Aquaporin 1, a potential therapeutic target for migraine with aura
© Xu et al; licensee BioMed Central Ltd. 2010
Received: 27 August 2010
Accepted: 25 October 2010
Published: 25 October 2010
The pathophysiology of migraine remains largely unknown. However, evidence regarding the molecules participating in the pathophysiology of migraine has been accumulating. Water channel proteins, known as aquaporins (AQPs), notably AQP-1 and AQP-4, appears to be involved in the pathophysiology of several neurological diseases. This review outlines newly emerging evidence indicating that AQP-1 plays an important role in pain signal transduction and migraine and could therefore serve as a potential therapeutic target for these diseases.
Migraine is a chronic, paroxysmal, neurovascular disorder that can start at any age, and affects up to 6% of males and 18% of females in the general population . Two major forms of migraine exist: migraine without aura and migraine with aura. An often debilitating, unilateral, throbbing headache typically characterizes attacks of migraine without aura. This type of headache which may last 4 to 72 hours is aggravated by physical activity, and is accompanied by autonomic symptoms such as vomiting, nausea, photophobia, and phonophobia . However, the attack may also be preceded by premonitory symptoms (prodrome) in some patients. In one third of migraineurs, the headache phase is preceded or accompanied by transient focal symptoms of neurologic aura (migraine with aura). These are usually visual but may also involve sensory disturbances, speech difficulties, and motor symptoms .
Aquaporins (AQPs), a family of water channel proteins, became a very hot area of research in biochemistry and molecular cell biology, with increasing physiological, medical, and biotechnological implications. The characteristics, tissue distribution, functions and some pathophysiological implications of individual AQPs are briefly presented below and references of detailed reviews on each topic are given. The recent advances on relating AQPs and the pathophysiology of migraine are the focus of this review.
Structure, distribution and functions of AQPs
AQPs are expressed in various tissues including urinary, respiratory, digestive, and nervous systems , and they provide the molecular basis for water transport in the tissues. AQP channels facilitate bi-directional water transport across the plasma membrane in response to osmotic gradients created by solute movement. Water permeation through AQP channels is characterized by sensitivity to mercurial agents like HgCl2 [21, 22] and tetraethylammonium (TEA) . Most of AQPs (except for AQP-4 and AQP-7) are sensitive to HgCl2. The genetic manipulation of rodents and the identification of humans with altered aquaporin genes have provided considerable insights into aquaporin-related physiology. For example, the AQP-1 or AQP-4 deficient mice have impairments in urinary concentrating ability [24, 25], cerebral fluid balance , corneal fluid balance , hearing , and water transport in the lungs [29, 30]. Defective secretion in salivary and submucosal glands [31, 32] and altered lung fluid transport  have been shown in AQP-5 knockout mice. Defects in AQP-2 have been shown to be linked to nephrogenic diabetes insipidus [33, 34]. These examples demonstrate that AQPs are required for normal water homeostasis, and are likely to be important players in a variety of human diseases.
AQPs in the central nerve system (CNS)
AQPs in the CNS appear to be of great physiological and pathological importance, especially given the rigid physical constraint that is imposed by the bony cranium. However, current knowledge of aquaporin expression and function in the nervous system is very limited. Generally, AQPs are involved in water movement in nervous tissue; nevertheless, recent data would suggest the involvement of AQPs in neurotransmission. Several studies have reported the expression of AQP water channels, AQP-1, AQP-4, and AQP-9 in the brain [9, 35, 36], and AQP-4 and AQP-9 in the spinal cord . AQP-4, the predominant water channel in the central nervous system, is mainly expressed in astrocytes throughout the brain and spinal cord . AQP-4 plays a role in cerebral edema, glial cell migration and neuroexcitation . However, mechanisms of AQP-4 modulation of cortical spreading depression (CSD) remain unclear. AQP-9 is found in a subset of astrocyte processes that form the glia limitans  and specialized ependymal cells in the brain and spinal cord .
Brain AQP-1 is mainly expressed in the cerebrospinal fluid (CSF)-facing membranes of the ventricular choroid plexus, where it regulates the formation of CSF presumably due to its functions as a water pore and ion channel . Interestingly, various neuropathological conditions involve the up-regulation of AQP-1 expression in the CNS. Upregulation of brain AQP-1 expression is found in Alzheimer patients , Creutzfeldt-Jakob disease , traumatic brain injury patients, and human hemangioblastomas. In all cases, the elevated AQP-1 expression seems to occur in astrocytes residing in diseased brain tissue, even though these astrocytes and other glial cells do not normally express AQP-1. The possible roles of increased expression of AQP-1 in the etiology of different neuropathological conditions are still unknown, but it is likely that AQP-1 up-regulation may contribute to edema and cyst formation-typical outcomes in most of these pathological conditions. Unfortunately, the mechanisms that control AQP-1 gene expression in the CNS, under normal or pathological conditions, are still poorly understood. However, Kim et al  showed that the thyroid transcription factor-1 up-regulates AQP-1 synthesis and thus facilitates CSF formation in the brain. Moreover, in CNS, hypertonicity induces AQP-1 synthesis via extracellular signal-regulated kinases, p38 kinase, and c-Jun terminal kinase .
In the spinal cord, AQP-1 is also expressed in the ependymal cells lining the central canal, but more robustly in the sensory fibers of the superficial laminae of the dorsal horn [45–47]. Considering the expression of AQP-1 in the dorsal horn, it has been suggested that AQP-1 has a role in physiological pain sensation, known as nociception. Two groups [48, 49] showed recently that AQP-1-deficient mice are less sensitive to noxious thermal stimuli or capsaicin (the pungent component of chili peppers which also activates nociceptive skin afferents), and even in human dorsal horn with neuropathic pain . However, Shields et al.  provided evidence against this role. They reported that AQP-1-null mice did not have altered nociception. The possibility for relating AQP-1 and nociception at spinal cord level, remains speculative.
AQPs in peripheral sensitization of nociception
A growing body of evidence showed that AQPs appear to be involved in the peripheral sensitization of nociceptors. AQP-1 is expressed in small afferent sensory nerve fibers in the peripheral nervous system. In research published by Oshio's group, both the small neurons and small afferent nerve fibers in normal mouse dorsal root ganglion were shown the co-localization of AQP-1 and capsaicin receptor (TRPV1) . The TRPV1 receptors have the function of transmitting the painful stimuli in vivo . Furthermore, recent studies showed that thermal inflammatory pain perception was greatly reduced in AQP1-/- mice evoked by bradykinin, prostaglandin E2, and capsaicin as well as reduced cold pain perception . Nav1.8 currents and expression were significantly reduced in AQP1-/- mice DRG neurons. The reduction in Nav1.8 currents would contribute to the impairment in repetitive AP firing and to the accelerated adaptation observed in AQP-1-deficient DRG neurons. In addition, immunoprecipitation studies and single molecule tracking indicated a physical interaction between AQP-1 and Nav1.8. These data provide a physical and functional link between AQP-1 expression and Nav1.8 function, and implicate the involvement of AQP1 in DRG neurons for the perception of inflammatory thermal pain . Interestingly, GFAP-positive, injured Schwann cells in the peripheral nervous system (PNS) are known to express AQP-1 , but not AQP-4, a protein abundant in spinal cord astrocytes . AQP-2 expression was not detectable either in the spinal cord or in the dorsal root ganglia of naive rats. However, AQP-2 expression was dramatically increased in small-diameter dorsal root ganglia neurons in response to chronic constriction injury treatment . These data support the hypothesis that AQP-1 and AQP-2 might be involved in pain processing under inflammatory and neuropathic nerve injury conditions. However, the detailed mechanisms of such roles warrants to be further investigated.
AQP-1 in migraine pathophysiology
The major symptom of migraine, the headache pain, is mediated by neuronal activity along the trigeminovascular pathway. Activation and sensitization of primary afferent neurons (PANs) in the trigeminal ganglion (TG) is the first step in driving this nociceptive pathway. Using immunofluorescent staining, Shields et al. have described that AQP-1 is heavily expressed in a population of small diameter primary sensory neurons of TG, and co-localized with a marker of peptidergic nociceptors, substance P . In addition to the dorsal root ganglion, the expression of TRPV1 in rat TG was detected recently . Furthermore, the co-localization of 5-HT1B receptors with substance P was also identified in the human TG .
Migraine is among the more debilitating diseases, and current treatment modalities are unsatisfactory in more than half of the patients . More specific, well-tolerated, and effective methods of prophylaxis are desired. AQPs represent just one of many exciting potential therapeutic targets. Other possible candidates include NOTCH3, the causative gene for CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and SLC1A3, encoding the EAAT1 (excitatory amino acid transporter and glutamate transporter . The development of genetically sensitized mouse models has more or less opened up a completely new field for migraine research. Whereas previous research concentrated on elucidating the mechanisms of CSD and intracranial nociception, newer candidates will facilitate research into increased sensitivity to migraine triggers and metabolic homeostasis. In addition to treatment of acute attacks, a better understanding of the mechanism of migraine attack triggers will help in the development of specific preventive therapies.
We thank Dr. Benedict Alter and Dr. Dongsheng Jiang for their helpful comments. This work was supported by National Natural Science Foundation of China (No. 30900437 and No. 81070884), Natural Science Funding for Colleges and Universities in Jiangsu Province (No. 09KJB180008), Natural Science Funding of Jiangsu Province (BK2009118), Dong-Wu Scholar Funding of Soochow University (to Jin Tao), and Doctoral Funding of Ministry of Education of China (No. 20093201110018). This study was supported in part by NIH005158 (GYX).
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