Amelioration of hypoperfusion after traumatic brain injury by in vivo endothelin-1 knockout.
Endothelin 1 (ET-1) is one of the most powerful vasoconstrictors in the brain. Its expression is upregulated after traumatic brain injury (TBI) and is a major factor in the ensuing hypoperfusion. Attenuation of ET-1 effects has been mainly achieved by blockade of its receptors. The result of a direct blockade of ET-1 mRNA synthesis is not known. We used the Marmarou's model to inflict injury to male Sprague-Dawley rats injected with antisense ET-1 oligodeoxynucleotides (ODNs) before injury. Laser Doppler flowmetry in noninjured rats (2 groups, i.e., untreated and animals that received cODNs) revealed a constant cerebral blood flow of approximately 14 mL.min-1.100 g-1, whereas the values from injured animals pretreated with control ODNs (cODNs) or from animals subjected to TBI alone were approximately 8.0 mL.min-1.100 g-1 during the 18-48 h time period post-TBI. After antisense ET-1 ODNs pretreatment, however, cerebral blood flow in injured animals was approximately 17 mL.min-1.100 g-1 during the 6-48 h time period. Antisense ET-1 ODNs-treated animals also had 19%-29% larger microvessel cross-sectional area and approximately one-third less ET-1 immunoreactivity in the 50-75% range after injury than did cODNs-treated animals after TBI. The results indicate that this direct in vivo approach is an effective therapeutic intervention for the restoration of cerebral blood flow after TBI.
Petrov
Theodor
T
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA. tpetrov@med.wayne.edu
D000818:Animals; D001930:Brain Injuries / Q000503:physiopathology*; D002560:Cerebrovascular Circulation; D018932:Chemokine CCL2 / Q000096:biosynthesis; D019332:Endothelin-1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D019332:Endothelin-1; D020319:Oligodeoxyribonucleotides, Antisense