SHORT-TERM DIABETES IN THE BRAIN: EFFECTS ON NEUROACTIVE STEROIDS, CHOLESTEROL HOMEOSTASIS, AND MITOCHONDRIAL FUNCTIONALITY

Diabetes may induce neurophysiological and structural changes in the central nervous system (i.e., diabetic encephalopathy). Neuroactive steroids (i.e. molecules derived from cholesterol which exert their actions in the nervous system directly or after metabolization) are key regulators of the central nervous system and are affected in several neuropathological disorders. As previously observed by our laboratory, three months of diabetes modifies the levels of neuroactive steroids in different brain regions of an experimental model of diabetic rat (i.e. raised diabetic by streptozotocin). On this basis, we explored whether neuroactive steroid levels may be already affected after one month (i.e., a period in which diabetic encephalopathy is already apparent), in two brain regions such as hippocampus and cerebral cortex. By liquid chromatography-tandem mass spectrometry analysis we observed that the levels of several neuroactive steroids, such as pregnenolone, progesterone and its metabolites (i.e., tetrahydroprogesterone and isopregnanolone), testosterone and its metabolites (i.e., dihydrotestosterone and 3α-diol) in the hippocampus and cerebral cortex were altered. Interestingly these brain changes were not fully reflected by the plasma level changes, suggesting that early phase of diabetes directly affects steroidogenesis and/or steroid metabolism in these brain areas. To further explore this finding we analyzed crucial steps of the steroidogenic machinery, like for instance the gene expression of steroidogenic acute regulatory protein (i.e., molecule involved in the translocation of cholesterol into mitochondria) and cytochrome P450 side chain cleavage (i.e., enzyme converting cholesterol into pregnenolone). In addition, we analyzed cholesterol homeostasis (i.e., synthesis, trafficking and metabolism) as well as mitochondrial functionality, a key organelle in which the limiting step of neuroactive steroid synthesis takes place. Data obtained indicate that short-term diabetes alters steroidogenic machinery (e.g. Star and P450scc) in the hippocampus. On the contrary, in the cerebral cortex only the gene expression of StAR was down-regulated by short-term diabetes after one month, while P450scc remained unchanged. In addition, an impairment of cholesterol homeostasis as well as mitochondrial dysfunction, even if with different characteristics, was present in the hippocampus and cerebral cortex. In conclusion, data here reported indicate that short-term diabetes modifies the levels of neuroactive steroids in the hippocampus and cerebral cortex. These changes, depending on the brain structures considered, are associated with alteration of steroidogenic machinery, cholesterol homeostasis and mitochondrial dysfunction.