JZL-184 Alleviate Neurological Impairment through Regulation of Mitochondrial Transfer and Lipid Droplet Accumulation after Cardiac Arrest.

Abstract

Astrocytes are abundant glial cells in the central nervous system (CNS) that play important roles in brain injury following cardiac arrest (CA). Following brain ischemia, astrocytes trigger endogenous neuroprotective mechanisms, such as fatty acid transport. Lipid droplets (LDs) are cellular structures involved in neutral lipid storage and play essential roles in many biological processes. However, whether lipid droplet metabolism is related to the neurological prognosis after CA remains unclear. JZL-184 is a selective irreversible inhibitor of monoacylglycerol lipase (MAGL), and previous investigations revealed that JZL-184 confers neuroprotection in the brain following stroke. However, further investigations are warranted to explore the effect and mechanism of JZL-184 after CA. Here, we reveal that JZL-184 is neuroprotective after cardiac arrest, as it alleviates astroglial activation by upregulating the expression of transforming growth factor beta 1 (TGF-β1), promotes the transfer of mitochondria from astrocytes to neurons in the astrocyte‒neuron coculture system, and reduces lipid droplet accumulation in neurons. Mechanistically, this protective effect depends on the downstream genes DUSP4 and Rab27b. This study provides additional insights into strategies for inhibiting neurological impairment and suggests a potential therapeutic target after cardiac arrest.