title: The antioxidative, non-psychoactive tricyclic phenothiazine reduces brain damage after experimental traumatic brain injury in mice.
abstract: Oxidative stress due to free radical formation is an important mechanism of secondary brain damage following traumatic brain injury (TBI). Phenothiazine has been found to be a strong antioxidant in eukaryotic cells in vitro and in invertebrates in vivo. The present study was designed to determine the neuroprotective potency of unsubstituted phenothiazine in a paradigm of acute brain injury. Thirty minutes after pneumatic, controlled cortical impact (CCI) injury, C57BI6 mice were randomly assigned to "low dose" (3 mg/kg, LD) or "high dose" (30 mg/kg, HD) s.c. phenothiazine or vehicle treatment. Brain lesion, neurofunctional impairment, body weight, and markers of cerebral inflammation were determined 24h after the insult. Phenothiazine treatment dose-dependently reduced brain lesion volume (LD: -19.8%; HD: -26.1%) and posttraumatic body weight loss. There were no significant differences in the neurological function score and in markers of cerebral inflammation (Iba-1 positive cells, TNFα expression), whereas iNOS expression was significantly lower compared to vehicle-treated animals. Phenothiazine appears to modify in a post-treatment protocol certain aspects of secondary brain damage in vivo at unusually low concentrations, in particular the cortical contusion volume after TBI. The potential role of the reduced iNOS expression is unclear at present.
authors.affiliation: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Phuriphong
authors.initials: P
authors.lastname: Songarj
authors.affiliation: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Luh
authors.affiliation: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Staib-Lasarzik
authors.affiliation: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Engelhard
authors.affiliation: Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Moosmann
authors.affiliation: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address: thal@uni-mainz.de.
authors.forename: Serge C
authors.initials: SC
authors.lastname: Thal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D010640:Phenothiazines / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation
chemical_list: C491049:Aif1 protein, mouse; D000975:Antioxidants; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D010640:Phenothiazines; C031637:phenothiazine
keywords: Controlled cortical impact; Mice; Oxidative stress; Phenothiazine; Traumatic brain injury