title: The novel nitric oxide synthase inhibitor 4-amino-tetrahydro-L-biopterine prevents brain edema formation and intracranial hypertension following traumatic brain injury in mice.
abstract: Brain edema formation, resulting in increased intracranial pressure (ICP), is one of the most deleterious consequences of traumatic brain injury (TBI). Nitric oxide (NO) has previously been shown to be involved in the damage of the blood-brain barrier (BBB) and, thus, in the formation of post-traumatic brain edema; however, this knowledge never resulted in a clinically relevant therapeutic option because available NO synthase inhibitors have serious side effects in man. The aim of the current study was to investigate the therapeutic efficacy of VAS203, a novel tetrahydrobiopterine (BH3)-based NOS inhibitor, in experimental TBI. When added to isolated vessels rings obtained from rat basilar and middle cerebral arteries (n = 32-35) VAS203 showed the same vasoconstrictive effect as the classical NO synthase inhibitor L-(G)-nitro-arginine-methylester (L-NAME). VAS203 passed the BBB both in healthy and traumatized mouse brain (C57/BL6, n = 5 per group) and did not show any systemic side effects at therapeutic concentrations. When administered 30 min after experimental TBI (controlled cortical impact, 2.2 mg/kg/min i.v., n = 7 per group), VAS203 prevented any further increase in ICP or deterioration of cerebral blood flow. This effect was dose-dependent and long-lasting (i.e., 24 h after trauma, brain edema formation was still significantly reduced [-40%, p < 0.008; n = 7 per group] and functional improvements were present up to 7 days after TBI [p < 0.02 on post-trauma day 6; n = 8 per group]). Therefore, VAS203 may represent a promising candidate for the treatment of acute intracranial hypertension following TBI.
authors.affiliation: Department of Neurosurgery and Institute for Surgical Research, University of Munich Medical Center-Grosshadern, Munich, Germany.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Terpolilli
authors.forename: Klaus
authors.initials: K
authors.lastname: Zweckberger
authors.forename: Raimund
authors.initials: R
authors.lastname: Trabold
authors.forename: Lothar
authors.initials: L
authors.lastname: Schilling
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schinzel
authors.forename: Frank
authors.initials: F
authors.lastname: Tegtmeier
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Plesnila
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000187:drug effects; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control*; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D019586:Intracranial Hypertension / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; C106930:4-amino-tetrahydrobiopterin; D001708:Biopterins; D019001:Nitric Oxide Synthase