Abstract
Peripheral nerve injury (PNI) leads to the loss of motor, sensory, and autonomic functions, and often triggers neuropathic pain. During the last years, many efforts have focused on finding new therapies to increase axonal regeneration or to alleviate painful conditions. Still only a few of them have targeted both phenomena. Incipient or aberrant sensory axon regeneration is related to abnormal unpleasant sensations, such as hyperalgesia or allodynia. We recently have discovered NeuroHeal, a combination of two repurposed drugs; Acamprosate and Ribavirin. NeuroHeal is a neuroprotective agent that also enhances motor axon regeneration after PNI. In this work, we investigated its effect on sensory fiber regeneration and PNI-induced painful sensations in a rat model of spare nerve injury and nerve crush. The follow up of the animals showed that NeuroHeal treatment reduced the signs of neuropathic pain in both models. Besides, the treatment favored sensory axon regeneration, as observed in dorsal root ganglion explants. Mechanistically, the effects observed in vivo may improve the resolution of cell-protective autophagy. Additionally, NeuroHeal treatment modulated the P2X4-BDNF-KCC2 axis, which is an essential driver of neuropathic pain. These data open a new therapeutic avenue based on autophagic modulation to foster endogenous regenerative mechanisms and reduce the appearance of neuropathic pain in PNI.
Highlights
Peripheral nerve injury (PNI) due to complete or partial transection is a common injury that affects 13–23 people per 100,000 per year in the USA, leading to huge economic costs in healthcare [1,2].Reconnection between the central nervous system and target organs is mandatory to ensure correct function after nerve disruption
NeuroHeal-treated dorsal root ganglia (DRG) presented a significant increasein the in number and maximum length of neurites outgrowth compared to vehicle-treated ones the number and maximum length of neurites outgrowth compared to vehicle-treated ones(Figure (Figure1)
We observed that NeuroHeal treatment significantly reduced the presence of mature BDNF and the levels of glycosylated P2X4, with respect to the vehicle group (Figure 6B)
Summary
Peripheral nerve injury (PNI) due to complete or partial transection is a common injury that affects 13–23 people per 100,000 per year in the USA, leading to huge economic costs in healthcare [1,2].Reconnection between the central nervous system and target organs is mandatory to ensure correct function after nerve disruption. Several works have been reported on the systemic administration of drugs, such as FK506, geldanamycin, and N-acetyl-cysteine, that increase the growth of sensory fibers in vitro and in vivo experimental models [3] Most of those compounds did not target the secondary development of hyperalgesia after PNI. Neuropathic pain is defined as a disturbance of the somatosensory system triggered by neural injuries, which may affect up to 10% of the general population [4]. It is characterized by the appearance of spontaneous pain, dysesthesia, hyperalgesia, and allodynia.
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