Traumatic brain injury (TBI) causes disruption of the blood brain barrier (BBB) leading to hemorrhage which can complicate an already catastrophic illness. Matrix metalloproteinases (MMPs) involved in the breakdown of the extracellular matrix may lead to brain hemorrhage. We explore the contribution of the 70 kDa heat shock protein (Hsp70) to outcome and brain hemorrhage in a model of TBI. Male, wildtype (Wt), Hsp70 knockout (Ko) and transgenic (Tg) mice were subjected to TBI using controlled cortical impact (CCI). Motor function, brain hemorrhage and lesion size were assessed at 3, 7 and 14 days. Brains were evaluated for the effects of Hsp70 on MMPs.In Hsp70 Tg mice, CCI led to smaller brain lesions, decreased hemorrhage and reduced expression and activation of MMPs compared to Wt. CCI also significantly decreased right-biased swings and corner turns in the Hsp70 Tg mice. Conversely, Hsp70 Ko mice had significantly increased lesion size, worsened brain hemorrhage and increased expression and activation of MMPs with worsened behavioral outcomes compared to Wt. Hsp70 is protective in experimental TBI. To our knowledge, this is the direct demonstration of brain protection by Hsp70 in a TBI model. Our data demonstrate a new mechanism linking TBI-induced hemorrhage and neuronal injury to the suppression of MMPs by Hsp70, and support the development of Hsp70 enhancing strategies for the treatment of TBI.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institutes of Health ( NS40516 ) and the Veteran's Merit Award to MY, an American Heart Association Western States Affiliate Postdoctoral Fellowship ( 13POST14810019 ) to JYK and Basic Science Research Program through the NRF of KOREA funded by the Ministry of Education, Science and Technology ( 2012-0005827 ) to JEL. Grants to MY and JYK were administered by the Northern California Institute for Research and Education , and supported by resources of the Veterans Affairs Medical Center , San Francisco, California. The authors wish to thank Dr. Linda Noble-Haeusslein for helpful discussion and advice.
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