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Neuropathology of pyridoxine toxicity

Pires, Manuel Melo; (1994) Neuropathology of pyridoxine toxicity. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Pyridoxine can cause sensory neuropathy in man. Previous experimental studies have demonstrated selective neurofilament accumulation in dorsal root ganglion cells which, in most cases, was associated with axonal damage without causing cell death, but in others produced death of cells. From these observations the following hypotheses were formulated and tested in this thesis. 1. Pyridoxine interferes with axonal transport of neurofilaments and organelles and would thus cause a dying back neuropathy. 2. As the dorsal root ganglion cells, in many cases, do not die, regeneration should take place. 3. The major action of pyridoxine in causing a dying back neuropathy is due to interference with dorsal root ganglion cell metabolism rather than a local effect on the axon. A total of 100 rats was used in these experiments. In the first group of animals, rats were dosed daily with pyridoxine for periods of 7-90 days. Following perfusion with fixative, fifth cranial nerve, dorsal root and autonomic ganglia, the saphenous nerve (a purely sensory nerve) were removed and examined by light and electron microscopy. Immunocyto-chemistry was performed using the RT97 antibody against phosphorylated neurofilaments. Axonal degeneration, axonal regeneration, neurofilament and microtubule numbers and distribution were quantified. In the second group of animals the sciatic nerve was crushed immediately followed by the intraneural injection of pyridoxine and the degree of axon degeneration and regeneration were quantified. Damage to dorsal root ganglion cells (used as a measure of toxicity) was very variable so that the effects were only approximately dose-related. The hypotheses set out above were all proved in that: 1. There was distal degeneration of axons tending to affect the largest myelinated nerve fibres but also affecting the unmyelinated fibres. Posterior column axons in the spinal cord showed severe damage. 2. Affected dorsal root ganglion cells showed dispersion and degranulation of rough endoplasmic reticulum (RER), active Golgi bodies and increased neurofilaments. Immunocytochemistry showed increased staining for phosphorylated neurofilaments within small dorsal root ganglion cells compatible with interference with axonal transport. 3. Neurofilaments within axons were reduced and there was clustering of microtubules which probably preceded: 4. Axonal atrophy. 5. Axonal regeneration occurred while dosing continued. 6. Intraneural injection of pyridoxine caused axonal degeneration but paradoxically appeared to stimulate axonal regeneration. The results of this study suggests that pyridoxine has a direct toxic effect upon dorsal root ganglion cells which interferes with axoplasmic transport and thus results in a "dying back" neuropathy. The biochemical actions involved remain to be elucidated.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Neuropathology of pyridoxine toxicity
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10119567
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