Valproate Plays a Protective Role against Migraine by Inhibiting Protein Kinase C Signalling in Nitroglycerin‐treated Mice

Abstract Migraine is a common disease with a high morbidity. Valproate ( VP ) is used as an anti‐epilepsy drug in clinic. This study aimed to investigate the role of VP in nitroglycerin ( NTG )‐induced migraine using a mouse model. NTG was employed by intraperitoneal injection to induce a migraine model in mice. The NTG administration caused mouse head discomforts, decreased tolerance to cold or hot stimulation and increased content of nitric oxide, calcitonin gene‐related peptide and neuropeptide Y in serum, which were ameliorated by intraperitoneal injection of VP . The levels of two inflammatory factors, interleukin ( IL )‐1β and inducible nitric oxide synthase, in dura mater were increased by NTG treatment, while the increase was attenuated by application of VP . In addition, the phosphorylation levels of protein kinase C ( PKC ) α, γ, δ and ε were increased by NTG and decreased by VP . However, their total expression at the transcriptional and translational levels did not change significantly. Two substrates of PKC , cAMP ‐response element binding protein 1 and signal transducer and activator of transcription 1 were also phosphorylated by NTG application, and the phosphorylation level was attenuated by VP , consistent with the change of PKC informs. Together, we demonstrated that VP prevented damage due to migraine by inhibiting PKC signalling in NTG ‐injected mice, which may provide a basis for investigating the clinical treatment of migraine.