Dose‐dependent expression of neuronopathy after experimental pyridoxine intoxication

Abstract

We examined the sequence of nervous system abnormalities that resulted when rats were given excess amounts of vitamin B6 (pyridoxine). High doses of pyridoxine (1,200 or 600 mg/kg/d) for 6 to 10 days caused a neuronopathy with necrosis of dorsal root ganglion (DRG) sensory neurons, accompanied by centrifugal axonal atrophy and breakdown of peripheral and central sensory axons. Large diameter neurons with long processes and large cytoplasmic volumes were especially affected. Smaller doses (300 to 150 mg/kg/d) for up to 12 weeks had minor effects on DRG neurons, but produced a neuropathy with axonal atrophy and degeneration. Guinea pigs given 1,800 mg/kg/d developed sensory neuronopathy, whereas mice given similar or higher doses did not have neuropathologic abnormalities. Multiple factors including rate of administration, differential neuronal vulnerability, and species susceptibility have bearing on the final expression of pyridoxine neurotoxicity.

Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy

“…Pyridoxine is a toxin known to target large fiber sensory neurons (Albin et al, 1987); Krinke and Fitzgerald, 1988;Schaeppi and Krinke, 1982;Windebank et al, 1985;Xu et al, 1989). As such, we have previously demonstrated that pyridoxine intoxication causes a reduction in the mean area of A-and B-cells in the DRG .…”

“…The rationale for selecting pyridoxine to produce an animal model of large-fiber neuropathy is based on several factors, including the selective and severe neurotoxic actions of this compound on large DRG neurons in rodents (Xu et al, 1989), dogs (Schaeppi and Krinke, 1982), and humans (Albin et al 1987). Our interest in this particular animal model of sensory neuropathy is that the rapidly developing, large fiber neurodegeneration may be considered to model one aspect of clinical diabetic peripheral neuropathy.…”

“…A component of this dysfunction is associated with altered visceral sensory nerve function. It is likely that afferents mediating these autonomic reflexes, which are disturbed in diabetic neuropathy, harbor GLP-1 receptors Excess ingestion of pyridoxine (vitamin B6) causes peripheral sensory neuropathy in rodents (Xu et al, 1989), dogs (Schaeppi and Krinke, 1982) and humans (Albin et al, 1987). We have previously reported that the peripheral nerve degeneration associated with pyridoxine intoxication in rodents models at least one aspect of clinical diabetic peripheral neuropathy; specifically, damage to large fiber sensory neurons Kuntzer et al, 2004).…”

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

“…Lower, more prolonged doses caused sublethal neuronal injury, with associated nerve fiber degeneration that was more profound distally (62). Another pattern of evolution of pyridoxine-induced neuropathy was somatofugal axonal atrophy with modest axonal degeneration (112). One study indicates that there is relatively uniform fiber degeneration along the entire length of the nerve with oral doses of 300 mg/kg for 8 or more days in dogs (60 (24), and the family of pyrimidines is known to have structurally dependent neurotoxic potential (93).…”

Pyridoxine Dependent Epilepsy with Iatrogenic Sensory Neuronopathy

“…Nous presentons le cas d'un homme de 18 ans traite de facon chronique depuis sa naissance par des doses elevees de pyridoxine (vitamine B 6 ), jusqu'a 2000 mg par jour, pour une epilepsie resistante a la pyridoxine. En moins de deux ans du debut du traitement, il a developpe une neuropathie sensitive qui n'a pas progresse pendant les 16 annees suivantes.…”