Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection.

Abstract

Neurons in the rat medial septum (MS) and vertical limb of the diagonal band of Broca (VDB) undergo a rapid and severe cell death after transection of their dorsal projection to the hippocampus by aspiration of the ipsilateral fimbria fornix and supracallosal striae. By 2 weeks posttransection, the extent of neuronal loss was 50% of the total neurons and 70% of the cholinergic neurons in the MS and 30% of the total neurons and 40% of the cholinergic neurons in the VDB.We hypothesized that (t) the death was due to the loss of a hippocampus-derived neuronotrophic factor, and (ii) exogenous nerve growth factor (NGF) might provide trophic support to the MS/VDB cholinergic neurons, in light of recent reports that the septal diagonal band cholinergic neurons are responsive to NGF and that NGF is present and produced in the hippocampus. In the present study, we attempted to prevent the transection-induced neuronal death by continuous infusion of exogenous 7S NGF (1 jag/wk) through an intraventricular cannula device. We report here that NGF treatment significantly reduces both the total neuronal and cholinergic neuronal death found 2 weeks after runbria fornix transection; there was a sparing of 50% of the neurons in the MS and essentially 100% of those in the VDB that otherwise would have died. We conclude that NGF also has a protective effect on noncholinergic neurons since calculations indicate that 80% of the NGFaffected neurons are noncholinergic.

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

“…Consistent with our results that NGF was not neurotrophic for cortical 5-HT axons are the findings that NGF fails to elicit 5-HT neurite outgrowth in embryonic raphe cultures , or cause serotonergic axon sprouting in the adult rat striatum (Kawaja and Gage, 1991), despite its ability to promote robust sprouting of cholinergic (Williams et al, 1986;Kawaja and Gage, 1991) and sympathetic (Isaacson et al, 1992) fibers. Moreover, NT-3, in this study, was considerably less potent than BDNF in promoting the survival of serotonergic axons after PCA, which remarkably parallels the relative potencies of these neurotrophins in augmenting 5-HT metabolism and analgesia (Siuciak et al, 1994).…”

“…Based on the findings from other neurodegeneration models, a tropic role for the neurotrophins in promoting axonal growth after injury has been proposed, in addition to their role in supporting neuronal survival (reviewed by Gage et al, 1990). For example, after fimbria-fornix transection, exogenous administration of NGF causes sprouting of local cholinergic axons in the lateral septum (Williams et al, 1986) and promotes the regrowth of lesioned septal cholinergic fibers across a "grafting bridge" into the hippocampus (Hagg et al, 1990;Tuszynski et al, 1990). In addition to its effects upon axotomized neurons, NGF can elicit the sprouting of mature, uninjured sympathetic axons (Isaacson et al, 1992) and promote neurite growth from nonlesioned cholinergic neurons in the adult brain (Koliatsos et al, 1991;Tuszynski et al, 1991).…”

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

“…Notably, BDNF is also involved in the development of motor coordination (Strand et al, 2007). Several studies have demonstrated that age-and AD-related dysfunctions of the cholinergic system related to physical activity as well as cognitive function are ameliorated by NGF and BDNF treatment (Williams et al, 1986;Casamenti et al, 1994;Kordower et al, 1994;Murray et al, 1994).…”

Brain‐derived neurotrophic factor‐transduced fibroblasts: Production of BDNF and effects of grafting to the adult rat brain

“…Neurotrophic molecules promote neuronal survival when exogenously administered in amounts that exceed normal physiological levels. NGF, the best-characterized member of the neurotrophin family, has been extensively studied for its role in the cholinergic septohippocampal model, where administration of exogenous NGF to the axotomized septohippocampal projection rescues up to 90% of the transected septal cholinergic neurons (Hefti, 1986;Williams et al, 1986;Kromer, 1987;Gage et al, 1988). A decrease in neurotrophic factors during aging has also been hypothesized to predicate degenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD; Appel, 1981;Hefti, 1983), where the loss of dopaminergic neurons of the substantia nigra pars compacta (SNC) is correlated with the major motor disability of PD, and the loss of cholinergic neurons in the basal forebrain is associated with memory loss in AD (Bernheimer et al, 1973;Olton, 1990).…”