ABSTRACT:3-Nitropropionic acid (3-NPA) — a suicide inhibitor of succinate dehydrogenase — is a widely distributed plant and fungal neurotoxin known to induce damage to basal ganglia, hippocampus, spinal tracts and peripheral nerves in animals. Recent reports from Northern China indicate that 3-NPA is also likely to be responsible for the development of putaminal necrosis with delayed dystonia in children after ingestion of mildewed sugar cane. This article discusses the role of 3-NPA in the causation of the disease in China, its neurotoxic effects in animals and the potential role for this compound as a probe of selective neuronal vulnerability.

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A number of chemically unrelated neurotoxic compounds and several types of metabolic abnormalities cause strikingly similar patterns of distal symmetrical polyneuropathy in humans and animals. Experimental studies with laboratory species have demonstrated that many toxic polyneuropathies are associated with distal and retrograde axonal degeneration occurring in vulnerable nerve fiber tracts in the central as well as the peripheral nervous system. This has been termed central-peripheral distal axonopathy. Recent observations from the authors' laboratories regarding (1) the spatial-temporal evolution of nerve fiber degeneration in experimental toxic neuropathies and (2) the inhibition of glycolytic enzymes by chemically unrelated neurotoxic compounds point to a common metabolic basis for many distal axonopathies. It is postulated that neurotoxic compounds deplete energy supplies in the axon by inhibiting nerve fiber enzymes required for the maintenance of energy synthesis. Resupply of enzymes from the neuronal soma fails to meet the increased demand for enzyme replacement in the axon, causing the concentration of enzymes to drop in distal regions. This leads to a local blockade of energy-dependent axonal transport, which produces a series of pathological changes culminating in distal nerve fiber degeneration. The idea provides a working hypothesis with which to study the cause of inherited and acquired human and animal polyneuropathies.

Abstract— Cat sciatic nerves were exposed to iodoacetate for a period of 5–10 min and after washing out the iodoacetate, the enzymes, glyceraldehyde‐3‐phosphate dehydrogenase (d‐glyceraldehyde‐3‐phosphate: NAD oxidoreductase (phosphorylating); EC 1.2.1.12) and lactate dehydrogenase (l‐lactate: NAD oxidoreductase; EC 1.1.1.27) were extracted from the high‐speed supernatant fraction of nerve homogenates. Concentrations of iodoacetate as low as 2.5 mm could completely block activity of glyceraldehyde‐3‐phosphate dehydrogenase but had no effect on lactate dehydrogenase. These findings are in accord with the classical concept shown earlier for muscle that iodoacetate blocks glycolysis by its action on glyceraldehyde‐3‐phosphate dehydrogenase. A complete block of activity of the enzyme was found after treatment with 2 to 5 mm‐iodoacetate for a period of 10 min and such blocks were irreversible for at least 3 h. Glyceraldehyde‐3‐phosphate dehydrogenase activity was NAD specific, with NADP unable to substitute for NAD. The results are discussed in relation to the effect of iodoacetate in blocking glycolysis and in turn the fast axoplasmic transport of materials in mammalian nerve.