Biochemical studies on the pathogenetic mechanism of toxic neuropathies by using axonal transport.

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Various neurotoxic chemicals are thought to be classified into several groups according to their main targets. Among them three major groups were chosen and in vivo model systems were developed to investigate their biochemical mechanism of action. By analysing slow axonal transport under the influence of these drugs, the following results were obtained.u. Neurotoxicity of colchicine:Colchicine completely and exclusively blocks tubulin transport, without affecting that of actin and neurofilament proteins. when 4 g of colchicine is injected into fifth lumbar dorsal root ganglion of 7 week-old rat, almost all unmyelinated axons as well as a small portion of myel-nated ones are degenerated, then start regenerating within 4 days after treatment. At the same time tubulin transport also recovers to normal.2. Neurotoxicity of , '-iminodipropionitrile:Neurological symptoms develop a few days after an intraperitoneal injection of IDPN with dose of 1.5g/kg of body weight. Under these conditions axonal transport of neurofilament proteins is severely inhibited, without any disturbance of that of tubulin and actin. Neurofilament transportbecomes normal 6 weeks after IDPN administration, thoughneurological abnormalities never show recovery.3. Neurotoxicity of acrylamide:Marked acceleration of all components of slow axonal transport is found in rats after 13 week-administration of acrylamide with dose of 200 ppm in drinking water. This finding is interpreted to be the results of axonal degeneration and regeneration.4. Neurotoxicity of 2,5-hexanedione:2, 5-Hexanedione causes an increase of rate of neurofilament transport, leaving that of tubulin and actin unchanged even in early stage of administration when no symptom appears.5. Neurotoxicity of carbon disulfide:This drug shows a similar effect on neurofilament transport to that of 2, 5-hexanedione.