The effects of ciliary neurotrophic factor on experimental degeneration in the anterior thalamus: Implications for its mechanisms of action in the central nervous system

Ciliary neurotrophic factor (CNTF) is a member of a family of molecules known as cytokines which have a multitude of effects in the nervous system. Although significant work has been done at the molecular level in elucidating receptor components and signal transduction pathways for CNTF, little is known about its mechanisms of action at the level of the cellular microenvironment or its physiologic role in the nervous system.; To examine the effects of CNTF on experimental degeneration in the central nervous system, we developed a reproducible model of injury induced retrograde degeneration in the anterior thalamus of the rat. As a means of studying an established regeneration paradigm in this model, autologous peripheral nerve grafts were transplanted into the anterior thalamus following cingulotomy. These grafts ameliorated some of the retrograde cell death seen after cingulotomy and produced a marked hypertrophy of rescued neurons. These grafts also provided excellent conduits for the ingrowth and elongation of axons.; As CNTF is present in relative abundance in peripheral nerves, the effects of recombinant CNTF were examined in this model system. At two weeks, CNTF was able to prevent most of the retrograde cell death seen in the anterior thalamus after lesioning. In addition, polymerase chain reaction techniques demonstrated messenger RNA for both CNTF and its principal binding protein the CNTF receptor alpha in the anterior thalamus, suggesting a autocrine/paracrine function for this molecule. To further understand the role of CNTF in this model, immunocytochemistry for glial fibrillary acidic protein (GFAP) was employed to examine astrocytes. CNTF appears to induce the expression of GFAP and alter astrocytic morphology. Messenger RNA for CNTF and CNTF receptor alpha were then demonstrated in the optic nerve, and sequence analysis of the GFAP promoter revealed DNA elements thought to confer transcriptional response to CNTF. This suggests a role for CNTF in glial cell-cell interaction.; In the light of our data and what is known, we propose that CNTF is used in the nervous system as an autocrine/paracrine cytokine involved in glial responses to injury.