Abstract
ABSTRACTMigraine is a highly prevalent headache disorder, especially in women. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinases (TrkB), as well as extracellular signal-regulated kinase (ERK) and its downstream target c-AMP-responsive element binding protein (CREB) are strongly associated with the transmission of nociceptive information. However, the involvement of these substances in migraine has rarely been examined. In the present study, intraperitoneal injection of nitroglycerin (NTC) successfully induced rat migraine attack, as evidenced by behavioral testing. The location and abundance of these substances in the migraine model were determined by immunohistochemistry, real-time polymerase chain reaction (RT-PCR), western blot and enzyme-linked immunosorbant assays (ELISA). Results showed that BDNF, TrkB, phosphor(p)-ERK and p-CREB were up-regulated in the brain neurons of both male and female rats with NTG-induced migraine compared to non-migraine control, whereas their expression levels were decreased in headache-free intervals of the migraine compared to migraine attacks. Estrogen is an important contributor to migraine. Female ovariectomized rats showed significant reduction in the expression of BDNF, TrkB, p-CREB and p-ERK in both attacks and intervals of NTG-induced migraine, relative to rats that have their ovaries. But, intraperitoneal administration of exogenous estrogen recovered their expression in ovariectomized rats. Collectively, this study unveiled a positive correlation of BDNF/TrkB and ERK/CREB axes in NTG-induced migraine and promoting effects of estrogen on their signals in the migraine. These findings contribute to further understanding the pathogenesis of migraine in the molecular basis.
Highlights
Migraine is a common brain disorder, adversely affecting about 11% of global population (Fischer et al, 2012)
This study initially investigated the involvement of Brain-derived neurotrophic factor (BDNF), TrkB, p-extracellular signalregulated kinase (ERK) and p-c-AMP-responsive element binding protein (CREB) in the migraine attacks that were induced by nitroglycerin (NTG) injection in rats
BDNF and its receptor TrkB were up-regulated in the brain neurons of both male and female rats with NTG-induced migraine compared to non-migraine control, as evidenced by PCR and western blot assays, while their expression had a notable decrease in headache-free intervals of migraine compared to the migraine episodes
Summary
Migraine is a common brain disorder, adversely affecting about 11% of global population (Fischer et al, 2012) It is characterized by predominantly unilateral pulsating head pain with a series of complications, including nausea, vomiting, hypersensitivity to light, cognitive, emotional and motor disturbances, as well as sound, smell and visual disorders (Gölöncsér and Sperlágh, 2014). Reports from more than 50% of female patients show that migraine attacks are positively correlated with their menstrual cycle (Merki-Feld et al, 2015) These data imply a positive association between migraine attacks and fluctuations of serum estrogen level. Estrogen has been proposed to play a critical role in the pathogenesis of migraine, the underlying molecular basis is not well understood
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