Named for its role in stimulating hematopoiesis, erythropoietin (EPO) is also a neuroprotective agent that helps minimize damage to brain tissue after destructive events like trauma or stroke. Gunnarson et al. describe a mechanism by which EPO might produce at least part of its protective effects. Tissues surrounding damaged areas in the brain are subject to further damage as a consequence of swelling. One way in which this occurs is through excessive signaling by metabotropic glutamate receptors (mGluRs), which cause increased permeability of aquaporin 4 (AQP4) water channels in glial cells known as astrocytes. In a mouse model that reproduces such swelling-induced damage, Gunnarson et al. showed that administration of EPO improved neurological symptoms. In brain slices, treatment with EPO eliminated swelling caused by administration of an agonist for mGluRs in hypotonic conditions. In primary cultures of astroglial cells, stimulation of mGluRs caused characteristic oscillating increases in the concentration of intracellular free Ca2+ with a period of about 15 seconds in about a third of the cells. In cells exposed to EPO before stimulation of mGluRs, however, the number of cells with oscillations decreased and the regularity of the oscillations was disrupted. EPO has a range of effects that probably contribute to its beneficial effects in minimizing brain injury. It can inhibit apoptosis and can directly inhibit release of glutamate. The authors argue that inhibition of glutamate-induced increases in water permeability and consequent swelling should be added to the list.
E. Gunnarson, Y. Song, J. M. Kowalewski, H. Brismar, M. Brines, A. Cerami, U. Andersson, M. Zelenina, A. Aperia, Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc. Natl. Acad. Sci. U.S.A. 106, 1602–1607 (2009). [Abstract] [Full Text]