Microglial-targeting induced by intranasal linalool during neurological protection postischemia

Stroke is the second cause of death and first cause of physical disability around the world; it affects the brain parenchyma through oxygen deficiency and spreads excitotoxicity. The complexity of the disease has made it difficult to find effective therapies. It is necessary to identify new treatments that effectively act within the narrow therapeutic window but also offer long-term protection poststroke. Our previous work found that oral linalool reversed the hippocampal and peripheral pro-inflammatory phospholipidomic biomarkers in ischemic rats; based on these observations, the "proof of concept" was to demonstrate that intranasal administration of linalool has a faster delivery to the central nervous system to protect it after focal ischemia in Wistar rats. The ischemic animals treated with linalool (25 mg/kg) showed a decrease in infarct volume at 24 h and seven days, and the treated animals had better neurological and motor skills at both poststroke times. Additionally, one month after daily intranasal administration of linalool, the ischemic rats showed improved relearning performance in the Morris water maze test. They also exhibited a reduction in microgliosis and decreased COX2, IL-1Beta and Nrf2 markers in the cerebral cortex and hippocampus. In astrocyte and microglial cultures, linalool reduced pro-inflammation and had a potent effect on microglial cells, generating Nrf2 subcellular redistribution under glutamate excitotoxicity conditions. Together, our findings indicate an acute and chronic recovery after ischemia induced by a daily intranasal puff of linalool, which mainly acts on microglial populations with anti-inflammatory actions.