Neurotrophic agents prevent motoneuron death following sciatic nerve section in the neonatal mouse

Abstract

We have examined the ability of different neurotrophic and growth factors to prevent axotomy-induced motoneuron cell death in the developing mouse spinal cord. After postnatal unilateral section of the mouse sciatic nerve, most motoneuron (MN) loss occurs in the lateral motor column of the fourth lumbar segment (L4). Significant axotomy-induced cell death occurred after surgery performed on or before postnatal day (PN) 5. In contrast, no significant cell loss was found when axotomy was performed after PN10. Axotomy on PN2 or PN5 resulted in a 44% loss of L4 motoneurons by 7 days, and a 66% loss of motoneurons by 10 days postsurgery. Implantation of gelfoam presoaked in various neurotrophic factors at the lesion site rescued axotomized motoneurons. Nerve growth factor (NGF), neurotrophin-4/5 (NT-4/5) and ciliary neurotrophic factor (CNTF) rescued 20%-30% of motoneurons, whereas brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and insulin-like growth factor 1 (IGF-1) rescued virtually all motoneurons from axotomy-induced death. By contrast, platelet-derived growth factor (PDGF)-AA, PDGF-AB, basic fibroblast growth factor (bFGF), and interleukin (IL-6) were ineffective on motoneuron survival following axotomy. NGF, BDNF, NT-3, IGF-1, and CNTF also prevented axotomy-induced atrophy of surviving motoneurons. These data show that mouse lumbar motoneurons continue to be vulnerable to axotomy up to about 1 week after birth and that a number of trophic agents, including the neurotrophins, CNTF, and IGF-1, can prevent the death of these neurons following axotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential responses to the application of exogenous NT‐3 are observed for subpopulations of motor and sensory neurons depending on the presence of skeletal muscle

“…Limb bud ablation (i.e., lack of target tissue) and deafferentation experiments, using developing chicks, have shown a rescue of MANs through administration of exogenous neurotrophin Qin-Wei et al, 1994). Similar studies have also been carried out using adult mammals showing a rescue of almost all MNs in the L4 SC after axotomy of the sciatic nerve Li et al, 1994). However, a recent study published by our laboratory was the first to complete an in vivo investigation into the effects of a single neurotrophin, BDNF, on the survival of subpopulations of MANs during EPCD in developing mammals.…”

“…Neurotrophin-3 knockout experiments have noted no loss of MNs in the LMC and MMC (Yan et al, 1993;Snider, 1994;Huang and Reichardt, 2001;Patel et al, 2003) and facial motor nucleus neuron loss is shown to be nonsignificant, i.e., no obvious deficits were detected, in the brainstem of newborn NT-3Ϫ/Ϫ mice . Whereas certain in vitro studies have demonstrated inadequate promotion of chick motoneuron survival through the use of NT-3 and BDNF, the application of these same neurotrophic factors on cultured fetal rat motoneurons demonstrated a survival-promoting effect for these agents (reviewed in Li et al, 1994).…”

“…In the first injection studies of this type, where P12 mice that had been axotomized at P5 and treated at the site of axotomy with gel foam (soaked in 10 l of NT-3), the investigators found that 102% of L4 MNs were counted relative to the unoperated contralateral side and a larger 183% relative to the saline-treated ipsilateral SC MN numbers Li et al, 1994). Dorsal root ganglion neuron numbers were not investigated for NT-3 treatment; however, NGF was found to increase neuron numbers by 40% in the L3 DRG of embryonic chicks and by 65% in fetal mice injected on E14 and examined on E18 .…”

“…Others have demonstrated that application of exogenous NT-3 serves to rescue both SC and cranial motor and proprioceptive neurons from axotomy-induced and deafferentation cell death in developing chicks and in adult mice (Yan et al, 1993;Li et al, 1994). In the current study, we examine the ability of NT-3 to rescue neurons and increase neuron numbers during EPCD and NPCD, respectively.…”

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

“…The role of neurotrophins in preventing the inappropriate paring of synaptic connections in perinatal animals leaves these neurons much more susceptible to cell death following the removal of a trophic source, either through biochemical manipulations or via de-efferentation by axotomy, than neurons in adult animals [76,77]. Sciatic lesion in neonatal mice results in a loss of approximately two-thirds of the lower motor neurons in the lumbar enlargement, which is completely ameliorated with the application of BDNF, NT-3, or insulin-like growth factor I (IGF-I) [78]. This death of neonatal motor neurons is in stark contrast to lower motor neurons that not only survive, but regenerate following adult sciatic nerve injury; sciatic injury has been shown to result in increased NGF, BDNF, IGFs, cilliary neurotrophic factor, and glial-derived neurotrophic factor secretion from Schwann cells [44][45][46][47][48][49][50][51][52][53].…”