Spastic paresis after 6-aminonicotinamide: Metabolic disorders in the spinal cord and electromyographically recorded changes in the hind limbs of rats

Abstract

In rats the application of 10 mg/kg 6-amino-nicotinamide (6-AN) leads to an accumulation of 6-phosphogluconate, by inhibition of 6-phosphogluconate dehydrogenase in the pentose phosphate pathway, in the cells of the spinal cord. The accumulation reaches its maximum after 18-24 h. It seems that there exists a relationship between the accumulation of 6-phosphogluconate and the lesion of the neuroglia, which is found in electron microscopic studies. Symptoms of a spastic paresis only develop later when the spinal interneurones are destroyed as a consequence of the lesion of the neuroglia. The accumulation of 6-phosphogluconate almost exceeds the 400 fold of the norm. No considerable differences are found between the effects of a dose of 35 mg 6-AN/kg and one of 10 mg 6-AN/kg. Free gluconate is identified enzymically in the cells of the spinal cords of the rats treated with 6-AN. The compound is very probably formed by dephosphorylation and diffuses into the blood. 6-Phosphogluconate is an inhibitor of the phosphoglucose isomerase. Its accumulation shifts the equilibrium towards glucose 6-phosphate. The lactate concentration decreases as compared with the untreated controls. Muscular action potentials are recorded extracellularly with a concentric needle electrode from the musculus gastrocnemius of rats treated with 6-AN. First activations of the electromyograms are found 48 h after the application of 10 mg 6-AN/kg. The electrical activities increase during the time in which a progressive destruction of the interneurones occurs. The electromyogram displays a permanent state of excitation with high amplitudes and an increased frequency. The continuity and intensity of the increased activity recorded by the electromyograph is the most important pathological finding. p-Chlorophenyl-GABA and, still more so, chlorpromazine cause temporary reduction of the excitation processes and an electromyogram nearly at rest. Under the same conditions, haloperidol is only slightly effective. The symptoms developed by the chemical destruction of the interneurones of the spinal cord, with rigidity and spasticity of the hind limbs, are suitable for testing antispastic drugs.

Molecular properties and regulation of NAD+ kinase (NADK)

“…TN administration as a single dose in human xenograft mouse models produced a promising result comparable to that of NADK downregulation (50%) with shRNA [ 73 ]. Another NAD + analog, 6-amino nicotinamide, showed promising pre-clinical anti-cancer activity but was associated with neurological toxicity [ 80 ]. The neurotoxicity of 6-amino nicotinamide was ascribed to its ability to block the pentose phosphate pathway via phosphogluconate dehydrogenase inhibition [ 81 ] and inhibit NADK2 phosphorylation [ 79 ].…”

NAD+ Kinase as a Therapeutic Target in Cancer

“…The only NADK inhibitor that has been tested in the clinic is 6-amino nicotinamide, which had shown promising preclinical anticancer activity, although animal studies showed that neurologic toxicity was dose limiting (41). Unfortunately, neurotoxicity prevented dose escalation, and minimal activity was seen at the maximum tolerated dose in clinical trials (42).…”