Progesterone and its derivatives as protective agents in experimental diabetic neuropathy

Deleterious effects of diabetes on the nervous system are responsible for several disorders including damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Because of the importance of neuroactive steroids in the control of the nervous system functions and of their neuroprotective effects in several experimental models of neurodegenerative diseases, we have assessed whether chronic treatment with progesterone (P), and its derivatives, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), had protective effects against (STZ)-induced peripheral neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Data obtained have indicated that chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na+,K+-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22. Moreover, protective effects of these neuroactive steroids in STZ-rat were also evident on morphological degeneration of the sciatic nerve. Indeed, treatment with P or DHP induced a significant reduction in the number of fibers with myelin infoldings. Altogether these observations suggest that these neuroactive steroids might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while morphological integrity of myelin, the expression of myelin proteins and Na+,K+-ATPase activity are only influenced by P and DHP, (i.e., two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoid to evaluate the role of PR and GABA-A receptor in these protective effects. (PRIN-2005060584_004 and FIRST from University of Milan).