Atorvastatin prevents depressive behavior improving the sphingolipid metabolism and triggering neurovascular coupling via Apolipoprotein E

Depression is a common mental disorder, but classical antidepressants have many adverse reactions in clinical application. Many clinical studies show that lipid metabolism plays an important role in depression. In this study, chronic unpredictable mild stress (CUMS) model was established to evaluate the antidepressant activity and mechanism of classic lipid regulating drugs - atorvastatin (ATV) by ethology and multichannel electrophysiology etc., Laser speckle flow imaging and Doppler ultrasound measurement showed that ATV increased the cerebral blood flow and carotid blood flow of depressed mice. At the same time, ApoE-/- mice were compared to verify the important role of Apolipoprotein E (ApoE) in ATV antidepressant mechanism. Lipomics and Western blot showed that ATV administration could inhibit the increase of synaptic plasma membrane acidic sphingomyelinase (ASMase) stimulated by CUMS. Through further analysis of immunofluorescence and primary cell culture technology etc., it was found that ATV administration can inhibit the decrease of neuronal glutamate caused by the disorder of nerve sphingolipid, and increase the expression of metabotropic glutamate receptor (mGluR) and IP3 receptor (IP3R) in astrocytes. These findings suggest that ATV can regulate ApoE protein in central cortex, regulate sphingolipid metabolism in cortical synaptic plasma membrane, and alleviate the decline of cerebral blood flow in depressed mice through neurovascular coupling mechanism (NVC), so as to improve depression like symptoms. This means that atorvastatin may be a potential candidate for the treatment of depression. At the same time, it also provides a basis for lipid metabolism to become an antidepressant target.