Abstract: This study investigated the neuroprotective effects of lactate in subarachnoid hemorrhage, a severe cerebrovascular disease that is commonly caused by arterial aneurysm rupture and has limited early treatment options. Lactate, a metabolic byproduct, has been shown to have neuroprotective properties, including enhancing cerebral microcirculation and reducing intracranial pressure in acute brain injury patients. However, the protective mechanisms of lactate in subarachnoid hemorrhage remain unknown. In this study, we showed that lactate alleviates early brain damage in subarachnoid hemorrhage by promoting neuronal lipid synthesis and the formation of lipid droplets in astrocytes. In vivo experiments using a subarachnoid hemorrhage mouse model showed that lactate treatment significantly improved neurological scores, reduced brain inflammation, and promoted lipid droplet formation in astrocytes within 24 hours. Lactate treatment increased free fatty acids levels in the brain. The results suggest that astrocytes absorbed these free fatty acids and converted them into lipid droplets, thus reducing cellular lipotoxicity. Moreover, lactate enhanced the antiapoptotic capacity of astrocytes by upregulating the expression of PLIN5, a protein crucial for lipid droplet formation. The inhibition of lipid synthesis or lipid droplet formation counteracted the neuroprotective effects of lactate, indicating that lactate’s protective role is closely linked to lipid metabolism and lipid droplet formation. In vitro experiments on HT22 neuronal cells exposed to hemin—an agent used to simulate subarachnoid hemorrhage injury—demonstrated that lactate mitigated cellular damage by reducing lipid peroxidation and preserving mitochondrial membrane potential. Lactate treatment in HT22 cells and astrocytes also showed that inhibition of lipid synthesis or lipid droplet formation reversed its protective effects, further emphasizing the importance of lipid metabolism in the neuroprotective action of lactate. This study provides insights into the neuroprotective mechanisms of lactate in subarachnoid hemorrhage. It indicates that lactate plays a role in promoting lipid synthesis in neurons and enhancing lipid droplet formation in astrocytes, thus mitigating brain damage and improving cell survival. These findings suggest that lactate, through its regulation of lipid metabolism, could be a potential therapeutic agent for subarachnoid hemorrhage.

Key words: apoptosis, astrocytes, free fatty acids, lactate, lipid droplets, lipid metabolism, neuronal lipid synthesis, neuroprotection, PLIN5, subarachnoid hemorrhage