Mode of action

The peripheral, rather than the central, nervous system is the main target in n-hexane toxicity. Studies in rats exposed to n-hexane have demonstrated a decrease in nerve-specific marker proteins in the distal segment of the sciatic nerve, whereas the concentrations remained unchanged in the brain and proximal sciatic nerve (Huang et al., 1992). The metabolites of n-hexane are more neurotoxic than the parent compound (Krasavage et al., 1980; Abou-Donia et al., 1982). In animals the relative neurotoxicity of these 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 2,5-hexanedione was 38 times more potent than n-hexane (Krasavage et al., 1980). Neuropathy has been induced in animals administered 2,5-hexanedione (Spencer and Schaumburg, 1975).

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 and 3,6-octanedione) are also neurotoxic whereas a- and P-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 supplements 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.

Neurofilament accumulation has been observed in n-hexane neuropathy (DeCaprio and O'Neill, 1985). There are 3 main hypotheses on the causes, 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 resulting 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 the clinical course 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).

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

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