Abstract
Organophosphate-induced delayed neuropathy (OPIDN) is characterized by progressive axonal degeneration and demyelination of the spinal cord and sciatic nerves. The neuregulin 1/epidermal growth factor receptor (ErbB) signaling pathway is crucial for axonal myelination. In this study, we investigated whether the neuregulin 1/ErbB signaling pathway mediated the progression of OPIDN. Adult hens were given tri-o-cresyl phosphate (TOCP), a typical neuropathic organophosphorus compound, to induce OPIDN. The ErbB inhibitor lapatinib was administered to hens 4 h prior to and 4 days after TOCP exposure. The neuregulin 1/ErbB signaling pathway was examined for their role in maintaining spinal cord and sciatic nerve fiber integrity. Schwann cell line sNF96.2 was used as the in vitro cell model. The in vivo results showed that TOCP (750 mg/kg body weight, p.o.) induced prominent ataxia and significant axon degeneration in the spinal cord and sciatic nerves. Lapatinib (25 mg/kg body weight, p.o.) treatment attenuated OPIDN clinically and histopathlogically and partially prevented the TOCP-induced activation of neuregulin 1/ErbB signaling pathway. Lapatinib also prevented the TOCP-induced inhibition of neuropathy target esterase (NTE), a key enzyme during the development of OPIDN, and the disturbed metabolism of phosphatidylcholine in sciatic nerves. In addition, lapatinib was shown, in vitro, to protect sNF96.2 cells from TOCP-induced dedifferentiation through neuregulin 1/ErbB signaling. Our results suggest that neuregulin 1/ErbB, through regulation of NTE activity in the peripheral nervous system, mediates the progression of OPIDN. Thus, this signal may serve as a potential target for the treatment of OPIDN.
Highlights
Organophosphorus compound (OP)-induced delayed neuropathy (OPIDN) is a neurodegenerative disorder characterized by distal degeneration of long and large-diameter axons in the spinal cord and peripheral nerves (Lotti, 1991; Abou-Donia, 1993; Johnson, 1993)
We investigated whether neuregulin 1/ErbB2 and its downstream signals were activated in hens exposed to tri-o-cresyl phosphate (TOCP) or lapatinib plus TOCP
The present study showed that, the ErbB1/2 inhibitor lapatinib failed to delay the latent period of Organophosphate-induced delayed neuropathy (OPIDN), it effectively attenuated the neurodegenerative manifestations induced by TOCP in hens and attenuated their pathological damage in spinal cord and sciatic nerves
Summary
Organophosphorus compound (OP)-induced delayed neuropathy (OPIDN) is a neurodegenerative disorder characterized by distal degeneration of long and large-diameter axons in the spinal cord and peripheral nerves (Lotti, 1991; Abou-Donia, 1993; Johnson, 1993). Neuregulin 1/ErbB Activation Mediates OPIDN that occurs in neurons distal to the site of traumatic axonal injury (Bouldin and Cavanagh, 1979). There were occurrences of OPIDN in Morocco, Holland, Fiji, Yugoslavia, France, South Africa, Sri Lanka and India. These incidences were caused by consumption of cooking oil contaminated with lubricating oil containing TOCP, which lead to paralysis in thousands of individuals (Nanda and Tapaswi, 1995). Mice with a conditional deletion of NTE in neuronal cells displayed distal degeneration of the longest spinal axons (Read et al, 2009)
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