Gastrodin Alleviates Post-Stroke Headache and Neuronal Injury via Activating the PI3K/Akt Pathway

Acute ischemic stroke (AIS) is frequently accompanied by severe neurological deficits and post-stroke headache (PSH). These complications significantly worsen clinical outcomes. Although gastrodin has been reported to exert neuroprotective effects, whether it relieves PSH and the underlying mechanisms remain unclear. In this study, using a rat model of PSH that exhibits orbital mechanical allodynia and increased facial grooming, we demonstrated that gastrodin dose-dependently alleviated pain-related behaviors, reduced the number of c-Fos-positive neurons in the trigeminal nucleus caudalis, and decreased protein levels of calcitonin gene-related peptide (CGRP) and substance P in the trigeminal ganglion. Mechanistically, gastrodin restored PI3K/Akt pathway activity in the ischemic penumbra, as reflected by increased PI3K and Akt expression and a higher p-Akt/Akt ratio, which was accompanied by reduced cerebral infarct volume, alleviated neuronal pathological damage, and suppressed oxidative stress, inflammation, and apoptosis. All these protective effects were significantly reversed by the PI3K inhibitor LY294002. To validate clinical relevance, we enrolled 80 AIS patients and 50 healthy controls. Peripheral blood PI3K/Akt expression was significantly lower in AIS patients and was correlated with PSH severity and neurological deficits. In conclusion, we revealed that gastrodin exerts dual analgesic and neuroprotective effects by restoring the PI3K/Akt pathway, providing novel insights and experimental support for the treatment of AIS complicated with PSH.