Pyridine and other coal tar constituents as free radical-generating environmental neurotoxicants

Summary We have tested the hypothesis that chronic exposure to the principal constituents of the aqueous fraction of coal tar extracts can lead to the in vivo formation of substances which may produce neurological damage as the result of free radical generation and lipid peroxidation, these may be involved in the etiology of some neurological disorders. Artificial mixtures of the aqueous fraction of coal tar extracts were given in low concentrations to pigmented mice in their drinking water over a 3-month period. This resulted in significant increases in lipid peroxidation in the striatum, cerebellum and liver of the mice under test, the rank order being striatum > cerebellum > liver. These results are compatible with the possibility that coal tar emissions (as would be recovered or liberated in the burning, refining or beneficiation of coal) constitute a potential source of neurotoxicants with a predilection for damaging the nigrostriatal neuronal pathway. Our observations may thus have identified an important and hitherto unsuspected environmental source of neurotoxic chemicals, a possibility consistent with the proposed involvement of an environmental chemical factor in Parkinson's disease and perhaps in other neurological disorders.     

Effect of 2,5-hexanedione and 3,4-dimethyl-2,5-hexanedione on retrograde axonal transport in sciatic nerve

The effects of systemically introduced neurotoxic solvents 2,5-hexanedione (2,5-HD) and 3,4-dimethyl-2,5-hexanedione (DMHD) on retrograde axonal transport (RT) of¹²⁵I-labeled tetanus toxin (TT) was studied in rat and mouse sciatic nerves. The rate of retrograde transport of TT in control rat sciatic nerves was slightly higher (6.8±0.4 mm/h) than in mouse sciatic nerves (5.4±0.5 mm/h). A single high dose of 2,5-HD (1,000 mg/kg, i.p.) produced a time-dependent effect on RT in mouse sciatic nerves. 2,5-HD caused a gradual decrease in the velocity of RT (approximately 65% inhibition between 2.0–2.5 h) with a reversal to normal rate 3–5 h after the toxin administration. The effect of DMHD on RT was examined following semi-chronic treatment in rats. DMHD caused a significant decrease (approximately 50%) in the rate of TT transport, in addition, it produced weight loss and hind-limb paralysis.I had the good opportunity of being a member of Professor Alan N. Davison' research team during 1971–1977. This research paper is dedicated to his retirement.     

Prevention of inflammation‐mediated neurotoxicity by butylidenephthalide and its role in microglial activation

Microglial cells are the prime effectors in immune and inflammatory responses of the central nervous system (CNS). During pathological conditions, the activation of these cells helps restore CNS homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory molecules and neurotoxins. Thus, negative regulators of microglial activation have been considered as potential therapeutic candidates to target neurodegeneration, such as that in Alzheimer's and Parkinson's diseases. The rhizome of Ligusticum chuanxiong Hort. (Ligusticum wallichii Franch) has been widely used for the treatment of vascular diseases in traditional oriental medicine. Butylidenephthalide (BP), a major bioactive component from L. chuanxiong, has been reported to have a variety of pharmacological activities, including vasorelaxant, anti‐anginal, anti‐platelet and anti‐cancer effects. The aim of this study was to examine whether BP represses microglial activation. In rat brain microglia, BP significantly inhibited the lipopolysaccharide (LPS)‐induced production of nitric oxide (NO), tumour necrosis factor‐α and interleukin‐1β. In organotypic hippocampal slice cultures, BP clearly blocked the effect of LPS on hippocampal cell death and inhibited LPS‐induced NO production in culture medium. These results newly suggest that BP provide neuroprotection by reducing the release of various proinflammatory molecules from activated microglia. Copyright © 2013 John Wiley & Sons, Ltd.