Mode of action

The peripheral rather than the central nervous system is the main target in y-diketone toxicity. The metabolites of methyl n-butyl ketone are more neurotoxic than the parent compound (Krasavage et al., 1980; Abou-Donia et al., 1982). In animals, the relative neurotoxicity of compounds in decreasing order of potency were: 2,5-hexanedione, 5-hydroxy-2-hexanone, 2,5-hexanediol, methyl n-butyl ketone, 2-hexanol and n-hexane (Krasavage et al., 1980; Abou-Donia et al., 1982). In terms of neurotoxicity, the potency of 2,5-hexanedione was 3.3 times that of methyl n-butyl ketone, and methyl n-butyl ketone was 12 times more potent than n-hexane (Krasavage et al., 1980). Consequently, methyl n-butyl ketone is likely to cause neuropathy sooner and at a lower exposure concentration than n-hexane.

2,5-Hexanedione is a y-diketone compound with a 1,4 spacing of the carbonyl groups. Other y-diketones (e.g., 2,5-heptanedione, 3,6-octanedione) are also neurotoxic whereas a- and ß-diketone compounds (e.g., 2,3-hexanedione and 2,4-hexanedione) are not (Spencer et al., 1978; O'Donoghue and Krasavage, 1979; DeCaprio et al., 1982). The neurotoxic effect of 2,5-hexanedione is thought to be due to it binding with axonal components (DeCaprio et al., 1982). 2,5-Hexanedione has been shown to bind to functional amino (NH2) groups of axonal proteins forming substituted pyrrole groups (DeCaprio and O'Neill, 1985; Genter et al., 1987). Both neurotoxic and non-neurotoxic diketones bind to these amino groups but only the neurotoxic compounds form pyrrole adducts (DeCaprio et al., 1982). Rats exposed to 2,5-hexanedione excreted less pyrroles when given zinc supplementation compared to controls (Mateus et al., 2000). However, this was only a short-term study and the potential protective effect of zinc against 2,5-hexanedione induced neurotoxicity was not investigated.

There are 3 main hypotheses on the causes of the neurofilament accumulation observed in y-diketone induced neuropathy (DeCaprio and O'Neill, 1985), these are as follows:

• Physicochemical changes triggered by the hydrophobic pyrrole adduct resulting in the disruption of function or transport of neurofilaments (DeCaprio and O'Neill, 1985).

• Auto-oxidation of pyrrole adducts result in crosslinking between the neurofilaments (Graham et al., 1982; Anthony et al, 1983; Graham et al., 1995).

• Disruption of the normal relationships between neurofilaments and cytoskeletal components, particularly microtubules (Griffin et al., 1983).

Whatever the cause of neurofilament accumulation, the ultimate effect of these changes is thought to be physical blockade of the axonal nutrient flow and subsequent nerve degeneration (DeCaprio and O'Neill, 1985).

In animal studies, the number of 'giant' axons was inversely related to the neurotoxic index of the compound and to the length of time required to produce paralysis. This suggests that axonal swelling may not be a pre-requisite for axonal dysfunction and is possibly a secondary phenomenon (Krasavage et al., 1980).

The acute CNS depressant effects of methyl n-butyl ketone are thought to be due to the metabolite 2-hexanol, an aliphatic alcohol with general anaesthetic properties (Feldman, 1999). Less marked acute effects are seen with methyl n-butyl ketone compared to n-hexane, this may be because 2-hexanol is not an obligatory metabolite of methyl n-butyl ketone and less is formed (Feldman, 1999).

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Peripheral Neuropathy Natural Treatment Options

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