Evidence of aquaporin involvement in human central pontine myelinolysis

BACKGROUND Central pontine myelinolysis (CPM) is a demyelinating disorder of the central basis pontis that is often associated with osmotic stress. The aquaporin water channels (AQPs) have been pathogenically implicated because serum osmolarity changes redistribute water and osmolytes among various central nervous system compartments. RESULTS We characterized the immunoreactivity of aquaporin-1 and aquaporin-4 (AQP1 and AQP4) and associated neuropathology in microscopic transverse sections from archival autopsied pontine tissue from 6 patients with pathologically confirmed CPM. Loss of both AQP1 and AQP4 was evident within demyelinating lesions in four of the six cases, despite the presence of glial fibrillary acidic protein (GFAP)-positive astrocytes. Lesional astrocytes were small, and exhibited fewer and shorter processes than perilesional astrocytes. In two of the six cases, astrocytes within demyelinating lesions exhibited increased AQP1 and AQP4 immunoreactivities, and gemistocytes and mitotic astrocytes were numerous. Blinded review of medical records revealed that all four cases lacking lesional AQP1 and AQP4 immunoreactivities were male, whereas the two cases with enhanced lesional AQP1 and AQP4 immunoreactivities were female. CONCLUSIONS This report is the first to establish astrocytic AQP loss in a subset of human CPM cases and suggests AQP1 and AQP4 may be involved in the pathogenesis of CPM. Further studies are required to determine whether the loss of AQP1 and AQP4 is restricted to male CPM patients, or rather may be a feature associated with specific underlying precipitants of CPM that may be more common among men. Non-rodent experimental models are needed to better clarify the complex and dynamic mechanisms involved in the regulation of AQPs in CPM, in order to determine whether it occurs secondary to the destructive disease process, or represents a compensatory mechanism protecting the astrocyte against apoptosis.