Increased autophagic activity in dorsal root ganglion attenuates neuropathic pain following peripheral nerve injury

Guo, Jiwei; Jing, Peng-Bo; Wang, Jian; Zhang, Rui; Jiang, Bao‐Chun; Gao, Yong‐Jing; Zhang, Zhijun

doi:10.1016/j.neulet.2015.05.046

Cited by 37 publications

(36 citation statements)

References 27 publications

(40 reference statements)

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“…Studies have shown that DMSO affects the structure and functions of sciatic nerve in rats [96], and induces apoptosis in the mouse brain [97]. My findings support the results of previous studies, which have shown that nerve injury upregulates LC3 [98,99]. Rapamycin has been shown to protect against neurodegeneration by activating autophagy [100], and improves myelination in PNS [101].…”

Section: Resultssupporting

confidence: 85%

Autophagy in Peripheral Neuropathy

Osman¹

2017

Linköping University Medical Dissertations

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Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor. Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy. In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury. Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits. 6 Populärvetenskaplig sammanfattningNervskador (neuropati) orsakade av sjukdomar eller olycksfall påverkar miljontals individer runt om i världen. Nervskador som orsakas av diabetes kallas diabetesneuropati och drabbar varannan patient med diabetes. Neuropati kan också orsakas av kronisk inflammation i nerven eller uppstå utan känd orsak, så kallad kronisk idiopatisk axonal polyneuropati. Patienterna som drabbas av neuropati uppvisar varierande symptom beroende på vilka nerver som drabbas men domningar, stickningar, smärta, känselbortfall och muskelsvaghet finns ofta i symptombilden. Nervskador efter trauma kräver oftast kirurgisk rekonstruktion. För närvarande finns det ingen behandling för diabetesneuropati. Allt fler människor i fysiskt aktiv ålder drabbas av åldersdiabetes (typ 2 diabetes). Detta leder till att fler patienter med diabetes drabbas av traumatiska nervskador som kräver nervreparation. Det är därför viktigt att utveckla reparationsmetoder som fungerar br...

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Section: Resultssupporting

confidence: 85%

Autophagy in Peripheral Neuropathy

Osman¹

2017

Linköping University Medical Dissertations

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“…Besides, some articles reported that autophagy flux is blocked within the dorsal horn neurons after chronic constriction injury (CCI) or SNI, which may trigger neuropathic pain [24]. Moreover, enhanced autophagy in DRG can prevent the chronicity of pain [44]. Autophagy is also involved in microgliosis.…”

Section: Discussionmentioning

confidence: 99%

NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

Casas

2020

Cells

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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.

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“…Autophagy is a process of self‐digestion in which the cell degrades useless proteins and organelles to sustain cellular function . Increasing evidence has indicated that autophagy is correlated with neuropathic pain after peripheral nerve injury . Additionally, increased markers of autophagy after SNL represent the accumulation of autophagosomes; however, the exact mechanism remains controversial.…”

Section: Discussionmentioning

confidence: 99%

Metformin relieves neuropathic pain after spinal nerve ligation via autophagy flux stimulation

Weng

Yao

Poonit

et al. 2018

J Cellular Molecular Medi

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Neuropathic pain is a well‐known type of chronic pain caused by damage to the nervous system. Autophagy is involved in the development and/or progression of many diseases, including neuropathic pain. Emerging evidence suggests that metformin relieves neuropathic pain in several neuropathic pain models; however, metformin's cellular and molecular mechanism for pain relief remains unknown. In this study, we investigated the therapeutic effects of metformin on pain relief after spinal nerve ligation (SNL) and its underlying mechanism of autophagy regulation. Behavioural analysis, histological assessment, expression of c‐Fos and molecular biological changes, as well as ultrastructural features, were investigated. Our findings showed that the number of autophagosomes and expression of autophagy markers, such as LC3 and beclin1, were increased, while the autophagy substrate protein p62, as well as the ubiquitinated proteins, were accumulated in the ipsilateral spinal cord. However, metformin enhanced the expression of autophagy markers, while it abrogated the abundance of p62 and ubiquitinated proteins. Blockage of autophagy flux by chloroquine partially abolished the apoptosis inhibition and analgesic effects of metformin on SNL. Taken together, these results illustrated that metformin relieved neuropathic pain through autophagy flux stimulation and provided a new direction for metformin drug development to treat neuropathic pain.

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Increased autophagic activity in dorsal root ganglion attenuates neuropathic pain following peripheral nerve injury

Cited by 37 publications

References 27 publications

Autophagy in Peripheral Neuropathy

Autophagy in Peripheral Neuropathy

NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

Metformin relieves neuropathic pain after spinal nerve ligation via autophagy flux stimulation

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