Boosting 2-arachidonoylglycerol, but not N-acylethanolamine, ameliorates autism symptoms in VPA-exposed rats by modulating abnormal neuroinflammation.

Research has implicated endocannabinoids (eCBs) as significant regulators of neuroinflammation that may contribute to autism spectrum disorder (ASD). This study investigated the effect of the main eCBs, namely N-acylethanolamine (NAE) and 2-arachidonoylglycerol (2-AG), on ASD and their underlying mechanisms through in vivo and in vitro experiments. Results showed that elevating NAE or 2-AG ameliorated social deficits and restricted and repetitive behaviors and corrected neuropathological damage. Additionally, enhancing 2-AG protected valproic acid (VPA)-exposed rats against nerve damage by modulating abnormal neuroinflammation, as evidenced by the fact that 2-AG decreased microglial reactivity with reduced pro-inflammatory responses and increased anti-inflammatory responses. While, NAE only had a subtle effect on regulating neuroinflammation. Collectively, these findings suggested that elevating both NAE and 2-AG could improve ASD symptoms. Elevating 2-AG may play a neuroprotective role by generating a reparative milieu reactive to abnormal neuroinflammation, but NAE does not. Therefore, eCBs may be a promising therapeutic target for ASD.