A major event following brain trauma is the loss of autoregulatory capacity of brain microvessels which results in sustained hypoperfusion and improper delivery of vital metabolites to brain tissue. Previously we established that the sustained hypoperfusion and the lack of autoregulatory capacity post trauma are largely due to the capability of injured cells in the vascular wall and in other brain compartments to synthesize and maintain excessive amounts of endothelin-1 (ET-1). ET-1, as well as its two isoforms ET-2 and ET-3, exert signal-transducing, vasoconstrictor effects through their only known receptors ET-RA and ET-RB. Although activation of both receptors is known to cause vasoconstriction in both in vitro preparations and non-neural tissues, little is known of their role in the injured brain and the development of secondary cell injury. In fact the role of ET-RA and ET-RB in vasoconstriction and their pharmacological manipulation to prevent cell injury after traumatic brain injury (TBI) have never been studied. ? ? We propose that upregulation of the genes encoding for the synthesis of ET-RA and ET-RB in smooth muscle and endothelium (where they are expressed most abundantly), as well as in other perivascular cells, underlie the enhanced contractility previously observed in the microvascular wall after TBt. In this proposal our specific aims are to: 1) characterize quantitatively in time the expressions of ET- RA and ET- RB (mRNA) in distinct cellular compartments of the vascular wall and surrounding neuropil prior to and after TBI, 2) translationaly inhibit the expression of ET- RA and ET- RB before TBI to improve the impaired microcirculation, and 3) pharmacologically attenuate hypoperfusion post TBI by application of selective antagonists to ET- RA and ET- RB. ? ? We will use in situ hybridization to measure mRNA synthesis and in vivo intracerebroventricular application of antisense oligodeoxynucleotides to attenuate ET- RA and ET- RB gene expressions."""""""" In tandem use of selective receptor antagonist with the 14C iodoantipyrine technique we will assess antagonist effects on cerebral cortical blood flow. By similar in tandem use of antisense application and the 14C iodoantipyrine technique we will determine the reciprocal effects of the receptors and their antgonist on each other and respective affect on the microcirculation after TBI. Histological and motor behavior studies will be used to assess neurological outcome following the therapeutic interventions. ? ? The results will provide valuable information on the expression of endothelin receptors (mRNA and proteins), their cellular distribution and the causal relationships of this expression to the alterations in the brain microcirculation after TBI. Precise times of ET- RA and ET- RB expressions will be established that should allow us to establish effective therapeutic interventions. The study will also provide direct evidence on the therapeutic value of suppressing gene regulation or receptor activation on cortical perfusion, histologic or neurologic injury, and its effect on impaired motor skills after TBI. ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039860-08
Application #
7407435
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hicks, Ramona R
Project Start
2000-03-10
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
8
Fiscal Year
2008
Total Cost
$332,009
Indirect Cost
Name
Wayne State University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Wang, Tony; Chou, David Yu-Te; Ding, Jamie Y et al. (2013) Reduction of brain edema and expression of aquaporins with acute ethanol treatment after traumatic brain injury. J Neurosurg 118:390-6
Shenaq, Mohammed; Kassem, Hassan; Peng, Changya et al. (2012) Neuronal damage and functional deficits are ameliorated by inhibition of aquaporin and HIF1ýý after traumatic brain injury (TBI). J Neurol Sci 323:134-40
Kreipke, Christian W; Reynolds, Christian A; Schafer, Patrick C et al. (2011) Endothelin receptors A and B are expressed in distinct cellular compartments of rat hippocampus following global ischemia: an immunocytochemical study. Neurol Res 33:162-8
Higashida, Tetsuhiro; Kreipke, Christian W; Rafols, José A et al. (2011) The role of hypoxia-inducible factor-1?, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury. J Neurosurg 114:92-101
Kreipke, Christian W; Schafer, Patrick C; Rossi, Noreen F et al. (2010) Differential effects of endothelin receptor A and B antagonism on cerebral hypoperfusion following traumatic brain injury. Neurol Res 32:209-14
Petrov, Theodor (2009) Amelioration of hypoperfusion after traumatic brain injury by in vivo endothelin-1 knockout. Can J Physiol Pharmacol 87:379-86
Ding, Jamie Y; Kreipke, Christian W; Schafer, Patrick et al. (2009) Synapse loss regulated by matrix metalloproteinases in traumatic brain injury is associated with hypoxia inducible factor-1alpha expression. Brain Res 1268:125-34
Ding, Jamie Y; Kreipke, Christian W; Speirs, Susan L et al. (2009) Hypoxia-inducible factor-1alpha signaling in aquaporin upregulation after traumatic brain injury. Neurosci Lett 453:68-72
Huttemann, M; Lee, I; Kreipke, C W et al. (2008) Suppression of the inducible form of nitric oxide synthase prior to traumatic brain injury improves cytochrome c oxidase activity and normalizes cellular energy levels. Neuroscience 151:148-54
Petrov, Theodor; Kreipke, Christian; Alilain, Warren et al. (2007) Differential expression of adenosine A1 and A2A receptors after upper cervical (C2) spinal cord hemisection in adult rats. J Spinal Cord Med 30:331-7

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