1. A new insight in interpreting brain tumor edema Aristotelis S. Filippidis M.D., Christos Tsonidis M.D. Ph.D. 1 Medical school, University of Thessaly, Larissa, GREECE 2 B’ Neurosurgical Department, Aristoteleion University of Thessaloniki, GREECE

2.  Family of more than 13 water channel proteins  First described in 1991 as aquaporin -1 (AQP1)  Nobel prize in Chemistry 2003 (Peter Agre)  Aquaporin-4 (AQP4) is the dominant form in brain Agre et al. Towards a molecular understanding of water homeostasis in the brain. Neuroscience (2004) vol. 129 (4) pp. 849-50

3.  Astrocyte foot processes around capillaries that form Blood-Brain-Barrier (BBB)  Glia limitans  Ependymal cells  Supraoptic and suprachiasmatic nuclei of hypothalamus  Cerebellum  Hippocampal dentate gyrus,  Hippocampal areas CA1-CA2  Neocortex  Nucleus of stria terminalis  Medial habenular nucleus Badaut et al. Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab (2002) vol. 22 (4) pp. 367-78

4.  AQP4 knockout mouse  Xenopus laevis oocyte-swelling assays  Neuromyelitis optica  (autoantibodies against AQP4 formed in human patients possibly related to the disease) Jarius et al Jarius et al. Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica. Nature clinical practice Neurology (2008) vol. 4 (4) pp. 202-14 Saadoun and Papadopoulos. Aquaporin-4 in brain and spinal cord oedema. Neuroscience (2009) pp. Tait et al. Water movements in the brain: role of aquaporins. Trends Neurosci (2008) vol. 31 (1) pp. 37-43

5. Brain edema types (revised Klatzo classification) Klatzo. Evolution of brain edema concepts. Acta neurochirurgica Supplementum (1994) vol. 60 pp. 3-6 Acta neurochirurgica Supplementum (1994) vol. 60 pp. 3-6 CYTOTOXIC VASOGENIC HYDROCEPHALIC

6. AQP4 Elimination routes of Brain edema Blood-Brain-Barrier H2OH2OH2OH2O Endothelial Cell Tight junction Astrocyte foot process H2OH2OH2OH2O AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4

7. Elimination routes of Brain edema Ependyma CSF in the 3 rd ventricle AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 AQP4 Ependyma cell H2OH2OH2OH2O H2OH2OH2OH2O H2OH2OH2OH2O GLIA LIMITANS

8. Elimination routes of Brain edema Glia limitans – subarachnoid space H2OH2OH2OH2O H2OH2OH2OH2OPIA GLIALIMITANS ARACHNOID Subarachnoid space AQP4 AQP4 NOT an established route BUT indirect evidence exists Filippidis et al. Transmembrane resistance and histology of isolated sheep leptomeninges. Neurol Res (2009) pp. Reulen et al. Role of pressure gradients and bulk flow in dynamics of vasogenic brain edema. J Neurosurg (1977) vol. 46 (1) pp. 24-35 Filippidis et al. Ouabain increases transmembrane resistance of isolated sheep leptomeninges. Mol. Biol. Cell 19 (suppl), abstract #1354/B569.(2008) (CD-ROM) Rekate et al. The importance of the cortical subarachnoid space in understanding hydrocephalus. Journal of Neurosurgery: Pediatrics (2008) vol. 2 (1) pp. 1-11 Tait et al. Water movements in the brain: role of aquaporins. Trends Neurosci (2008) vol. 31 (1) pp. 37-43

9. Brain tumor edema characteristics  Disruption of Blood-Brain-Barrier  High protein content in the interstitial cellular space  Fluid accumulation in interstitial space  Expansion of interstitial space  Post contrast CTs and MRIs enhance at the site of edema Klatzo. Evolution of brain edema concepts. Acta neurochirurgica Supplementum (1994) vol. 60 pp. 3-6

10. Vasogenic Edema – brain tumors H2OH2OH2OH2O H2OH2OH2OH2O H2OH2OH2OH2O Protein Endothelial Cell Klatzo. Evolution of brain edema concepts. Acta neurochirurgica Supplementum (1994) vol. 60 pp. 3-6

11.  So Brain tumors present with VASOGENIC edema

12. AQP4 and vasogenic edema deteriorates  Loss of AQP4 expression deteriorates vasogenic edema in AQP4 knockout mice  Role in homeostasis is suggested via an AQP4 route  Probably VASOGENIC edema is eliminated via an AQP4 route Papadopoulos et al. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J (2004) vol. 18 (11) pp. 1291-3

13. AQP4 and brain tumors  UPREGULATED in low and high grade astrocytomas  UPREGULATED in edematous meningiomas  UPREGULATED in metastatic adenocarcinomas in brain Papadopoulos et al. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J (2004) vol. 18 (11) pp. 1291-3 Saadoun et al. Aquaporin-4 expression is increased in oedematous human brain tumours. J Neurol Neurosurg Psychiatr (2002) vol. 72 (2) pp. 262-5 Ng et al. Aquaporin-4 expression is increased in edematous meningiomas. Journal of clinical neuroscience;(2009) pp. Sawada et al. Expression of aquaporine-4 in central nervous system tumors. Brain tumor pathology (2007) vol. 24 (2) pp. 81-4

14. AQP4 and brain tumors - Theories  Role of edema “scavanger” which is upregulated is suggested in order to aid the increased demand of brain fluid elimination and maintain homeostasis  Role of edema “inducer” that is upregulated and aggravates vascular peritumoral brain edema Papadopoulos et al. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J (2004) vol. 18 (11) pp. 1291-3 Saadoun et al. Aquaporin-4 expression is increased in oedematous human brain tumours. J Neurol Neurosurg Psychiatr (2002) vol. 72 (2) pp. 262-5 Ng et al. Aquaporin-4 expression is increased in edematous meningiomas. Journal of clinical neuroscience;(2009) pp.

15. FUTURE AQP4 and brain tumors - FUTURE  For decades neurosurgeons utilize steroids for brain tumor edema treatment  Research on AQP-4 modulators a new era for regulating brain tumor edema ???  Research is quite difficult cause current AQP4 behavior modulation compounds are highly toxic (AgNO 3, sulfadiazine) Niemietz and Tyerman. New potent inhibitors of aquaporins: silver and gold compounds inhibit aquaporins of plant and human origin. FEBS Lett (2002) vol. 531 (3) pp. 443-7

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