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.

Comparative Efficacies of Antimigraine Drugs Using Nitroglycerin Induced Migraine Rats Model

“…The increased level of Nitric Oxide in a person's blood indicates that this individual has a head discomfort. NTG significantly increased the expression of two pain-related peptides CGRP and neuropeptide Y (NPY) in sera [34]. These reports agree with the earlier study that NO, CGRP was detected in plasma and various parts of the brain region [33].…”

Involvement of P2Y12 receptors in a nitroglycerin‐induced model of migraine in male mice

“…Nitroglycerin administration is known to induce a spontaneous‐like migraine attack, which is associated with mechanical and thermal hypersensitivity in pain‐free migraine patients and in mice (Demartini et al, 2019). Nitroglycerin treatment also causes other features of migraine, such as photophobia and up‐regulation of c‐fos and CGRP (Iyengar et al, 2017; Long et al, 2018; Markovics et al, 2012; Yi et al, 2018), as well as an alteration in monoamine levels (Wang et al, 2016; Tassorelli et al, 2002) in migraine‐related brain areas in mice.…”

Sodium Valproate Versus Dopamine Antagonists for Acute Migraine in the Emergency Department: A Systematic Review

“…[10][11][12][13][14] The mechanism by which SV provides pain relief in the context of migraine is unknown, however, inhibition of protein kinase C, increased neuroinhibitory effects of the upregulation of gamma-aminobutyric acid (GABA), and/or direct suppression of voltagegated sodium channel activity are suggested mechanisms. [15][16][17] Given its established role in reducing migraine frequency in patients with chronic migraine, there has been interest in exploring whether intravenous SV could be used to treat acute episodic migraine. [18][19][20]…”