Monoacylglycerol Lipase Inhibition by JZL184 Improves Neurological Outcomes and Survival after Cardiac Arrest via 2-AG-Mediated Restoration of Cerebral Microcirculation
Nan Gu, Xu Ma, Wanrong Wang, Tongjie Pan, Xue Cao, Li Shen, Chenhui Ma, Wenxun Liu, Yong Yang, Shaozhang Hou, Kerong HaiBackground:
Improving long-term survival rates after cardiac arrest (CA) is an important clinical challenge. The endocannabinoid 2-arachidonoylglycerol (2-AG) exerts endogenous neuroprotective and anti-inflammatory effects; its hydrolysis by monoacylglycerol lipase (MAGL) not only terminates 2-AG signaling but also releases arachidonic acid (AA), a precursor to multiple proinflammatory mediators. We hypothesized that inhibiting MAGL with JZL184 would improve neurological outcomes after CA by increasing the levels of 2-AG and suppressing AA-induced inflammation.
Methods:
In a clinical cohort, we assess the correlations between plasma endocannabinoid levels and the neurological outcomes of CA patients at 7 days postresuscitation. In rat models of asphyxia-induced CA, the animals were randomly allocated to the Sham, cardiopulmonary resuscitation (CPR), or CPR + JZL184 (16 mg/kg, intraperitoneal) groups. Within 7 days after the return of spontaneous circulation (ROSC), we assessed survival, neurological deficit scores (NDSs), spatial memory, cerebral edema, cerebral blood volume (CBV) (
Results:
A favorable outcome was associated with higher 2-AG levels at 6 h and lower AA levels at 1 and 5 days after ROSC among the patients (
Conclusions:
The MAGL inhibitor JZL184 confers substantial neuroprotection after CA and CPR by modulating the lipid mediator network in the brain. It alleviates cerebral injury and improves survival and neurological recovery primarily by increasing the levels of 2-AG and concurrently suppressing the AA-induced inflammatory cascade.