Clenbuterol stimulates neurotrophic support in streptozotocin-diabetic rats

Background: The diabetic neuropathies are characterized by axonal degeneration of peripheral nerves. The commonest variant of this condition is distal symmetrical polyneuropathy, in which the principal presenting features can be explained by impaired neurotrophic support of sensory neurones. Aims: The aims of these experiments were to determine whether deficits in nerve growth factor (NGF) content and the products of its target genes (substance P and calcitonin-gene related peptide; CGRP) in the sciatic nerve of streptozotocin-induced rats could be prevented using clenbuterol, which has been demonstrated to induce NGF synthesis in vitro. Results: Diabetes of 8 weeks duration produced a reduction in measurable sciatic nerve NGF-like immunoreactivity (NGF-LI) content of 53% (p < 0.01). This was accompanied by depletion of substance P (of 43%; p < 0.01) and CGRP (of 45%; p < 0.01). Treatment with clenbuterol (30 mu g/kg, 100 mu g/kg and 300 mu g/kg; daily subcutaneous injection) significantly increased the NGF-LI and neuropeptide content of the sciatic nerve, with 30 mu g/kg of clenbuterol normalising the levels in diabetic animals. The alterations in steady state sciatic nerve NGF-LI were proportionally related to the amount of NGF-LI delivered to the primary afferent neurones via retrograde transport. Thus, there was a significant reduction in accumulation of NGF-LI distal to a 12-h ligature in diabetic untreated rats (p < 0.01), which was normalized by clenbuterol (30 mu g/kg; p < 0.05). Treatment of control or diabetic rats with clenbuterol did not affect the local production of NGF-LI in the sciatic nerve adjacent to and triggered by an occluding ligature. The change in NGF-LI content of neuronal tissue in the clenbuterol treated rats was a reflection of the capture of NGF derived from the peripheral targets of the sciatic nerve. The soleus and EDL muscles showed reductions in NGF-LI in untreated diabetic animals. Clenbuterol significantly (p < 0.05) increased NGF-LI in the soleus muscle. Conclusion: Clenbuterol could be a useful tool in alleviating the deficits in neurotrophin support in diabetes.