The Role of Pyrrole Formation in the Alteration of Neurofilament Transport Induced during Exposure to 2,5-Hexanedione

Evidence for the Importance of High-Valent FeO and of a Diketone in the Molecular Mechanism of Action of Antimalarial Trioxane Analogs of Artemisinin

“…The two major products of FeBr 2 reduction of 3-phenyltrioxane 15 are ring-contracted tetrahydrofuran 16 and 1,5-diketone 17 , formed plausibly via electron transfer to oxygen-1 of trioxane 15 (eq 2) . Because some dicarbonyl compounds are known to alkylate proteins, as does artemisinin, the in vitro antimalarial activity of 1,5-diketone 17 was determined (IC 50 = 330 ng/mL, 1400 nM). This is the first time that any diketone has been reported to have antimalarial activity ; the low antimalarial activity of diketone 17 may be due to its relative difficulty in reaching the malaria parasite inside the red blood cell.…”

2,5‐Hexanedione Alters Elemental Composition and Water Content of Rat Peripheral Nerve Myelinated Axons

“…It is likely that axon loss is a consequence of both degeneration and the assignment of atrophied large fibers to smaller size classes (i .e ., medium and small) . Previous studies involving subchronic and subacute administration of 2,5-HD or its structural analogues have also reported internodal atrophy of central and peripheral axons with corresponding shifts in fiber caliber (Monaco et al ., 1985(Monaco et al ., , 1988(Monaco et al ., , 1989Pyle et al ., 1992) . How internodal morphological and elemental changes in peripheral nerve axons might be related to the development of hexanedione neurotoxicity is unknown at present.…”

“…The apparent regulated nature of these axoplasmic changes is consistent with homeostatic processes possibly occurring in response to 2,5-HD-induced decreases in axoplasmic volume and subsequent axonal caliber. Hexanedione-induced axonal atrophy is mediated presumably by a reduction in neurofilament content that occurs as a consequence of accelerated slow component a (SCa) of anterograde axonal transport (Monaco et al ., 1989;Watson et al ., 1991 ;Pyle et al, 1992) . It is, therefore, possible that, in association with reduced neurofilament proteins, loss of internodal dry weight axoplasmic K and water are consequential, but necessary, steps in the process 2275 of axon-caliber reduction .…”

“…Clearly, the elemental profile of 2,5-HD swellings is not consistent with an acrylamide-like effect, nor is it likely to be a repercussion of axolemmal or metabolic disturbance (for review, see LoPachin et al ., 1992c) . Substantial evidence suggests that 2,5-HD disrupts axonal cytoskeleton by direct covalent modification of neurofilaments, which subsequently accumulate (DeCaprio and Fowke, 1992 ;Pyle et al, 1992) . The minimal elemental alterations of axonal swellings are consistent with a mechanism that involves expansive mechanical forces imposed, for example, by accumulating modified neurofilaments .…”

Association between metabolic gene polymorphisms and susceptibility to peripheral nerve damage in workers exposed ton-hexane: A preliminary study

“…In addition, decreased adenosine triphosphate production and inhibition of state 3 respiration also occurred in rat brain mitochondria exposed to 2,5-HD (Medrano & LoPachin 1989). Studies also showed that 2,5-HD could react directly with axonal protein by the formation of n -substituted 2,5-dimethylpyrrole adducts at o-amine nitrogen of the lysine residues of neurofilaments (Pyle et al 1992, Graham et al 1995, Decaprio et al 1997. Secondary oxidation of the pyrrole ring to an electrophile reacted with neurofilament nucleophiles resulting in intra-and intermolecular protein cross-linking, and this was considered to be the determinant event in 2,5-HD neuropathy (Graham et al 1982, Zhu et al 1994).…”