Ciliary Neurotrophic Factor for Acceleration of Peripheral Nerve Regeneration: An Experimental Study

The objective of this study was to investigate the effect of topically administrated ciliary neurotrophic factor (CNTF) on peripheral nerve regeneration. Sixty-eight Sprague Dawley rats underwent a unilateral sciatic nerve transection and silicon tubulization, with a 10-mm gap between the proximal and distal nerve stumps. Recombinant human CNTF (1 mg/kg) was injected into the rats of the experimental group, while normal saline was injected into the control group animals. Electrophysiologic and histologic studies, including nerve morphometry and electron microscopic observation, were performed at 1, 3, and 4 months postoperatively. HRP tracing was carried out at 3 months postoperatively to label spinal-cord, ventral-horn, and dorsal-root ganglia. The results revealed that CNTF-treated animals showed a higher motor nerve conduction velocity of the sciatic nerve and a higher muscle action potential amplitude of the anterior tibial muscle, compared to the controls (p < 0.01). Nerves repaired with CNTF had larger axon diameter, greater number of axons, and more advanced myelination (p < 0.05). More HRP-labeled motor neurons were also found in the ventral horns of CNTF-treated animals. These results indicate that topical application of CNTF to the injury site potentiates motor nerve axonal regrowth and axon maturation during peripheral nerve regeneration.

KEYWORDS

Ciliary neurotrophic factor (CNTF) - peripheral nerve regeneration

REFERENCES

• 1 Adler R, Landa K B, Manthorpe M, Varon S. Cholinergic neurotrophic factors: intraocular distribution of soluble trophic activity for ciliary neurons.  Science. 1979;  204 1434-1436
• 2 Manthorpe M, Skaper S D, Adler R et al.. Cholinergic neurotrophic factors: fractionation properties of an extract from selected chick embryonic eye tissues.  J Neurochem. 1980;  34 69-75
• 3 Barbin G, Manthorpe M, Varon S. Purification of the chick eye ciliary neurotrophic factor.  J Neurochem. 1984;  43 1468-1478
• 4 Blottner D, Bruggemann W, Unsicker K. Ciliary neurotrophic factor supports target-deprived preganglionic sympathetic spinal cord neurons.  Neurosci Lett. 1989;  105 316-320
• 5 Ernsberger U, Sendtner M, Rohrer H. Proliferation and differentiation of embryonic chick sympathetic neurons: effects of ciliary neurotrophic factor.  Neuron. 1989;  2 1275-1284
• 6 Arakawa Y, Sendtner M, Thoenen H. Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines.  J Neurosci. 1990;  10 3507-3515
• 7 Oppenheim R W, Prevette D, Qin-Wei Y et al.. Control of embryonic motoneuron survival in vivo by ciliary neurotrophic factor.  Science. 1991;  251 1616-1618
• 8 Sendtner M, Kreutzberg G W, Thoenen H. Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy.  Nature. 1990;  345 440-441
• 9 Apfel S C, Arezzo J C, Moran M, Kessler J A. Effects of administration of ciliary neurotrophic factor on normal motor and sensory peripheral nerves in vivo.  Brain Res. 1993;  604 1-6
• 10 Ip N Y, Li Y P, van de Stadt I et al.. Ciliary neurotrophic factor enhances neuronal survival in enbryonic rat hippocampal culture.  J Neurosci. 1991;  11 3124-3134
• 11 Friedman B, Scherer S S, Rudge J S et al.. Regulation of ciliary neurotrophic factor expression in myelin-related Schwann cells in vivo.  Neuron. 1992;  9 295-305
• 12 Smith G M, Rabinovsky E D, MacManaman J L, Shine H D. Temporal and spatial expression of ciliary neurotrophic factor after peripheral nerve injury.  Exp Neurol. 1993;  121 239-247
• 13 Lindsay R M, Wiegand S J, Alter C A, DiStefano P S. Neurotrophic factors: from molecule to man.  Trends Neurosci. 1994;  17 182-190
• 14 Davis S, Aldrich T H, Ip N V. Released form of CNTF receptor alpha component as a soluble mediator of CNTF responses.  Science. 1993;  259 1736-1739
• 15 Newman J P, Verity A N, Hawatmeh S et al.. Ciliary neurotrophic factor enhances peripheral nerve regeneration.  Arch Otolaryngol Head Neck Surg. 1996;  122 399-403
• 16 Sahenk Z, Seharaseyon J, Mendell J R. CNTF potentiates peripheral nerve regeneration.  Brain Res. 1994;  655 246-250
• 17 Stockli K A, Lottspeich F, Sendtner M. Molecular cloning expression and regional distribution of rat ciliary neurotrophic factor.  Nature. 1989;  342 920-923
• 18 Helgren M E, Squinto S P, Davis H L. Trophic effect of ciliary neurotrophic factor on denervated skeletal muscles.  Cell. 1994;  76 493-504
• 19 Mata M, Chuan-Fang J, Fink D J. Axotomy increases CNTF receptor mRNA on rat spinal cord.  Brain Res. 1993;  610 162-165
• 20 Utley D S, Lewin S L, Cheng E T et al.. Brain-derived neurotrophic factor and collagen tubulization enhance functional recovery after peripheral nerve transection and repair.  Arch Otolaryngol Head Neck Surg. 1996;  122 407-413