Hypersensitivity of aquaporin 4-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrah.ydropyrindine and astrocytic modulation

Aquaporm 4 (AQP4) is a predominant water channel protein in mammalian brains, which is localized in the astrocyte plasma membrane. AQP4 has gained much attraction due to its involvement in the physiopathology of cerebral disorders including stroke, tumor, infection, hydrocephalus, epilepsy, and traumatic brain injury. But there is almost no evidence whether abnormal AQP4 levels are associated with degenerative diseases, such as Parkinson's disease (PD). In our studies, we established PD animal models by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to test the hypothesis that abnormal AQP4 expression is involved in the pathophysiology of this disease. We show that mutant mice lacking AQP4 were significantly more prone to MPTP-induced neurotoxicity than their wild-type littermates. Furthermore, after administration of MPTP, astroglial proliferation and GDNF protein synthesis were inhibited by AQP4 deficiency. This study demonstrates that AQP4 is important in the MPTP neurotoxic process and indicates that the therapeutic strategy targeted to astrocytic modulation with AQP4 may offer a great potential for the development of new treatment for PD. 0 2007 Elsevier Inc. All rights reserved.