Therapeutic strategies for stroke: targeting the neurovascular unit

Abstract

Abstract: Over the past two decades, researches have heavily emphasized on basic mechanisms of irreversible damage in brain cells after stroke.Many studies focused on what makes neurons die easily and what kind of strategies render neurons resistant to ischemic injury.In the past few years, clinical experience with clot-lysing drugs had confirmed expectations that early reperfusion improves clinical outcome.With recent research emphasizing methods to reduce tissue damage, both vascular and cell-based mechanisms, the spotlight is now shifting towards the study of how blood vessels and brain cells communicate with each other.The neurovascular unit (NVU) origins from an integrative blood vessel and neural system response in which all cellular and matrix elements involved in.The new research focus provides challenges and opportunities for research and therapy of stroke.

Key words: stroke, neurovascular unit, blood brain barrier, MMPs

CLC Number:

GAO Mei, LIU Rui, DU Guan-hua. Therapeutic strategies for stroke: targeting the neurovascular unit[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(7): 813-821.

References

[1] del Zoppo GJ. Stroke and neurovascular protection[J]. N Engl JMed, 2006, 354(6): 553-555.
[2] Green AR, Shuaib A. Therapeutic strategies for the treatment of stroke[J]. Drug Discovery Today, 2006, 11(15/16): 681-693.
[3] Lo EH. Experimental models, neurovascular mechanisms and translational issues in stroke research[J]. Br J Pharmacol, 2008, 153(Suppl 1): 396-405.
[4] Green AR. Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly[J]. Br J Pharmacol, 2008, 153(Suppl 1): 325-338.
[5] Lo EH, Turgay D,MoskowitzMA. Mechanisms, challenges, and opportunities in stroke[J]. Nat Rev of Neurosci, 2003, 4(5): 399-416.
[6] Cao G, Pei W, Ge H, et al. In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis[J]. J Neurosci, 2002, 22(13): 5423-5431.
[7] Bruno V, Battaglia G, Copani A, et al. Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs[J]. J Cereb Blood Flow Metab, 2001, 21(9): 1013-1033.
[8] Horn J, Limburg M. Calcium antagonists for ischemic stroke: a systematic review[J]. Stroke, 2001, 32(2): 570-576.
[9] Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain[J]. J Cereb Blood Flow Metab, 2001, 21(1): 2-14.
[10] Kroemer G, Reed JC. Mitochondrial control of cell death [J]. NatMed, 2000, 6(5): 513-519.
[11] Bernardi P, Petronilli V, Di LF, et al. A mitochondrial perspective on cell death[J]. Trends Biochem Sci, 2001, 26: 112-117.
[12] Nicotera P, Leist M, Fava E, et al. Energy requirement for caspase activation and neuronal cell death[J]. Brain Pathol, 2000, 10(2): 276-282.
[13] Nicotera P, Lipton SA. Excitotoxins in neuronal apoptosis and necrosis [J]. J Cereb Blood Flow Metab, 1999, 19 (6): 583-591.
[14] Budd SL, Tenneti L, Lishnak T, et al. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons[J]. Proc Natl Acad Sci USA, 2000, 97 (11): 6161-6166.
[15] Martin A, Herr I, Jeremias I, et al. Cd95 ligand (fas-l/apo-11) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons [J]. J Neurosci, 1999, 19: 3809-3817.
[16] Salvesen GS. A lysosomal protease enters the death scene [J]. J Clin Invest, 2001, 107(1): 21-22.
[17] Report of the Stroke Progress Review Group[R]. 2002: (National Institute of Neurological Disorders and Stroke, Maryland) 1-116.
[18] Petty MA, Lo EH. Junctional complexes of the bloodbrain barrier: permeability changes in neuroinflammation [J]. Prog Neurobiol, 2002, 68(5): 311-323.
[19] Zhao BQ, Tejima E, Lo EH. Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke[J]. Stroke, 2007, 38(2 Suppl): 748-752.
[20] Rosell A, Cuadrado E, Ortega-Aznar A, et al. MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke[J]. Stroke, 2008, 39(4): 1121-1126.
[21] Zinaida S, Vexler A, Tang XN, et al. Inflammation in adult and neonatal stroke [J]. Clin Neurosci Res, 2006, 6: 293-313.
[22] Han HS, Suk K. The function and integrity of the neurovascular unit rests upon the integration of the vascular and inflammatory cell systems[J]. Curr Neurovasc Res, 2005, 2(5): 409-423.
[23] Fabry Z, Raine CS, Hart MN. Nervous tissue as an immune compartment: the dialect of the immune response in the CNS[J]. Immunol Today, 1994, 15(5): 218-224.
[24] Romanic AM, White RF, Arleth AJ, et al. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size[J]. Stroke, 1998, 29(5): 1020-1030.
[25] Bolton SJ, Anthony DC, Perry VH. Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo [J]. Neuroscience, 1998, 86(4): 1245-1257.
[26] Bazzoni G, Martinez OM, Orsenigo F, et al. Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occluding [J]. J Biol Chem, 2000, 275(27): 20520-20526.
[27] Ballabh P, Braun A, NedergaardM. The blood-brain barrier: an overview: structure, regulation, and clinical implications[J]. Neurobiol Dis, 2004, 16(1): 1-13.
[28] Asahi M, Wang X, Mori T, et al. Effect of matrix metalloproteinase 9 gene knockout on the proteolysis of bloodbrain barrier and white matter components after cerebral ischemia[J]. J Neurosci, 2001, 21(19): 7724-7732.
[29] Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women[J]. N Engl J Med, 2000, 342(12): 836-843.
[30] Tanne D, Haim M, Boyko V, et al. Soluble intercellular adhesion molecule-1 and risk of future ischemic stroke: a nested case-control study from the bezafibrate infarction prevention (bip) study cohort[J]. Stroke, 2002, 33(9): 2182-2186.
[31] Hughes PM, Allegrini PR, Rudin M, et al. Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model[J]. J Cereb Blood Flow Metab, 2002, 22(3): 308-317.
[32] Iadecola C, Niwa K, Nogawa S, et al. Reduced susceptibility to ischemic brain injury and n-methy ld-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice [J]. Proc Natl Acad Sci USA, 2001, 98: 1294-1299.
[33] Boutin H, LeFeuvre RA, Horai R, et al. Role of IL-1alpha and IL-1beta in ischemic brain damage[J]. J Neurosci, 2001, 21(15): 5528-5534.
[34] Yong VW. The potential use of MMP inhibitors to treat CNS diseases[J]. Exp Opin Invest Drugs, 1999, 8(3): 255-268.
[35] Tsuji K, Aoki T, Tejima E, et al. Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia[J]. Stroke, 2005, 36(9): 1954-1959.
[36] Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia[J]. Glia, 2005, 50(4): 329-339.
[37] Lee SR, Lo EH. Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation [J]. J Cereb Blood Flow Metab, 2004, 24(7): 720-727.
[38] Wang X, Tsuji K, Lee SR, et al. Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke[J]. Stroke, 2004, 35(11 Suppl 1): 2726-2730.
[39] Lee SR, Wang X, Tsuji K, et al. Extracellular proteolytic pathophy siology in the neurovascular unit after stroke[J]. Neurol Res, 2004, 26(8): 854-861.
[40] Tsuji K, Aoki T, Tejima E, et al. Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia[J]. Stroke, 2005, 36(9): 1954-1959.
[41] Petty MA, Wettstein JG. White matter ischaemia[J]. Brain Res Rev, 1999, 31(1): 58-64.
[42] Schaller B, Graf R. Cerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy [J]. J Cereb Blood Flow Metab, 2004, 24(4): 351-371.
[43] Zivin JA. Thrombolytic stroke therapy: past, present, and future[J]. Neurology, 1999, 53(1): 14-19.
[44] Richard A, Odergren T, Ashwood T. Animal models of stroke: do they have value for discovering neuroprotective agents[J] ? Trends Pharmacol Sci, 2003, 24 (8): 402-408.
[45] Mohr JP, Gautier JC, Hier DB, et al. Middle cerebral artery in stroke[M] (Barnett, HJM. et al. eds). Churchill Livingstone. Pathophysiology, Diagnosis andManagement, 1986, pp: 377-450.
[46] Ringelstein EB, Biniek R, Weiller C, et al. Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization [J]. Neurology, 1992, 42(2): 289-298.
[47] Stroke therapy academic industry roundtable. Recommendations for clinical trial evaluation of acute stroke therapies [J]. Stroke, 2001, 32(7): 1598-1606.
[48] Stroke therapy academic industry roundtable. Recommendations for standards regarding preclinical neuroprotective and restorative drug development[J]. Stroke, 1999, 30 (12): 2752-2758.
[49] Aneesh B, Singhal T, Lo EH. Advances in stroke neuroprotection: hyperoxia and beyond[J]. Neuroimag Clin N Am, 2005, 15(3): 697-720.
[50] Green AR. Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly[J]. Br J Pharmacol, 2008, 153(Suppl 1): 325-338.