dinitrobenzenes and Nervous-System-Diseases

The topography and cellular events in the experimental lesions caused by chlorosugars, 6-aminonicotinamide, dinitrobenzene and tribromoimidazole in animals are considered in relation to those features in human acute thiamine deficiency (Wernicke's) encephalopathy and for comparison in Leigh's disease. The topography and cellular changes when closely examined are different and particular to each condition, although there is a basic cellular process common to all. The pathogenesis of each condition must be considered as multifactorial and a search for the factors responsible for the neuronal and cellular selective vulnerability of different regions of the neuraxis will lead us to understanding the pathogenesis of the disease process in each instance. The experimental models offer much for the understanding of the human conditions, particularly in the search for satisfactory therapeutic strategies.

Topics: 6-Aminonicotinamide; Acute Disease; Animals; Dinitrobenzenes; Disease Susceptibility; Energy Metabolism; Humans; Imidazoles; Leigh Disease; Nervous System Diseases; Wernicke Encephalopathy

To test the hypothesis that glutathione (GSH) status in brain tissue plays an important role in the selective neurotoxicity of m-dinitrobenzene (DNB), the sensitivity to intoxication of three groups of male F344 rats were studied and correlated with brain tissue GSH levels. In Group I were young 6-8 week old rats with normal GSH levels, and in Group II were rats of the same age whose brain GSH levels had been reduced by intracerebroventricular (i.c.v.) injections of L-buthionine-[S,R]-sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. In Group III were 6 month old rats that, as a result of normal aging, show GSH levels of 16-29% below those seen in younger animals. All three groups were subjected to a 1 to 4 dose schedule of dosing with DNB (7.5 mg/kg/day i.p.) and killed 1 day after the last dose of DNB. It was found that whereas Group I animals developed ataxia and brain stem lesions after 4 doses, Group III animals showed these changes after 3 doses, while Group II animals had brain stem lesions after only 2 doses of DNB. The timing of the onset of these changes correlated closely with the degree of reduction of brain tissue levels of GSH, this being greatest in those animals infused i.c.v. with BSO. This demonstration indicates that GSH status in brain tissue is likely to be an important factor in determining regional sensitivity to gliovascular damage from this agent.

Topics: Animals; Ataxia; Brain; Chromatography, High Pressure Liquid; Dinitrobenzenes; Glutathione; Injections, Intraventricular; Male; Nervous System Diseases; Rats; Rats, Inbred F344

m-Dinitrobenzene is a multitarget toxicant. This study presents a concentration-time threshold model in m-dinitrobenzene (m-DNB)-induced neurotoxicity in F344 rats based on pharmacokinetic modeling and variable duration infusions with neuropathological end points. Pharmacokinetic parameters for m-DNB were determined after giving a single i.v. dose of 10 mg/kg m-DNB. Time dependency of the brain lesions was studied by either giving a single bolus i.v. dose of 30 mg/kg m-DNB or infusing this dose over 6, 12, or 24 h, or 2, 4, 6, 8, or 14 days. The results show that the 6-day infusion, in which the theoretical steady-state blood concentration was 2.0 microM, caused brain damage, whereas the 8- and 14-day infusions, in which the steady-state blood concentrations were 1.5 and 0.8 microM, respectively, did not induce apparent brain damage. When this dose was infused over 6 h, the peak blood concentration of m-DNB was 35 microM and the time (T(m)) for which m-DNB exceeded the 2-microM concentration threshold was 18.8 h, but no brain damage was observed. However, when the same total dosage was infused over periods of either 12 or 24 h, or 2, 4, or 6 days, the theoretical blood concentrations were from 21.9 to 2.0 microM and the T(m) was from 22. 7 to 144 h, and brain damage was produced. Hence a T(m) of 22.7 h was considered to be the time threshold for m-DNB-induced brain damage. It is concluded that a high concentration alone does not result in m-DNB-induced neurotoxicity and that in addition to a concentration threshold, there also exists a time threshold. Both apparently need to be exceeded before neurotoxicity is seen.

Topics: Aniline Compounds; Animals; Brain; Chromatography, High Pressure Liquid; Dinitrobenzenes; Dose-Response Relationship, Drug; Female; Infusions, Intravenous; Injections, Intravenous; Models, Biological; Nervous System Diseases; Rats; Rats, Inbred F344; Time Factors; Tissue Distribution