Antioxidants attenuate acute toxicity of tumor necrosis factor-alpha induced by brain injury in rat.
Tumor necrosis factor-alpha alpha (TNF-alpha) and reactive oxygen species (ROS) are produced in the brain after traumatic injury and have deleterious effects. In a rat model of closed head injury (CHI), the synthetic antioxidant from the nitroxide family, Tempol, improved recovery and protected the blood-brain barrier. Similar protection was found after CHI in heat-acclimated rats, in which the endogenous antioxidants have been shown to be elevated after CHI. The present study examined the relationship between TNF-alpha and ROS after CHI, namely, whether after CHI, antioxidants that afforded cerebroprotection also attenuated brain levels of TNF-alpha. Three groups of rats were subjected to CHI: (1) control, nontreated, (2) Tempol-treated, and (3) heat-acclimated (30 days at 34 degrees C). Four hours after injury (time for peak production of TNF-alpha), the activity of TNF-alpha was measured. Although clinical recovery was facilitated in rats of the two treated groups, TNF-alpha activity was as high as in the traumatized, untreated rats. Moreover, direct injection of TNF-alpha into mouse brain induced disruption of the blood-brain barrier, indicating its acute harmful effect. This toxic effect was attenuated by before and after treatment with Tempol. Our results support the hypothesis that in vivo antioxidants neutralize TNF-alpha toxicity, probably by interfering with activation of the transcription factor NF-kappa-B.
Trembovler
V
V
Department of Pharmacology, The Hebrew University, School of Pharmacy and Medicine, Jerusalem, Israel.
Beit-Yannai
E
E
Younis
F
F
Gallily
R
R
Horowitz
M
M
Shohami
E
E
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000627:therapeutic use; D016489:Head Injuries, Closed / Q000150:complications / Q000378:metabolism*; D006358:Hot Temperature; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha; C001803:tempol