Aquaporin-4-dependent edema clearance following status epilepticus

Department of Neurological Surgery, University of California, Davis, CA, United States.
Epilepsy research (Impact Factor: 2.19). 02/2012; 98(2-3):264-8. DOI: 10.1016/j.eplepsyres.2011.09.016
Source: PubMed

ABSTRACT We investigated the role of aquaporin-4 in the development of cerebral edema following kainic acid-induced status epilepticus (SE) using specific gravimetry and T2 MRI techniques at 6 h, 1 day, 4 days and 7 days after SE. Our results indicate significantly greater tissue edema and T2 MRI changes in AQP4(-/-) compared to AQP4(+/+) mice that peaks at about 1 day after SE (greater in hippocampus relative to cortex). These results have implications for the mechanisms of edema formation and clearance following intense seizure activity.

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Available from: Devin K Binder, Dec 10, 2014
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    • "ct BBB ( Manley et al . , 2000 ; Papadopoulos and Verkman , 2013 ) . It is of interest that in vasogenic edema , AQP4 plays an oppos - ing role . In established models of BBB disruption such as cortical freeze injury , brain tumor , brain abscess ( Bloch et al . , 2005 ) , sub - arachnoid hemorrhage ( Tait et al . , 2010 ) and status epilepticus ( Lee et al . , 2012 ) , AQP4 - null mice develop more edema than do wild - type mice . This increased vasogenic component from dele - tion of AQP4 reaffirms that vasogenic elimination of water into the CSF and blood occurs via AQP4 - dependent routes ( Saadoun and Papadopoulos , 2010 ; Papadopoulos and Verkman , 2013 ) . AQP4 mediates bidirectional water f"
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    ABSTRACT: Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4-null mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K+-channels (Kir4.1) and glial K+ uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4-null mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.
    Frontiers in Cellular Neuroscience 03/2015; 9(34). DOI:10.3389/fncel.2015.00108 · 4.18 Impact Factor
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    • "J.M. Malheiros et al. acid indicate significantly greater tissue edema (AQP-4) and T2 MRI changes (Lee et al., 2012). AQP-4 is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments , including cerebrospinal fluid (CSF) and blood. "
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    ABSTRACT: Manganese-enhanced MRI (MEMRI) has been considered a surrogate marker of Ca+2 influx into activated cells and tracer of neuronal active circuits. However, the induction of status epilepticus (SE) by kainic acid does not result in hippocampal MEMRI hypersignal, in spite of its high cell activity. Similarly, short durations of status (5 or 15 min) induced by pilocarpine did not alter the hippocampal MEMRI, while 30 min of SE even reduced MEMRI signal Thus, this study was designed to investigate possible explanations for the absence or decrease of MEMRI signal after short periods of SE. We analyzed hippocampal caspase-3 activation (to evaluate apoptosis), T2 relaxometry (tissue water content) and aquaporin 4 expression (water-channel protein) of rats subjected to short periods of pilocarpine-induced SE. For the time periods studied here, apoptotic cell death did not contribute to the decrease of the hippocampal MEMRI signal. However, T2 relaxation was higher in the group of animals subjected to 30 min of SE than in the other SE or control groups. This result is consistent with higher AQP-4 expression during the same time period. Based on apoptosis and tissue water content analysis, the low hippocampal MEMRI signal 30 min after SE can potentially be attributed to local edema rather than to cell death.
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    • "mice have markedly decreased accumulation of brain water (cerebral edema) following water intoxication and focal cerebral ischemia (Manley et al., 2000) and impaired clearance of brain water in models of vasogenic edema (Papadopoulos et al., 2004). A recent study indicates that clearance of seizure-induced edema may also be AQP4-dependent (Lee et al., 2011). Impaired water flux into (in the case of cytotoxic edema) and out of (in the case of vasogenic edema) the brain makes sense based on the bidirectional nature of water flux across the AQP4 membrane channel at the blood-brain barrier. "
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