Premature onset of fast axonal transport in bromophenylacetylurea neuropathy: an electrophoretic analysis of proteins exported into motor nerve

Mechanisms of Toxic Injury in the Peripheral Nervous System: Neuropathologic Considerations

“…This compound is a neurotoxicant that produces a progressive central-peripheral distal axonopathy that affects both sensory and motor myelinated fibers (49,78,81). There is a delay in the onset of clinical signs of about 1 week following treatment of animals with neurotoxic dosages of this compound (49,55 (79,82,83). In some fashion, these alterations are thought to lead to sporadic local stasis of the fast-transported proteins, with associated intra-axonal tubulomembranous accumulations that are an ultrastructural feature of the neuropathy (82).…”

“…The mechanism of neurotoxicity is related to the complex effects that BPAU has on fast axonal transport, which is initiated during this preclinical period. Specific alterations leading to this neu-ropathy include toxicant-induced accelerated processing of proteins in the neuronal Golgi apparatus, with associated premature onset of anterograde fast axonal transport and reduction of axonally delivered protein (79,83). Protein that undergoes this abnormal Golgi processing is thought to have alterations that may lead to inefficient switching at the anterograde/retrograde axonal transport turnaround in the distal level of the axon, with associated reduction in the amount of recycled protein (79,82,83).…”

“…Specific alterations leading to this neu-ropathy include toxicant-induced accelerated processing of proteins in the neuronal Golgi apparatus, with associated premature onset of anterograde fast axonal transport and reduction of axonally delivered protein (79,83). Protein that undergoes this abnormal Golgi processing is thought to have alterations that may lead to inefficient switching at the anterograde/retrograde axonal transport turnaround in the distal level of the axon, with associated reduction in the amount of recycled protein (79,82,83). In some fashion, these alterations are thought to lead to sporadic local stasis of the fast-transported proteins, with associated intra-axonal tubulomembranous accumulations that are an ultrastructural feature of the neuropathy (82).…”

“…Studies have shown that the rat is the experimental animal of choice, and the single intraperitoneal neurotoxic dose is in the 200-400 mg/kg range. In this model, neurological signs are noted at about 1 week postdosing, and these signs include hind-leg ataxia and weakness, which progresses to paralysis over the next 2 weeks (49,50,55,81,83). Some studies have used 2 or more doses by either the intraperitoneal or oral (gavage) route without a significant change in the clinical picture (12,78,79).…”