Hypoxia-mediated neurotoxicity contributes to various neurodegenerative disorders, including Alzheimer's disease and multiple sclerosis. Tetramethylpyrazine (TMP), a major bioactive component purified from Ligusticum wallichii Franchat, exhibited potent neuroprotective effect. However, the mechanism of TMP-exerted neuroprotective effect against hypoxia was not clear. In the study, we investigated the mechanism of the neuroprotective effect of TMP against hypoxia induced by CoCl 2 in vitro and in vivo. The results showed that TMP could protect against CoCl 2 -induced neurotoxicity in PC12 cells and in rats, as evidenced by enhancement of cell viability in PC12 cells and improvement of learning and memory ability in rats treated with CoCl 2 . TMP could inhibit mitochondrial dysfunction, mitochondrial apoptotic molecular events, and thus apoptosis induced by CoCl 2 . TMP inhibited CoCl 2 -increased reactive oxygen species (ROS) level, which may contribute to hypoxia-related neurotoxicity induced by CoCl 2 . The antioxidant and neuroprotective activities of TMP involved two pathways: one was the enhancement of nuclear factor erythroid 2-related factor 2 (Nrf2)/catalytic subunit of cglutamylcysteine ligase-mediated regulation of GSH and the other was the inhibition of hypoxia-inducible factor 1 a/NADPH oxidase 2 (NOX2)-mediated ROS generation. These two pathways contributed to improvement of oxidative stress and thus the amelioration of apoptosis under hypoxic conditions. These results have appointed a new path toward the understanding of pathogenesis and TMP-related therapy of hypoxiarelated neurodegenerative diseases.

This study provides Class I evidence that for people with PDPH, IV aminophylline reduces headache severity.