Potentiation of endocannabinoid signaling alleviates depressive-like behavior in diabetic mice

Abstract

People with poorly managed diabetes frequently feel repressed pleasure and are more prone to developing anxiety and depression. The molecular reasons causing the increased incidence of mood and cognitive impairments after hyperglycemia remain unknown. However, current research suggests that disturbances in the endocannabinoid (eCB) system play a critical role in the initiation and progression of diabetes-related mood and cognitive deficits. Our findings reveal that lower levels of two critical eCB, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in the medial prefrontal cortex (mPFC) are related to increased anxiety-like and depressive-like behavior in diabetic mice. Additionally, the brains of diabetic mice exhibit elevated levels of Fatty Acid Amide Hydrolase (FAAH), an important enzyme involved in the metabolism of AEA and 2AG, which contributes to the polarization of microglia and the promotion of chronic neuroinflammation. Furthermore, cannabidiol (CBD), a non-psychoactive component of cannabis, administered intraperitoneally for two weeks, improves mood and memory in diabetic mice via transforming the eCB system, as evidenced by higher levels of AEA and 2-AG. The cellular changes induced by CBD treatment in the mPFC included notable modulation of microglia towards a beneficial anti-inflammatory M2 phenotype and a reduction in microglial hypertrophy. CBD therapy resulted in several beneficial molecular alterations in the mPFC, such as a reduction in proinflammatory cytokine levels, an elevation in 2AG and AEA, and a suppression of HMGB1-TLR4 pathway activation. The administration of CBD did not influence the activity of the NAPE-PLD and DAGL-α enzymes, responsible for the synthesis of 2AG and AEA. This indicates that the therapeutic benefits of CBD are not dependent on the enhanced synthesis of AEA and 2AG. Additionally, the administration of CBD significantly reduces fasting blood glucose levels in diabetic mice, indicating that the positive effects of CBD on the brain function of diabetic mice are likely facilitated by enhanced glucose metabolism.