br Materials and methods br Discussion Few

Materials and methods
Discussion Few studies have examined peripheral PACAP levels in migraineurs, and no reports have described PACAP levels in blood samples from patients with CM. Here, we demonstrated that plasma PACAP concentrations were lower in patients with interictal migraine (in both EM and CM) than in healthy controls, consistent with the findings of a previous study [10]. Moreover, plasma PACAP immunoreactivity has been shown to be elevated during the attack phase relative to that during the attack-free period in 21 migraineurs [10]. In contrast, PACAP levels have been shown to decrease with the amelioration of migraine headache following treatment with sumatriptan [12]. Thus, these studies have revealed the link between plasma PACAP levels and the migraine phase. Growing evidence in animal models and humans has shown that PACAP has a variety of functions in the pathogenesis of migraine, including activation of the trigeminovascular system and dilation of the intracranial vasculature [6], [7]. Experimental animal studies have found elevated PACAP-like immunoreactivity in response to activation of the trigeminovascular system in rats, suggesting that PACAP has an important role in the central sensitization involved in migraine [13]. In clinical studies, PACAP infusion could increase the diameter of the superficial temporal Canrenone sale and decrease the mean blood flow velocity in the middle cerebral arteries [8]. Taken together, these studies support the hypothesis that PACAP plays an important role in the pathogenesis of migraine. A previous study has reported a negative correlation between interictal PACAP levels and overall duration in a group of migraineurs [10]. However, in the current study, we observed a negative correlation between PACAP levels and duration only in the CM group. These contradictory results may be explained by the differences in the patients within the migraine group between the 2 studies. This previous study contained a total of 87 migraineurs, but no subgroup information was mentioned. According to the demographic and clinical characteristics information presented in Table 1, the mean duration of disease was 12.99±9.61y; thus, we speculate that most of the migraineurs in this previous study may have had episodic migraine (EM) with a long duration. However, in our EM group, the mean duration of disease was 8.72±7.64y, whereas that in our CM group was 19.32±10.84y. The shorter duration in our EM group may theoretically explain the lack of correlation between plasma PACAP concentrations and duration in our EM group. Additionally, no correlation was observed between plasma PACAP concentration and duration in our whole migraine group because patients with EM were the majority in our migraine group (95 EM vs 38 CM). It is widely accepted that pain pathways become sensitized and dysfunctional as a result of repeated episodes of trigeminal activation [14]. These results suggested that PACAP metabolism might be dysfunctional, contributing to the pathophysiology of migraine, particularly for individuals with CM who experience attacks more frequently and for a longer duration. The dysfunction of PACAP metabolism may be one source of the continued pain reported by patients and may be involved in pain sensitization in patients with CM. PACAP is a multifunctional neuropeptide that is widely distributed throughout the body, and plays a neurotrophic and neuroprotective role in the nervous system [15]. Previous observations have shown changes in plasma PACAP concentrations in central nervous system injury [16], Alzheimer's disease [17], and hemorrhagic stroke [18]. Moreover, migraines are also associated with dysregulation of other neurotrophic factors, such as brain-derived neurotrophic factor [19], which may mediate the neuroprotective effects of PACAP in rat cortical neurons [20]. This may partly explain the observation that the interictal plasma levels of PACAP decreased in migraineurs, particularly in individuals with CM. However, the connection between the neurotrophic and neuroprotective roles of PACAP and migraine mechanisms has not yet been determined.