Elsevier

Neuroscience

Volume 101, Issue 3, 15 November 2000, Pages 737-744
Neuroscience

Monocyte chemoattractant protein-1 is a mediator of acute excitotoxic injury in neonatal rat brain

https://doi.org/10.1016/S0306-4522(00)00399-7Get rights and content

Abstract

Monocyte chemoattractant protein-1 is a chemokine with potent monocyte activating and chemotactic effects. Monocyte chemoattractant protein-1 gene and protein expression is rapidly up-regulated in response to a variety of acute and chronic central nervous system disorders. The activation and recruitment of microglia and monocytes into areas of inflammation may play a critical role in the pathogenesis of acute brain injury. Monocyte chemoattractant protein-1 could be a pathophysiologically important mediator of the microglial and monocyte responses in the brain. Using a well-characterized model of acute excitotoxic brain injury in neonatal rats, experiments were designed to evaluate whether monocyte chemoattractant protein-1 plays a role in the progression of tissue damage. Direct co-administration of recombinant monocyte chemoattractant protein-1 with the excitotoxin N-methyl-d-aspartate exacerbated injury, both in the striatum and in the hippocampus, by 55% and 167%, respectively. Complementary experiments to determine the effect of functional inhibition of monocyte chemoattractant protein-1, using an anti-monocyte chemoattractant protein-1-neutralizing antibody, revealed that co-administration of the antibody with N-methyl-d-aspartate attenuated tissue injury in the striatum and hippocampus by 57% and 39%, respectively.

Together, these data suggest that monocyte chemoattractant protein-1 is a mediator of acute excitotoxic brain injury in neonatal rats and that inflammatory mechanisms contribute significantly to the pathogenesis of acute neonatal brain injury. Whether chemokines are pathophysiologically relevant mediators of neuronal injury in human neonates remains to be determined.

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.

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    Present address: Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.

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