title: Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia.
abstract: Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFalpha application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygen-glucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFalpha and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFalpha. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy.
authors: Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Tamer
authors: T
authors: Altay
authors: Bethann
authors: B
authors: McLaughlin
authors: Jane Y
authors: JY
authors: Wu
authors: T S
authors: TS
authors: Park
authors: Jeffrey M
authors: JM
authors: Gidday
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy*; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D009457:Neuroglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011971:Receptors, Immunologic / Q000008:administration & dosage; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*; D000097905:Roundabout Proteins
chemical_list: D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D000097905:Roundabout Proteins
references: Nature. 2001 Apr 19;410(6831):948-52
references: 11309622
references: Mol Cell Neurosci. 2001 May;17(5):883-94
references: 11358485
references: Neuroreport. 2001 Aug 28;12(12):2731-5
references: 11522957
references: Cell. 2001 Oct 19;107(2):209-21
references: 11672528
references: Ann Neurol. 1996 May;39(5):618-24
references: 8619547
references: Exp Neurol. 1996 Jun;139(2):188-202
references: 8654522
references: Neurosci Lett. 1996 Mar 15;206(2-3):149-52
references: 8710173
references: Neuroscience. 1996 May;72(2):343-54
references: 8737405
references: Stroke. 1996 Oct;27(10):1739-43
references: 8841321
references: J Cereb Blood Flow Metab. 1997 May;17(5):491-9
references: 9183286
references: Lab Invest. 1997 Aug;77(2):119-25
references: 9274853
references: Neurobiol Dis. 1996;3(3):215-27
references: 8980022
references: Mol Med. 1997 Nov;3(11):765-81
references: 9407552
references: Neuroscience. 1998 Sep;86(1):279-90
references: 9692761
references: J Biol Chem. 1998 Dec 11;273(50):33588-94
references: 9837942
references: Neurosurgery. 1998 Dec;43(6):1382-96; discussion 1396-7
references: 9848853
references: Cell Mol Neurobiol. 1998 Dec;18(6):695-701
references: 9876875
references: Glia. 1999 Feb 1;25(3):229-39
references: 9932869
references: Brain Pathol. 2000 Jan;10(1):95-112
references: 10668900
references: Stroke. 1999 May;30(5):1110-7
references: 10229752
references: J Korean Med Sci. 1999 Jun;14(3):304-14
references: 10402174
references: Genes Dev. 2005 Jan 1;19(1):1-49
references: 15630019
references: Brain Res Brain Res Rev. 2005 Feb;48(1):16-42
references: 15708626
references: Neurol Res. 2004 Dec;26(8):884-92
references: 15727272
references: Glia. 2005 Jun;50(4):307-20
references: 15846804
references: J Cereb Blood Flow Metab. 2005 Aug;25(8):949-58
references: 15758943
references: Neurosci Lett. 2006 Jan 30;393(2-3):122-6
references: 16356636
references: J Neuroimmunol. 2007 Mar;184(1-2):53-68
references: 17188755
references: J Immunol. 1999 Mar 1;162(5):2964-73
references: 10072547
references: Exp Neurol. 2002 Jan;173(1):168-81
references: 11771949
references: Eur J Pharmacol. 2002 Jun 28;447(1):37-42
references: 12106800
references: Genes Dev. 2002 Dec 1;16(23):2973-84
references: 12464628
references: Brain Res. 2002 Dec 20;958(1):89-99
references: 12468033
references: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):715-20
references: 12522260
references: Microcirculation. 2003 Jun;10(3-4):297-311
references: 12851647
references: Cell. 2003 Jul 25;114(2):201-14
references: 12887922
references: Cancer Cell. 2003 Jul;4(1):19-29
references: 12892710
references: Dev Biol. 2003 Sep 1;261(1):251-67
references: 12941633
references: Neurochem Int. 2004 Jan;44(2):107-18
references: 12971913
references: Nat Rev Neurosci. 2003 Dec;4(12):941-56
references: 14682358
references: J Appl Physiol (1985). 2004 Mar;96(3):1223-30; discussion 1196
references: 14766771
references: Cardiovasc Res. 2004 Feb 15;61(3):548-58
references: 14962485
references: Front Biosci. 2004 May 1;9:1339-47
references: 14977549
references: Curr Mol Med. 2004 Mar;4(2):193-205
references: 15032713
references: Acta Neurol Scand. 1992 Sep;86(3):256-9
references: 1414243
references: J Cereb Blood Flow Metab. 1993 Jul;13(4):683-92
references: 8314921
references: Stroke. 1994 Apr;25(4):869-75; discussion 875-6
references: 8160235
references: Stroke. 1994 Jul;25(7):1481-8
references: 8023366
references: Neurology. 1994 Sep;44(9):1747-51
references: 7936308
references: J Neurol Sci. 1994 Aug;125(1):3-10
references: 7964886
references: Brain Res Bull. 1994;35(4):387-92
references: 7850491
references: J Clin Invest. 1996 Jan 1;97(1):209-16
references: 8550836
references: J Cell Biol. 1996 Apr;133(2):445-55
references: 8609175
references: J Cereb Blood Flow Metab. 2000 Jan;20(1):53-65
references: 10616793
references: J Neurochem. 2000 Feb;74(2):457-71
references: 10646496
references: Brain Pathol. 2000 Jan;10(1):113-26
references: 10668901
references: J Clin Invest. 2000 Jul;106(1):15-24
references: 10880044
references: J Neurosci. 2000 Jul 15;20(14):5329-38
references: 10884317
references: J Neuroimmunol. 2000 Sep 22;109(2):181-7
references: 10996220
references: Circ Res. 2000 Dec 8;87(12):1141-8
references: 11110771
references: Development. 2001 Jan;128(2):207-16
references: 11124116
references: Neurosci Lett. 2001 Feb 2;298(2):103-6
references: 11163288
references: Am J Pathol. 2004 Jul;165(1):341-52
references: 15215188
references: Eur J Neurosci. 2004 Jun;19(12):3151-64
references: 15217371
references: Biochem Biophys Res Commun. 2004 Sep 17;322(2):440-6
references: 15325249
references: Ann Emerg Med. 1989 May;18(5):517-22
references: 2719363
references: J Cereb Blood Flow Metab. 1989 Aug;9(4):500-5
references: 2738115
references: J Neurol Neurosurg Psychiatry. 1989 Apr;52(4):526-8
references: 2486297
references: Neurosci Lett. 1989 Aug 28;103(2):162-8
references: 2570387
references: Nature. 1990 Aug 2;346(6283):425-34
references: 1974032
references: Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651-5
references: 1675786
references: Stroke. 1991 Oct;22(10):1276-83
references: 1926239
references: J Cell Biol. 1992 Sep;118(5):1223-34
references: 1355095