We suggest that pharmacologically active components of PNV modify the functional expression of AQP4 and GFAP in a distinct manner in the different cerebellum compartments examined based on the molecular, cellular, neuroanatomical and neurochemical characteristics

of each at a given period of post-natal life development. Aquaporin-4 belongs to a family of integral channel proteins that promote the transmembrane diffusion of water through the cell membrane and which is particularly concentrated in the endfeet of astrocytes. AQP4 is also concentrated in astrocyte membrane contacting synaptic sites where promotes potassium siphoning and normal neuronal signal transduction. By removing K+ excess from the extracellular peri-synaptic sites, AQP4 acts as a buffer thus avoiding excytotoxic activity of neurons. Astrocytes

are part of the glio-neural-vascular unit and hence function as intermediaries between neurons and endothelial Y-27632 cells at the BBB. Picomolar changes in the content of ions inside and/or outside astrocytes are enough to induce important changes in the neuronal activity. On the other Metabolism inhibitor hand, such changes lead astrocytes to release neurotransmitters which also affect neuronal activity. We suggest that the upregulation of AQP4 is probably an intrinsic protective mechanism triggered to mediate transcellular water movement out of cerebellum in order to counteract perivascular edema and swelling of astrocyte endfeet caused by P. nigriventer venom. The simultaneous reinforcement of astrocyte cytoskeleton promoted by upregulation of GFAP would be in line with protective mechanism to restore BBB functionality impaired by PNV. Moreover, since PNV causes excytotoxic signals

in rats, AQP4 intense upregulation around neurons of the cerebellar cortex may be a reactive response of astrocytes against a probable increase in glutamate and K+ ( Prado et al., 1996; Mafra et al., 1999; Reis et al., 2000; Vieira et al., 2003) resulting from neuronal activation by PNV ( Cruz-Höfling et al., 2007) and changes in the electric activity of neurons ( Ferrari et al., 2010). Taken together, the findings allow us to speculate that the upregulation of AQP4 in response to PNV may represent the involvement of this protein in neural signal transduction, particularly Pyruvate dehydrogenase in neurotransmitter and K+ siphoning and edema resolving thus with impact on the physiology of BBB impairment caused by PNV. The authors thank Instituto Butantan (São Paulo, SP, Brazil) for donation of venom, Ms. Stephanie Souto Maior for technical assistance and Mr. Miguel Silva for excellent animal care. The authors are indebted to Professor L. Sodek for revising the language. This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp # 2008/55748-1) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, # 302206/2008-6 and 481316/2008-6). L.M.S. was supported by a MSc studentship from CNPq and M.A.C.H.