Interaction of aquaporin 4 and N-methyl-D-aspartate NMDA receptor 1 in traumatic brain injury of rats

Document Type: Original Article


The Affiliated Bayi Brain Hospital, The PLA Army General Hospital, Beijing 100700, China


Objective(s): -methyl-D-aspartate NMDA receptor (NMDAR) and aquaporin 4 (AQP4) are involved in the molecular cascade of edema after traumatic brain injury (TBI) and are potential targets of studies in pharmacology and medicine. However, their association and interactions are still unknown.
Materials and Methods: We established a rat TBI model in this study. The cellular distribution patterns of AQP4 after inhibition of NMDAR were determined by Western blotting and immunoreactive staining. Furthermore, the regulation of NMDA receptor 1 by AQP4 was studied by injection of a viral vector targeting AQP4 by RNAi into the rat brain before TBI.
Results: The results suggest that AQP4 protein expression increased significantly (P<0.05) after TBI and was down-regulated by the NMDAR inhibitor MK801. This decrease could be partly reversed using the NMDAR agonist NMDA. This indicated that AQP4 mRNA levels and protein expression are regulated by the NMDA signaling pathway. By injection of AQP4 RNAi viral vector into the brain of TBI rat models, we found that the mRNA and protein levels of NMDAR decreased significantly (P<0.05). This suggested that NMDAR is also regulated by AQP4.
Conclusion: These data suggested that the inhibition of AQP4 down-regulates NMDAR expression, which might be one of the mechanisms involved in edema after TBI.


Main Subjects

1. Tolias CM, Bullock MR. Critical appraisal of neuroprotection trials in head injury: what have we learned? NeuroRx  2004;1:71-79.
2. Schouten JW. Neuroprotection in traumatic brain injury: a complex struggle against the biology of nature. Curr Opin Crit Care 2007;13:134-142.
3. Quillinan N, Herson PS, Traystman RJ. Neuropathophysiology of brain injury. Anesthesiol Clin 2016;34:453-464.
4. Carvajal FJ, Mattison HA, Cerpa W. Role of NMDA receptor-rediated glutamatergic signaling in chronic and acute europathologies. Neural Plast 2016;2016:2701526.
5. McIntosh TK, Vink R, Soares H, Hayes R, Simon R. Effect of noncompetitive blockade of N-methyl-D-aspartate receptors on the neurochemical sequelae of experimental brain injury. J Neurochem 1990;55:1170-1179.
6. Biegon A, Fry PA, Paden CM, Alexandrovich A, Tsenter J, Shohami E. Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci U S A 2004;101:5117-5122.
7. Badaut J, Lasbennes F, Magistretti PJ, Regli L. Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab 2002;22:367-378.
8. Xu M, Su W, Xu QP. Aquaporin-4 and traumatic brain edema. Chin J Traumatol 2010;13:103-110.
9. Papadopoulos MC, Verkman AS. Aquaporin-4 and brain edema. Pediatr Nephrol 2007;22:778-784.
10. Faden AI, Demediuk P, Panter SS, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989;244:798-800.
11. Verkman AS. Applications of aquaporin inhibitors. Drug News Perspect 2001;14:412-420.
12. Vizuete ML, Venero JL, Vargas C, Ilundáin AA, Echevarría M, Machado A, et al. Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury: potential role in brain edema. Neurobiol Dis 1999;6:245-258.
13. Zhang C, Chen J, Lu H. Expression of aquaporin-4 and pathological characteristics of brain injury in a rat model of traumatic brain injury. Mol Med Rep 2015;12:7351-7357.
14. Gunnarson E, Zelenina M, Axehult G, Song Y, Bondar A, Krieger P, et al. Identification of a molecular target for glutamate regulation of astrocyte water permeability. Glia 2008;56:587-596.
15. Clark RS, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM. Neutrophil accumulation after traumatic brain injury in rats: comparison of weight drop and controlled cortical impact models. J Neurotrauma 1994;11:499-506.
16. Chen JQ, Zhang CC, Jiang SN, Lu H, Wang W. Effects of Aquaporin 4 knockdown on brain edema of the uninjured side after traumatic brain injury in rats. Med Sci Monit 2016;22:4809-4819.
17. Shapira Y, Shohami E, Sidi A, Soffer D, Freeman S, Cotev S. Experimental closed head injury in rats: mechanical, pathophysiologic, and neurologic properties. Crit Care Med 1988;16:258-265.
18. Zhang M, Cui Z, Cui H, Cao Y, Zhong C, Wang Y. Astaxanthin alleviates cerebral edema by modulating NKCC1 and AQP4 expression after traumaticbrain injury in mice. BMC Neurosci 2016;17:60.
19. Unterberg AW, Stover J, Kress B, Kiening KL. Edema and brain trauma. Neuroscience 2004;129:1021-1029.
20. Bareyre F, Wahl F, McIntosh TK, Stutzmann JM. Time course of cerebral edema after traumatic brain injury in rats: effects of riluzole and mannitol. J Neurotrauma 1997;14:839-849.
21. Blixt J, Svensson M, Gunnarson E, Wanecek M. Aquaporins and blood-brain barrier permeability in early edema development after traumatic brain injury. Brain Res 2015;1611:18-28.
22. Bernert H, Turski L. Traumatic brain damage prevented by the non-N-methyl-D-aspartate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f] quinoxaline. Proc Natl Acad Sci U S A 1996;93:5235-5240.
23. Goebel DJ, Poosch MS. NMDA receptor subunit gene expression in the rat brain: a quantitative analysis of endogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C, NR2D and NR3A. Brain Res Mol Brain Res 1999;69:164-170.
24. Chen JH, Yang LK, Chen L, Wang YH, Wu Y, Jiang BJ, et al. Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of AQP4 expression in rabbits. Int J Mol Med 2016;37:1059-1066.
25. Lieberman DN, Mody I. Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 1994;369:235-239.