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Jérôme Badaut, L. Hirt et al. dans J Cereb Blood Flow Metab.

Aquaporin 4, a multifunctional Swiss-army knife for cerebral ischemia

Le 13 avril 2016


Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice.
 
Hirt L, Fukuda AM, Ambadipudi K, Rashid F, Binder D, Verkman A, Ashwal S, Obenaus A, Badaut J. J Cereb Blood Flow Metab. 2016 Jan 14. pii: 0271678X15623290. [Epub ahead of print]





The presence of water channel proteins, aquaporins (AQPs) was first described in the osmosensitive brain regions (Jung et al., 1994). AQP4 is a member of the aquaporin family composed by 13 members.
Since this first description of AQP4 in the brain intense research has been carried out to understand the underlying roles of each aquaporin in normal and pathological conditions (Badaut et al., 2014). Edema is a hallmark of various brain disorders including stroke and is an accumulation of water due to a dysregulation of the osmotic homeostasis. It contributes to aggravation and secondary injuries. Aquaporin 4 (AQP4), a water channel, has been proposed to be a key player in the edema process. 


 However, the precise role of AQP4 in edema formation remains unclear and there are conflicting results. Early inhibition of the water channel may have positive effects of prevention of edema formation in brain injuries (Fukuda et al, 2012) but at later time points during the course of a disease, the AQP is critical for clearance of water from the brain into blood vessels (Badaut et al, 2014). Our new study, published in the Journal of Cerebral Blood Flow and Metabolism (JCBFM) shows that the absence of AQP4 is associated with a better long-term cognitive outcome associated with reduced neuroinflammation but no direct effect on edema (Hirt et al., 2016). Therefore a larger understanding of the molecular mechanisms linking astrocytic AQP4 and neuroinflammation is needed for the future. Up to date, no specific therapeutic agent is available to either inhibit or enhance water flux through these channels. Our experimental results strongly underline the importance of this topic for future investigation.


Figure:Hemispheric swelling was also assessed by left/right (L/R) hemispheric asymmetry. Left panel illustrates sample L/R measures. Graphical analysis of the temporal evolution of brain swelling illustrates that there was increased swelling at three days and seven days post-stroke in the KO mice compared to WT. Despite the larger edema formation, the AQP4-KO mice will have a better outcome (Hirt et al., 2016)

Dr Jerome Badaut and Prof Hirt have a long-lasting very fruitful collaboration in the cerebral ischemia research field. The collaboration started in 1999 when Dr Badaut carried out a post-doctorate in Dr PJ Magistretti’s lab in Lausanne (Switzerland) working on astrocytes. Dr Badaut set up his research group in the Neurosurgery department of the CHUV (2005) mainly funded by the Swiss National Science Foundation. The collaboration continued when Dr Badaut moved to an assistant professor position at Loma Linda University (2010), where he received various NIH, NASA grants.
Dr Badaut is now a CNRS-research officer (CR1) and located in the Aquitaine Institute for Cognitive and Integrative Neuroscience (INCIA, CNRS UMR 5287, http://www.incia.u-bordeaux1.fr). From September 2015, Drs Hirt and Badaut will further collaborate with the support of a recent grant from the Swiss National Science Foundation. Dr Badaut is a renowned expert on the role of the astrocytic aquaporins in edema and other important functions such as brain energy metabolism. Areas of active research also include investigation on the roles of the astrocyte-endothelium-neuron interaction within the neurovascular unit in pathological processes after stroke and traumatic brain injury (TBI). Neurovascular unit changes have functional consequences on the blood-brain barrier properties, blood flow and consequently the behavioral outcome in relation to neuronal survival and recovery.

Dr Lorenz Hirt: Lorenz Hirt, MD, associate professor, is a neurologist specialized in stroke and working as a clinician at the Stroke Center, Department of Clinical Neurosciences of the CHUV (Lausanne University Hospital). Since 1999, he directs an experimental stroke lab studying mechanisms of cell death and neuroprotection in experimental models. Lab research interests are the role of the thrombin-JNK pathway, lactate pathway and, in collaboration with Dr. Jerome Badaut, aquaporins in cerebral ischemia as well as magnetic resonance spectroscopy biomarkers. The lab is hosted by the Department of Fundamental Neurosciences of UNIL (Lausanne University) providing an outstanding scientific environment and funded entirely by competitive grants, currently from the Swiss Science Foundation, the Swiss Heart Foundation and the Biaggi Foundation. https://wwwfbm.unil.ch/dnf/hirt_pres_en.html 

 

References: Jung JS, Bhat RV, Preston GM, Guggino WB, Baraban JM, Agre P. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):13052-6. “Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance.” Badaut J, Ashwal S, Obenaus A. Cerebrovasc Dis. 2011;31(6):521-31 “Aquaporins in cerebrovascular disease: a target for treatment of brain edema?” Fukuda AM, Badaut J. J Neuroinflammation. 2012 Dec 27;9:279. Aquaporin 4: a player in cerebral edema and neuroinflammation. Fukuda AM, Adami A, Pop V, Bellone JA, Coats JS, Hartman RE, Ashwal S, Obenaus A, Badaut J. J Cereb Blood Flow Metab. 2013 Oct;33(10):1621-32. “Posttraumatic reduction of edema with aquaporin-4 RNA interference improves acute and chronic functional recovery.” Hirt L, Fukuda AM, Ambadipudi K, Rashid F, Binder D, Verkman A, Ashwal S, Obenaus A, Badaut J. J Cereb Blood Flow Metab. 2016 Jan 14 “Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice”

Dr Badaut, CNRS-research officer (CR1) Aquitaine Institute for Cognitive and Integrative Neuroscience INCIA, CNRS UMR 5287
Dernière mise à jour le 29.04.2016