TNF-alpha accounts for short-term persistence of oxidative status in rat brain after two weeks of repeated stress.
Inducible nitric oxide synthase (NOS-2) accounts for the accumulation of oxidative and nitrosative mediators in brain after stress. To determine whether and when repeated exposure to immobilization stress leads to persistent oxidative status in rat brain, male Wistar rats were immobilized for 6 h/day for 7 or 14 days (S7, S14). Cerebral cortices were obtained immediately after the last session of stress or 1 day later. Stress increased NOS-2 activity after S7 or S14. This enzymatic activity returned to basal values 1 day after S7, but not 1 day after S14. Stress increased malondialdehyde (MDA) accumulation in cortex after S7 and S14. MDA levels returned to basal values 1 day after S7 but not 1 day after S14. In order to elucidate the possible mechanisms involved in this short-term persistence of oxidative status, brain levels of the cytokine tumour necrosis factor alpha (TNF-alpha) were determined. TNF-alpha levels did not increase after S7 or 1 day after S7, but increased after S14 and 1 day after S14. This was paralleled by an increase in TNF-alpha converting enzyme (TACE) activity in brain. When the increase in TNF-alpha at S14 was blocked by BB1101, an inhibitor of TACE, or its effects were blocked with anti-TNF-alpha, the accumulation of MDA and NOS-2 activity 1 day after S14 did not take place. These findings indicate that TACE and TNF-alpha account for stress-induced short-term persistence of NOS-2 activity and MDA accumulation after 14 days of repeated exposure and support a possible neuroprotective role for specific blockers of TNF-alpha in this situation.
Dpto. de Farmacologia, Facultad de Medicina, Universidad Complutense de Madrid, Spain.
Carolina
C
Munhoz
José L M
JL
Madrigal
Borja
B
García-Bueno
Jesús M
JM
Pradillo
María A
MA
Moro
Ignacio
I
Lizasoain
Pedro
P
Lorenzo
Cristoforo
C
Scavone
Juan C
JC
Leza
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat