Transforming growth factor-beta1-mediated neuroprotection against excitotoxic injury in vivo
Transforming growth factor-beta1-mediated neuroprotection against excitotoxic injury in vivo
Ischemic preconditioning is a phenomenon that describes how a sublethal ischemic insult can induce tolerance to subsequent ischemia. This phenomenon has been observed after focal or global ischemia in different animal models. However, the hypothesis that bacterial infection might lead to neuronal tolerance to injury has not been investigated. To mimic cerebral bacterial infection, we injected bacterial lipopolysaccharide (LPS) in the right dorsal hippocampus, followed 24 hours later by an excitotoxic lesion using kainic acid in the mouse model. Quantification of lesion size after cresyl violet counterstaining revealed that LPS pretreatment afforded neuroprotection to CA3 neurons against KA challenge. To investigate the events underlying this protection, we studied the cytokine profile induced after LPS injection. Interleukin (IL)-1 beta and transforming growth factor beta 1 (TGF-beta 1) were the main cytokines expressed at 24 hours after LPS injection. Because IL-1 beta has been described as deleterious in acute injury, we decided to investigate the function of TGF-beta 1. An adenovirus expressing a constitutively active form of TGF-beta 1 was injected intracerebrally 1 week before the induction of excitotoxic lesion, and neuronal protection was observed. To confirm the neuroprotective role of TGF-beta 1, the TGF-beta 1 adenovirus was replaced by recombinant human TGF-beta 1 protein and total neuroprotection was observed. Furthermore, the antibody-mediated blocking of TGF-beta 1 action prevented the protective effect of pretreatment with LPS. We have demonstrated in vivo that the cerebral tolerance phenomenon induced by LPS pretreatment is mediated by TGF-beta 1 cytokine.
Abbreviations: ANOVA, analysis of variance; CNS, central nervous system; DAB, 3,3 -diaminobenzidine; ELISA, enzyme linked immuno assay; IL, interleukin; KA, kainic acid; LPS, lipopolysaccharide; PAI-I, plasminogen activator inhibitor; PBS, phosphate buffered saline; tPA, tissue plasminogen activator; TGF1, transforming growth factor beta 1; TNF, tumor necrosis factor alpha; Rh, recombinant human
bacterial infection, neuroprotection, TGF-1, adenovirus
1174-1182
Boche, D.
bdcca10e-6302-4dd0-919f-67218f7e0d61
Cunningham, C.
6d675038-a4b1-46e2-9e4b-0a5ac27ea2b2
Gauldie, J.
97a5c632-0e54-4360-ac0d-4786155bf375
Perry, VH.
8f29d36a-8e1f-4082-8700-09483bbaeae4
October 2003
Boche, D.
bdcca10e-6302-4dd0-919f-67218f7e0d61
Cunningham, C.
6d675038-a4b1-46e2-9e4b-0a5ac27ea2b2
Gauldie, J.
97a5c632-0e54-4360-ac0d-4786155bf375
Perry, VH.
8f29d36a-8e1f-4082-8700-09483bbaeae4
Boche, D., Cunningham, C., Gauldie, J. and Perry, VH.
(2003)
Transforming growth factor-beta1-mediated neuroprotection against excitotoxic injury in vivo.
Journal of Cerebral Blood Flow and Metabolism, 23 (10), .
(doi:10.1097/01.WCB.0000090080.64176.44).
Abstract
Ischemic preconditioning is a phenomenon that describes how a sublethal ischemic insult can induce tolerance to subsequent ischemia. This phenomenon has been observed after focal or global ischemia in different animal models. However, the hypothesis that bacterial infection might lead to neuronal tolerance to injury has not been investigated. To mimic cerebral bacterial infection, we injected bacterial lipopolysaccharide (LPS) in the right dorsal hippocampus, followed 24 hours later by an excitotoxic lesion using kainic acid in the mouse model. Quantification of lesion size after cresyl violet counterstaining revealed that LPS pretreatment afforded neuroprotection to CA3 neurons against KA challenge. To investigate the events underlying this protection, we studied the cytokine profile induced after LPS injection. Interleukin (IL)-1 beta and transforming growth factor beta 1 (TGF-beta 1) were the main cytokines expressed at 24 hours after LPS injection. Because IL-1 beta has been described as deleterious in acute injury, we decided to investigate the function of TGF-beta 1. An adenovirus expressing a constitutively active form of TGF-beta 1 was injected intracerebrally 1 week before the induction of excitotoxic lesion, and neuronal protection was observed. To confirm the neuroprotective role of TGF-beta 1, the TGF-beta 1 adenovirus was replaced by recombinant human TGF-beta 1 protein and total neuroprotection was observed. Furthermore, the antibody-mediated blocking of TGF-beta 1 action prevented the protective effect of pretreatment with LPS. We have demonstrated in vivo that the cerebral tolerance phenomenon induced by LPS pretreatment is mediated by TGF-beta 1 cytokine.
Abbreviations: ANOVA, analysis of variance; CNS, central nervous system; DAB, 3,3 -diaminobenzidine; ELISA, enzyme linked immuno assay; IL, interleukin; KA, kainic acid; LPS, lipopolysaccharide; PAI-I, plasminogen activator inhibitor; PBS, phosphate buffered saline; tPA, tissue plasminogen activator; TGF1, transforming growth factor beta 1; TNF, tumor necrosis factor alpha; Rh, recombinant human
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Published date: October 2003
Keywords:
bacterial infection, neuroprotection, TGF-1, adenovirus
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Local EPrints ID: 27535
URI: http://eprints.soton.ac.uk/id/eprint/27535
PURE UUID: 162bab95-8c66-4aa8-bca6-4f66af629211
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Date deposited: 27 Apr 2006
Last modified: 16 Mar 2024 03:15
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Author:
C. Cunningham
Author:
J. Gauldie
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