Alteration of Neuronal Cytoskeletal Organization in Dorsal Root Ganglia Associated with Pyridoxine Neurotoxicity

The pathogenesis of the sensory neurotoxicity arising from high doses of pyridoxine is obscure. Beagle dogs were fed 200 mg pyridoxine/kg per day and killed at 4, 10, 14 and 16 days. Dorsal root ganglia (DRG) and their processes were processed for electron microscopy and teased-fiber preparation following perfusion of anesthetized animals with heparinized saline and a fixative solution of 3% paraformaldehyde, 1% glutaraldehyde. Four days after initiation of treatment a striking accumulation of neurofilament (NF) in proximal unmyelinated axons of the DRG was observed. Domains of altered NF cytoskeleton consisting of well-demarcated zones of higher packing density and anomalous orientation were observed, mainly in the myelinated part of the DRG segment. In addition, aggregates of microtubules (MT) were noted. In the cyton the Golgi complexes were abundant and the Nissl bodies together with the NF appeared increased in numbers. At 10 days NF and MT aggregations were readily apparent in both perikarya and proximal cell processes. This phenomena was diminished in the 14- and 16-day-treated animals and retrogressive histological features appeared in the soma and in axons. Degeneration of NF with subsequent reduction in size of the axonal swellings and axonal breakdown with phagocytosis were prominent in central and peripheral processes of DRG. Cytons distended by NF were less prominent. Necrotizing changes, evidenced by disruption of the soma with the proliferation of satellite cells, were present. These results indicate that an early morphological correlate of pyridoxine neurotoxicity is the accumulation of NF with MT-NF dissociation in the unipolar process of the DRG in the absence of extensive vacuolization, and that the observed cytoskeletal disruption may be related to an increased rate of NF protein synthesis together with mechanical obstruction of transport phenomena.