Monocyte chemoattractant protein-1 is a mediator of acute excitotoxic injury in neonatal rat brain
Section snippets
Animal methods
P7 rats were obtained from Charles River (Wilmington, MA). All surgical protocols were approved by the University of Michigan Committee on Care and Use of Animals. Efforts were made to minimize animal suffering and the numbers of animals used in these experiments. All in vivo lesioning experiments were performed in P7 Sprague–Dawley rats of both genders, using previously reported methods.30 Animals received intra-cerebral injections into either the right striatum or the right dorsolateral
Recombinant monocyte chemoattractant protein-1 exacerbates N-methyl-d-aspartate-induced brain injury
Microscopic examination of brain sections from P12 animals that received intra-striatal injections of 50 ng of active rMCP-1 alone showed no evidence of histopathological damage (data not shown). Loss of Nissl staining was restricted to regions directly surrounding the needle tract. Animals that received intra-striatal injections of heat-treated rMCP-1 alone showed a similar histological pattern. Intra-striatal injection of 5 nmol NMDA results in subtle loss of Nissl staining and striatal
Discussion
Our data show that co-administration of rMCP-1 and a low dose of NMDA exacerbates NMDA-induced injury in both the striatum and the hippocampus by 55% and 167%, respectively. In addition, complementary experiments designed to evaluate the effect of functional inhibition of MCP-1 in vivo, using an MCP-1-neutralizing antibody, showed attenuation of NMDA-induced striatal and hippocampal injury by 57% and 39%, respectively. These data demonstrate that MCP-1 is a mediator of NMDA-induced brain injury
Conclusions
Our data provide the first evidence of a functional role for MCP-1 in NMDA-induced neonatal brain injury. This information, in combination with other recent data, suggests that the induction of MCP-1 may be a pivotal point in the inflammatory response to acute brain injury. Furthermore, MCP-1 may be an attractive therapeutic target in certain inflammatory disorders of the CNS.
Acknowledgements
This work was supported by USPHS grants NS35059 and NS31054 to F.S.S., and HL48287 to J.S.W.
References (39)
- et al.
gp120, a human immunodeficiency virus-1 coat protein, augments excitotoxic hippocampal injury in perinatal rats
Neuroscience
(1997) - et al.
Overriding the brain’s intrinsic resistance to leukocyte recruitment with intraparenchymal injections of recombinant chemokines
Neuroscience
(1996) - et al.
Excitotoxic brain injury stimulates expression of the chemokine receptor CCR5 in neonatal rats
Am. J. Path.
(1998) - et al.
Experimental gliosarcoma induces chemokine receptor expression in rat brain
Expl Neurol.
(2000) - et al.
Chemokine inhibition in rat stab wound brain injury using antisense oligodeoxynucleotides
Neurosci. Lett.
(1998) - et al.
Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1 alpha and monocyte chemotactic protein-1
J. Neuroimmun.
(1998) - et al.
Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat
J. Neuroimmun.
(1995) - et al.
Tumor necrosis factor-α attenuates N-methyl-d-aspartate-mediated neurotoxicity in neonatal rat hippocampus
Brain Res.
(1999) - et al.
Quantitative assessment of neuroprotection against NMDA-induced brain injury
Expl Neurol.
(1989) - et al.
Excitotoxic injury induces monocyte chemoattractant protein-1 expression in neonatal rat brain
Molec. Brain Res.
(1998)
Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy
Am. J. Obstet. Gynecol.
Microglial response to N-methyl-d-aspartate-mediated excitotoxicity in the immature rat brain
J. comp. Neurol.
Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat
J. Immun.
Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant
Proc. natn. Acad. Sci. USA
Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia
Proc. natn. Acad. Sci. USA
Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn
Pediatr. Res.
Proinflammatory cytokines interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium
Ann. Neurol.
Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function
J. Neurosci.
Characterization of microglia and macrophages in the central nervous system of rats: definition of the differential expression of molecules using standard and novel monoclonal antibodies in normal CNS and in four models of parenchymal reaction
Glia
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Present address: Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.