Apoptosis of spinal interneurons induced by sciatic nerve axotomy in the neonatal rat is counteracted by nerve growth factor and ciliary neurotrophic factor

Abstract

We have previously shown that not only motoneurons and dorsal root ganglion cells but also small neurons, presumably interneurons in the spinal cord, may undergo apoptotic cell death as a result of neonatal peripheral nerve transection in the rat. With the aid of electron microscopy, we have here demonstrated that apoptosis in the spinal cord is confined to neurons and does not involve glial cells at the survival time studied (24 hours). To define the relative importance of the loss of a potential target (motoneuron) and a potential afferent input (dorsal root ganglion cell) for the induction of apoptosis in interneurons in this situation, we have compared the distributions and time courses for TUNEL labeling, which detects apoptotic cell nuclei, in the L5 segment of the spinal cord and the L5 dorsal root ganglion after sciatic nerve transection in the neonatal (P2) rat. In additional experiments, we studied the effects on TUNEL labeling of interneurons after treatment of the cut sciatic nerve with either ciliary neurotrophic factor (CNTF) to rescue motoneurons or nerve growth factor (NGF) to rescue dorsal root ganglion cells. The time courses of the TUNEL labeling in motoneurons and interneurons induced by the lesion show great similarities (peak at 8-48 hours postoperatively), whereas the labeling in dorsal root ganglion cells occurs later (24-72 hours). Both CNTF and NGF decrease the number of TUNEL-labeled interneurons, but there is a regional difference, in that CNTF preferentially saves interneurons in deep dorsal and ventral parts of the spinal cord, whereas the rescuing effects of NGF are seen mainly in the superficial dorsal horn. The results are interpreted as signs of a trophic dependence on both the target and the afferent input for the survival of interneurons neonatally.

Glial‐mediated neuroprotection: Evidence for the protective role of the NO‐cGMP pathway via neuron–glial communication in the peripheral nervous system

“…6). Scale bars ϭ 100 m. Oliveira et al, 2002). Furthermore, NGF and NT3 gene knockout mice show severe neuronal deficits and an early postnatal death (Conover and Yancopoulos, 1997).…”

The Neuroprotective Effects of Reg‐2 Following Spinal Cord Transection Injury

“…The neuroprotective effects of CNTF following SCI and other CNS disease have long been confirmed by previous researchers (Linker et al, 2002;Oliveira et al, 2002;Ye et al, 2004;Lu et al, 2009). Studies have shown that intracerebroventricular or intrathecal infusion, but not intravenous or local injection, is more effective at reversing neuronal deficits (Meazza et al, 1997).…”

“…Previous investigation has shown that CNTF can rescue motoneurons from apoptosis induced by sciatic nerve axotomy (Oliveira et al, 2002), and intrathecal infusion of exogenous CNTF following SCI can reduce tissue damage, protect the rubrospinal descending tracks, and enhance the functional recovery of adult rats (Ye et al, 2004).…”

Effects of systemic administration of ciliary neurotrophic factor on Bax and Bcl-2 proteins in the lumbar spinal cord of neonatal rats after sciatic nerve transection

“…Such cellular loss has been related to the interruption of trophic support provided by target cells (1). However, the exogenous administration of neurotrophic molecules can prevent the death of neurons after peripheral nerve sectioning during the neonatal period (2)(3)(4). The ciliary neurotrophic factor (CNTF), a cytokine produced by Schwann cells, is capable of protecting the axotomized motoneurons when CNTF increases Bcl-2/Bax heterodimerization www.bjournal.com.br administered systemically in neonatal rodents (2)(3)(4).…”

“…However, the exogenous administration of neurotrophic molecules can prevent the death of neurons after peripheral nerve sectioning during the neonatal period (2)(3)(4). The ciliary neurotrophic factor (CNTF), a cytokine produced by Schwann cells, is capable of protecting the axotomized motoneurons when CNTF increases Bcl-2/Bax heterodimerization www.bjournal.com.br administered systemically in neonatal rodents (2)(3)(4). This neuroprotective action of CNTF is considered to be due to the inhibition of apoptosis (4,5), while the effectiveness of systemic administration of CNTF may be due to its ability to cross the blood-brain barrier by a saturable transport system (6).…”