L¿ATTIVAZIONE DI TSPO E DI LXR STIMOLA LA NEUROSTEROIDOGENESI ED E¿ PROTETTIVA IN UN MODELLO DI NEUROPATIA PERIFERICA DI RATTO DIABETICO

Abstract

Diabetes mellitus (DM) is one of the first leading cause of death in most high-income countries and there is evidence that it is epidemic in many economically developing and newly industrialized nations. Beside these considerations, there are epidemiologic evaluations that show a dramatic increase of the number of diabetic and with impaired glucose tollerance patients in the next years. It is also important to underline that complications from diabetes, such as coronary artery and peripheral vascular disease, stroke, diabetic neuropathy, renal failure and blindness result in increasing disability, reduced life expectancy and enormous health costs for virtually every society. In particular, diabetic peripheral neuropathy can account for the 50-75% of non traumatic amputations; diabetes is therefore undoubtedly one of the most challenging health problems of our century. Recently, in an animal model of diabetic neuropathy (i.e. the rat raised diabetic with the injection of streptozotocin - STZ), it has been demonstrated that, in plasma and in sciatic nerve, the levels of neuroactive steroids are dramatically decreased. Promising results have been obtained in the same experimental model after treatments with progesterone, testosterone and their derivatives. The use of molecules able to increase the neuroactive steroid levels directly in the nervous system could be an interesting therapeutic approach because it may avoid the endocrine side effects usually observed after systemic treatment with steroids. In order to evaluate the possible neuroprotective effects mediated by an increase of neuroactive steroid levels in the peripheral nervous system, using the model of the STZ rat we here analyzed the effects of two different pharmacological approaches. In the first part of this thesis, we analyzed the effect of Ro5-4864, a ligand of the translocator protein of 18 kDa (TSPO). TSPO is a key regulator of neuroactive steroid synthesis and it is involved in the rate limitig step of this process (i.e. the entrance of cholesterol into the mitochondria). Indeed, it has been recently demonstrated that injection of TSPO ligands, like for instance Ro5-4864, was able to increase the capability of steroidogenic machinery in adrenal cortex, placenta, testis, ovary and glial cells. In the second part of this thesis, the effect of GW3965, a ligand of the Liver X Receptor (LXR), was analyzed. The rationale of this approach was based on the finding that cholesterol homeostasis is partially controlled by the regulation of different genes activated by LXR. Moreover, LXR activation is able to increase the steroidogenesis in the adrenal glands. At 2 months after STZ injection, two different protocols of TSPO ligand administration were assessed; in particular, animals were injected every 2 days or once a week whit the ligand (i.e., they received 16 or 4 injections). In the case of GW3965 treatment, at 2 months, diabetic animals were treated once a week (i.e., they received 4 injections). Functional and behavioural parameters, like for…