion. Two to three weeks after lesioning, the number of septal neurons expressing NGF-R was reduced by approximately 50% in parallel with the reduction of the number of neurons expressing cholinergic marker enzymes. Repeated intraventricular NGF injections during 4 weeks prevented the disappearance of these cells. Fimbrial transections also reduced the number of septal GABAergic neurons visualized by glutamate decarboxylase immunohistochemistry. The loss of GABAergic neurons was not prevented by NGF. These findings suggest that NGF prevents the lesion-induced degeneration of cholinergic neurons by directly acting on NGF-R expressed by cholinergic cells and that NGF does not affect any neuron with an axonal lesion. Delayed start of the NGF treatment failed to prevent the disappearance of lesioned cholinergic neurons, providing evidence that NGF treatment indeed promotes the survival of these cells rather than simply upregulating the expression of transmitter-specific enzymes. A single injection of NGF at the time of the lesion was not sufficient to prevent the lesion-induced degeneration of cholinergic neurons. Furthermore, termination of chronic NGF treatment after 4 weeks was followed by loss of septal cholinergic neurons after an additional 4 weeks. These findings suggest that the continuous presence of NGF during more than 4 weeks is required to prevent the degeneration of cholinergic cells. The data are discussed in the context of a possible physiological role of NGF in the function of adult forebrain cholinergic neurons.

Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer

“…This is in agreement with the subsequently lower NGF levels, and that some NGF effects are not maintained after abolishing treatment. 31,32 The diseased AD brain environment also shows increased inflammatory responses and oxidative stress, 33 --35 which might affect cells negatively in implanted devices. However, the inflammatory environment in the AD brain is less severe than in the QA-lesioned rat and therefore cell viability is unlikely to be affected.…”

Galanin regulates the postnatal survival of a subset of basal forebrain cholinergic neurons

“…Chronic intracerebroventricular infusion of NGF up-regulates ChAT gene expression and activity in the forebrain, thereby increasing ACh release (28-30). The trophic role played by NGF is evident because it prevents the death of cholinergic neurons in vivo after axotomy (31,32) and reverses the cognitive deficits associated with lesion-induced damage to cholinergic pathways (33). Further, targeted disruption of the high-affinity NGF receptor TrkA results in a developmental loss of 40% of ChAT-IR neurons in the medial septum associated with a doubling of the number of TUNELpositive neurons in the basal forebrain at P7 (34).…”

Brain Drug Delivery Systems for Neurodegenerative Disorders

“…The problem of this neurotrophic factor, as with many other neurotrophic factors, is that it is a labile molecule with a short half-life, does not cross the BBB when administered systemically [72] and therefore needs to be administered directly to their target in the brain [73], and needs to be continuously administered since non-clinical studies have found that when NGF is withdrawn, its effects are not maintained [74,75].…”