The effect of the liver x receptors activation on neuroactive steroids levels in the central nervous system of diabetic rats

Streptozotocin (STZ) –induced diabetic rats shows decreased levels of neuroactive steroids (NS) in the central nervous system (CNS) (1, 2, 3). Has been shown that these hormones counteract degenerative effects exerting protective effects in the CNS of this experimental model (2). Nervous system is not only a target, but it is also able to synthesize and to metabolize NS (4). Therefore, an interesting therapeutic strategy could be increase the levels of NS directly in the nervous system. This therapeutic approach could be very interesting because it may avoid possible endocrine side effects exerted by the systemic treatment with NS. In this study we have evaluated whether the levels of NS present in the CNS of diabetic animals would be affected by the activation of translocator protein-18 kDA (TSPO) or liver X receptors (LXRs). We observed that the treatment with either Ro5-4864 (i.e. a ligand of TSPO) or with GW3965 (i.e. a synthetic ligand of LXRs) induced an increase of NS in the spinal cord, the cerebellum and the cerebral cortex of STZ-rats. Interestingly, the pattern of induction was different among the three CNS areas analyzed and between the two pharmacological tools. The activation of LXRs might represent a promising neuroprotective strategy since the treatment with GW3965, with respect to Ro5-4864 treatment, did not induce significant changes in the plasma levels of NS. This suggest that activation of LXRs may selectively increase the CNS levels of NS avoiding possible endocrine side effects exerted by the systemic treatment with these molecules. References: 1. Caruso, et al. J Mol Neurosci 2008; 2. Pesaresi, et al. J Mol Neurosci 2010; 3. Melcangi and Garcia-Segura, Horm Beahv 2010; 4. Melcangi, et al. CMLS 2008.