Delayed Immediate Early Gene Responses Precede Delayed Initiation Of Regeneration In Diabetic Nerve

Nerve fiber regeneration is impaired in diabetic nerve and contributes to the relentless nerve fiber loss characterizing this disorder. Immediate early gene responses constitute the initial response to nerve injury and include upregulation of NGF and IGF-1 primarily by Schwann cells. These responses are believed to initiate macrophage recruitment necessary for initiation of axonal regeneration. We examined NGF, IGF-1 and CNTF mRNA in sciatic nerve at 10 timepoints (0.5hr to 24d) following sciatic nerve crush in diabetic BB/W-rats. The peak of the immediate upregulation of IGF-1 and NGF occurred at 0.5 and 6 hrs respectively in control nerves and was delayed to 24 hrs and 2d for IGF-1 and NGF respectively in diabetic nerve. Also the expression of NGF p75 receptor was significantly attenuated in diabetic nerve. CNTF mRNA showed an immediate downregulation following nerve crush with no significant differences between control and diabetic rats. These findings suggest that attenuations of the immediate gene responses of para- and autocrine IGF-1 and NGF in diabetic nerve may be responsible for the earlier reported defect in macrophage recruitment and delayed initiation of nerve fiber regeneration.