脳浮腫と脳水分バランスに対するaquaporin 4の役割

Brain edema and aquaporin 4

Water channelとして報告されたaquaporinは，水分子のみを選択的に通過させる膜蛋白であり，細胞膜に水専用の孔を開け，能動輸送によって水分子を通過させ，細胞内の水代謝を制御する。10種以上知られているaquaporin familyのうち，脳にはaquaporin 4が主として存在する。脳腫瘍，感染，外傷，水中毒，ミトコンドリア障害などの様々な病態において発現が増加して，脳浮腫を軽減させるような働きをしていると考えられるが，エネルギー障害の程度によりaquaporin 4の能動輸送は抑制される。現在，浸透圧利尿剤が脳浮腫の治療に用いられているが，aquaporin阻害剤により，浸透圧利尿によらない脳浮腫治療の可能性も考えられる。漢方薬の五苓散はaquaporin阻害作用を有していると報告されており，脳浮腫に対する今後の臨床応用が期待される。

Aquaporins（AQP）are a family of at least ten homologous water transporting proteins in mammals that are expressed in epithelial cells. Aquaporin 4 expression is highest in brain and localize astrocytic end foot. Astrocytes are believed to induce or at least maintain the blood-brain barrier in the brain capillary endothelial cells. Aquaporin 4 is a protein which regulate transcellular water permeability. Aquaporin 4 forms six domains on the cellular membrane as channel-forming integral protein. Aquaporins, as a water channel, transport only water molecule without ion or other molecules. Aquaporins regulate water balance without changing concentration of cellular ion or other substances. In the brain, water channel regulates cerebral edema, body water balance or cerebrospinal fluid metabolism and mediates water flow within the central nervous system. Brain edema has been analyzed as an aspect of ion channel injury or membrane injury, transportation of water molecule itself following cerebral ischemia is unknown. As only water molecule passes water channel, the functional changes of water channel following cerebral diseases is of great interest. We evaluate the role of aquaporin 4 in cerebral edema following ischemia and cerebral injection of mitochondrial toxin 3-nitropropianic acid. Aquaporin 4 expression is decreased following cerebral ischemia but is increased following mitochondrial injury. Suppression of the aquaporin 4 following ischemia indicated that the physiological regulation of water metabolism was impaired due to the depletion of energy supply. Both ischemia and mitochondrial injury induces energy suppression and aquaporin water channels have been recognized to have an important impact on the development of edematous swelling in the brain. But, without energy supply, aquaporin 4 expression is decreased and water is passively moved through the damaged ion channels. Aquaporin 4 increases in the various pathological conditions such as malignant glioma, astrocytoma,trauma, subarachnoid hemorrhage, intracerebral hemorrhage and meningitis. As aquaporin 4 is energy dependent, aquaporin 4 can not be expressed under the profound ischemia. Aquaporin 4 protects brain swelling, but the detailed physiological and pathological function is unknown. The transgenic mouse studies suggest that aquaporin inhibitors may have clinical indications as diuretics and in the treatment of cerebral edema and other conditions of abnormal fluid. Herbal medicine Goreisan is an inhibitor of aquaporin 4 and it should be the candidate of the clinical treatment of brain edema.