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The Journal of Neuroscience, October 4, 2006, 26(40):10281-10291; doi:10.1523/JNEUROSCI.2806-06.2006

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Neurobiology of Disease
Combination of Thrombin and Matrix Metalloproteinase-9 Exacerbates Neurotoxicity in Cell Culture and Intracerebral Hemorrhage in Mice

Mengzhou Xue,¹ Morley D. Hollenberg,² and V. Wee Yong¹

¹Hotchkiss Brain Institute and Department of Clinical Neuroscience and ²Department of Pharmacology and Therapeutics and Department of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Correspondence should be addressed to Dr. V. Wee Yong, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, Canada T2N 4N1. Email: vyong{at}ucalgary.ca

The rapid loss of neurons is a major pathological outcome of intracerebral hemorrhage (ICH). Several mechanisms may produce the neurotoxicity observed in ICH, and these include proteolytic enzymes such as thrombin and matrix metalloproteinase-9 (MMP-9). We tested the hypothesis that thrombin and MMP-9 combine to injure neurons in culture and that they interact to promote the acute neurotoxicity that occurs in ICH in vivo. We report that human fetal neurons die when exposed to thrombin or MMP-9 in isolation and that a combination of these two enzymes increased neurotoxicity. The toxicity of thrombin involved protease-activated receptor-1 and the conversion of proMMP-9 to active MMP-9. In ICH, which was induced in mice by the intracerebral injection of autologous blood, significant areas of brain damage, neuronal death, microglia/macrophage activation, and neutrophil accumulation occurred by 24 h of injury. Importantly, these neuropathological features were reduced in MMP-9 null mice compared with wild-type controls, and the concordant antagonism of thrombin using hirudin also alleviated the injury found in MMP-9 null mice. Our collective results demonstrate that thrombin and MMP-9 collaborate to promote neuronal death in culture and in ICH. To improve the prognosis of ICH, the neurotoxic actions of thrombin and MMP-9 must be inhibited early and simultaneously after injury.

Key words: thrombin; MMP-9; proteases; inflammation; neuronal death; ICH

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Received March 13, 2006; revised Aug. 9, 2006; accepted Aug. 10, 2006.

Correspondence should be addressed to Dr. V. Wee Yong, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, Canada T2N 4N1. Email: vyong{at}ucalgary.ca

This article has been cited by other articles:

				V. W. Yong, F. Giuliani, M. Xue, A. Bar-Or, and L. M. Metz Experimental models of neuroprotection relevant to multiple sclerosis Neurology, May 29, 2007; 68(22_suppl_3): S32 - S37. [Abstract] [Full Text] [PDF]

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