Tri-ortho-cresyl phosphate induces axonal degeneration in chicken DRG neurons by the NAD plus pathway

Wallerian degeneration (WD) is a well-known process by which degenerating axons and myelin are cleared after nerve injury. Although organophosphate-induced delayed neuropathy (OPIDN) is characterized by Wallerian-like degeneration of long axons in human and sensitive animals, the precise pathological mechanism remains unclear. In this study, we cultured embryonic chicken dorsal root ganglia (DRG) neurons, the model of OPIDN in vitro, to investigate the underlying mechanism of axon degeneration induced by tri-ortho-cresyl phosphate (TOCP), an OPIDN inducer. The results showed that TOCP exposure time-and concentration-dependently induced a serious degeneration and fragmentation of the axons from the DRG neurons. A collapse of mito-chondrial membrane potential and a dramatic depletion of ATP levels were found in the DRG neurons after TOCP treatment. In addition, nicotinamide nucleotide adenylyl transferase 2 (NMNAT2) expression and nicotinamide adenine dinucleotide (NAD+) level was also found to be decreased in the DRG neurons exposed to TOCP. However, the TOCP-induced Wallerian degeneration in the DRG neurons could be inhibited by ATP supple-mentation. And exogenous NAD+ or NAD+ processor nicotinamide riboside can rescue TOCP-induced ATP deficiency and prevent TOCP-induced axon degeneration of the DRG neurons. These findings may shed light on the pathophysiological mechanism of TOCP-induced axonal damages, and implicate the potential application of NAD+ to treat OPIDN.

Automated summary

Wallerian degeneration is a well-known process of clearing degenerating axons and myelin after nerve injury. Organophosphate-induced delayed neuropathy (OPIDN) is characterized by a similar degeneration of axons, but the underlying mechanism is unclear. In this study, the researchers used an in vitro model of embryonic chicken dorsal root ganglia (DRG) neurons to investigate the mechanism of axon degeneration induced by the OPIDN inducer tri-ortho-cresyl phosphate (TOCP). They found that TOCP exposure caused serious degeneration and fragmentation of the axons, as well as a collapse of mitochondrial membrane potential and depletion of ATP levels in the DRG neurons. They also observed a decrease in the expression of nicotinamide nucleotide adenylyl transferase 2 (NMNAT2) and nicotinamide adenine dinucleotide (NAD+) levels in TOCP-exposed DRG neurons. However, the TOCP-induced axon degeneration could be inhibited by ATP supplementation, and exogenous NAD+ or nicotinamide riboside could rescue the ATP deficiency and prevent axon degeneration. These findings provide insights into the pathophysiological mechanism of TOCP-induced axonal damage and suggest the potential application of NAD+ in treating OPIDN.