Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, supports the survival of developing basal forebrain cholinergic neurons in vitro and is retrogradely transported by cholinergic neurons of the medial septum and diagonal band following intrahippocampal injections in vivo. To substantiate a potential role for BDNF in the maintenance of forebrain cholinergic neurons in the adult brain, we assessed the ability of BDNF to sustain the phenotype of medial septal cholinergic neurons following a unilateral transection of the fimbria. BDNF, NGF, or vehicle solutions were infused continuously in adult female rats either into the lateral ventricle (intracerebroventricularly) or directly into the septum for 2 weeks beginning at the time of the transection. In vehicle-infused animals, only 28% of the ChAT-immunoreactive neurons remained on the side ipsilateral to the lesion compared to the contralateral intact side. When infused intracerebroventricularly, both BDNF and NGF reduced the extent of the phenotypic loss, in that 44% and 68%, respectively, of the ChAT-immunopositive neurons remained on the lesioned side. Intraseptal infusion proved even more effective, in that following BDNF and NGF treatment 60% and 86%, respectively, of the normal complement of ChAT-immunopositive neurons were apparent on the side ipsilateral to the lesion. Similar results were obtained when an antibody to the low-affinity NGF receptor was used to identify the cholinergic neurons. To determine if the apparent greater efficacy of NGF compared to BDNF might be related to differences in delivery, we examined the patterns of distribution of radiolabeled BDNF and NGF injected into the lateral ventricle. 125I-BDNF showed only very little diffusion from the ventricles into the adjacent neural tissue and negligible retrograde labeling of the neurons within the basal forebrain. 125I-NGF, however, diffused readily into the brain, resulting in widespread retrograde labeling of basal forebrain neurons. A similarly limited distribution pattern was observed where BDNF was detected immunohistochemically in animals infused intracerebroventricularly (12 micrograms/d) for 2 weeks. In contrast, when delivered intraseptally, the same dose of BDNF exhibited a widespread diffusion within the surrounding neuropil and retrograde labeling of neurons in the medial septum and the vertical limb of the diagonal band. Thus, when delivered effectively, BDNF has a substantial capacity to rescue axotomized cholinergic neurons.

No abstract

Recent studies showed that brain-derived neurotrophic factor (BDNF) prevents developing motoneurons from naturally occurring and axotomy-induced cell death. Here we examined whether adult motoneurons retain responsiveness to BDNF. Consistent with previous studies, we found that adult spinal and brainstem motoneurons expressed the mRNA of BDNF receptor, trkB. In addition, the trkB immunoreactivities were readily detected in the adult spinal and brainstem motoneurons. We then demonstrated that axotomized adult motoneurons responded to exogenous BDNF. BDNF administered locally markedly attenuated the lesion-induced decrease of ChAT immunoreactivity and activity and enhanced the lesion-induced reexpression of low-affinity NGF receptor immunoreactivity in adult facial motoneurons. Furthermore, we found BDNF administered subcutaneously, intravenously, and into the cerebral ventricle attenuated the lesion-induced decrease of ChAT immunoreactivity in adult facial motoneurons in a dose-dependent fashion. Our data indicate that adult motoneurons retain their responsiveness to BDNF, suggesting that BDNF may be useful as a therapeutic agent for adult motoneuron disease.

Injury to mammalian motor nerves can lead to paralysis, but relatively succul regeneration may occur when conditions are favorable. Elucidation of the mcanism upholding successful regeneration is of theoretical and clincal interest. In this study, the hypothesis that insulin-like growth factor H (IGF-ll) can stimulate motor nerve regeneration was tested. When IGF-H was infused continuously near a site of crush on the sciatic nerve, the distance of motor axon regeneration was increased snlfcantly in rats. In contrast, spontaneous regeneration was inhibited when an anti-IGF-H antiserum was infused through a "window" in the epineurium. Thus, infused IGF-il can increase, and endogenous IGFs can support, the regeneration of motor axons in lesioned nerves.Successful regeneration often is encountered following injury to the peripheral nervous system. Nevertheless, paralysis can result from injury to motor axons in nerves, particularly when lesions are in proximal nerve regions (closer to the spinal cord). Such paralysis might be reduced in incidence someday with improved understanding of the mechanisms supporting successful regeneration. The consequences of motor nerve injury continue to pose a serious medical, economic, and societal problem.The nerve distal to a site of injury contributes to spontaneous regeneration (1, 2). After transection, axons can cross a gap of several millimeters and enter the distal nerve stump, indicating the presence of soluble neurotrophic substances. Supporting cells in the nerve distal to a lesion indeed produce soluble factors, which attract and stimulate neurite growth (3)(4)(5). Freezing the distal nerve greatly reduces the population of Schwann, fibroblast, endothelial, and other cell types and impairs regeneration (6, 7). Motor (8)