Early metabolic changes during m-Dinitrobenzene neurotoxicity and the possible role of oxidative stress.
m-Dinitrobenzene (m-DNB) is an industrial chemical causing gliovascular lesions in the brain stem similar to those produced by nitroimidazoles and by thiamine deficiency. To identify early preneuropathic indices of toxicity we examined the action of m-DNB on glycolysis and on measures of oxidative stress in the brain both in vivo and in vitro. Significant increases in local cerebral glucose utilization were seen in 14 of 30 brain regions prior to development of lesions. Rat brain astrocyte cultures also showed increases in both glucose consumption and lactic acid formation in the first 24 h following exposure to 0.5 mM m-DNB and prior to the development of cytotoxicity. The concentration of reduced glutathione in these cultures was decreased to about half of control values over a 2-h incubation period, indicating an early disturbance of redox balance. The rate of reduction of nitroblue tetrazolium increased eightfold during a 1-h incubation period, suggesting a free radical-mediated process. Superoxide dismutase partially prevented this increase, although other protective agents failed to do so possibly due to lack of cellular penetration. These observations show that m-DNB neurotoxicity involves early metabolic stimulation and redox disruption that may be causally associated with the production of free radicals.
Romero
I A
IA
Physiology Group, Biomedical Sciences, King's College, Strand, London, UK.
Lister
T
T
Richards
H K
HK
Seville
M P
MP
Wylie
S P
SP
Ray
D E
DE
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004136:Dinitrobenzenes / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D009580:Nitroblue Tetrazolium / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D004136:Dinitrobenzenes; D007773:Lactates; D009580:Nitroblue Tetrazolium; D019344:Lactic Acid; C017906:3-dinitrobenzene; D005978:Glutathione