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Abstract

NEUROBEHAVIORAL AND NEUROCHEMICAL CHANGES IN TOLUENE-TREATED RATS AND THE EFFECT OF ANTIOXIDANTS

Mariam M Atef, Asmaa F Galal*, Omar M.E. Abdel-Salam, Nermeen Shafee, Mariane G. Tadros, Amani E. Khalifa

ABSTRACT

The present study aimed to investigate effects of repeated toluene administration on behavior, brain oxidative stress, dopamine, and neuronal damage in rats. The possibility of recovery after toluene abstinence was studied. Moreover, the role of antioxidant treatment with vitamin E and/or vitamin C was evaluated. Toluene was intraperitoneally (i.p.) administered once a day for 9 consecutive days at doses of 141.4, 282.8, 565.6 and 1131.2 mg/kg. Recovery was investigated using the highest dose (1131.2 mg/kg), two, four and eight weeks after cessation of toluene. To study the protective effects of antioxidants, vitamin E (α-tocopherol) (50 mg/kg, i.p.) and/or vitamin C (ascorbic acid) (50 mg/kg, i.p.) was co administered with toluene (565.6 mg/kg). Behavioral testing (grip strength, open field, and defensive aggression, water maze, forced swimming), was conducted in addition to measuring the lipid peroxidation marker malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and paroxonase-1 (PON-1) in brain homogenates. Striatal dopamine was also measured.Caspase-3, and tumor necrosis factor alpha (TNF-α) were evaluated using immunohistochemistry. Results indicated that toluene impaired motor function, and memory and produced depressant-like action in a dosedependant manner, dose dependently. Significant increases occurred in brain levels of MDA, and NO levels accompanied by a marked decrease in GSH level compared to control group. Toluene also resulted in marked reduction in butyryl cholinesterase (BuChE), acetylcholinesterase (AChE), and PON-1 activities. Toluene in addition resulted in markedly elevated dopamine level in the striatum. No significant recovery after 2 weeks while after 1, and 2 months, there was significant improvement in behavioral measures and biochemical changes compared to the control group. The concurrent administration of α-tocopherol and/or ascorbic acid conferred significant protection against deleterious effects of toluene, with protection being most effective with the combined administration of both antioxidants. These results indicate that: (1) short-term toluene administration results in motor and cognitive impairment accompanied by oxidative damage, neuroinflammation and apoptosis; (2) most of these changes are improved after abstinence from toluene; (3) Toluene’s effects respond to antioxidant therapy with a combination of α-tocopherol and ascorbic acid, suggesting that oxidative stress is a major contributing event in this rat model of toluene neurotoxicity.

Keywords: toluene; brain; behavioral; oxidative stress; ?-tocopherol; ascorbic acid.


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