scholarly journals NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 808 ◽  
Author(s):  
David Romeo-Guitart ◽  
Caty Casas
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Axonal Regeneration ◽  
Axon Regeneration ◽  
Sensory Axon ◽  
Nerve Crush ◽  
Repurposed Drugs ◽  
Therapeutic Avenue

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.

Continuation of fast axonal transport in regenerating axons in vitro

1979 ◽  
Vol 57 (11) ◽  
pp. 1251-1255
Author(s):  
M. A. Bisby ◽  
C. E. Hilton
Keyword(s):  
Sciatic Nerve ◽  
Vagus Nerve ◽  
Axonal Transport ◽  
Nerve Injury ◽  
Axon Regeneration ◽  
Free Medium ◽  
Fast Axonal Transport ◽  
Sensory Axons

A previous study by McLean and co-workers reported that regenerating axons of the rabbit vagus nerve were unable to sustain axonal transport in vitro for several months after nerve injury. In contrast, we found that sensory axons of the rat sciatic nerve were able to transport 3H-labeled protein into their regenerating portions distal to the site of injury within a week after injury when placed in vitro. Transport in vitro was not significantly less than transport in axons maintained in vivo for the same period. Transport occurred in the medium that was used by the McLean group, but was significantly reduced in calcium-free medium. When axon regeneration was delared, only small amounts of activity were present in the nerve distal to the site of injury, showing that labeled protein normally present in that part of the nerve was associated with axons and was not a result of local precursor uptake by nonneural elements in the sciatic nerve. We were not able to explain the failure of McLean and co-workers to demonstrate transport in vitro in regenerating vagus nerve, but we conclude that there is no general peculiarity of growing axons that makes them unable to sustain transport in vitro.

scholarly journals Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve

2016 ◽  
Vol 2 ◽  
pp. 205521731664170 ◽  
Author(s):  
Melissa M Gresle ◽  
Yaou Liu ◽  
Trevor J Kilpatrick ◽  
Dennis Kemper ◽  
Qi-Zhu Wu ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Axonal Regeneration ◽  
Antibody Therapy ◽  
Experimental Models ◽  
Therapeutic Effects ◽  
Axonal Loss ◽  
Nerve Crush ◽  
Acute Optic Neuritis ◽  
Injury Models

Background Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. Objective In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. Methods The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. Results In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. Conclusion These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.

scholarly journals Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats

2020 ◽  
Vol 21 (7) ◽  
pp. 2390
Author(s):  
Masamichi Shinoda ◽  
Satoshi Fujita ◽  
Shiori Sugawara ◽  
Sayaka Asano ◽  
Ryo Koyama ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Electrical Stimulation ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Spinal Cord Stimulation ◽  
Microglial Activation ◽  
In Vivo Optical Imaging ◽  
Stimulation Of

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

scholarly journals In Vitro and In Vivo Effects of Flavonoids on Peripheral Neuropathic Pain

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1171 ◽  
Author(s):  
Paramita Basu ◽  
Arpita Basu
Keyword(s):  
Neuropathic Pain ◽  
Side Effects ◽  
Nerve Injury ◽  
Somatosensory System ◽  
Present Review ◽  
Common Symptom ◽  
Murine Models ◽  
Peripheral Neuropathic Pain

Neuropathic pain is a common symptom and is associated with an impaired quality of life. It is caused by the lesion or disease of the somatosensory system. Neuropathic pain syndromes can be subdivided into two categories: central and peripheral neuropathic pain. The present review highlights the peripheral neuropathic models, including spared nerve injury, spinal nerve ligation, partial sciatic nerve injury, diabetes-induced neuropathy, chemotherapy-induced neuropathy, chronic constriction injury, and related conditions. The drugs which are currently used to attenuate peripheral neuropathy, such as antidepressants, anticonvulsants, baclofen, and clonidine, are associated with adverse side effects. These negative side effects necessitate the investigation of alternative therapeutics for treating neuropathic pain conditions. Flavonoids have been reported to alleviate neuropathic pain in murine models. The present review elucidates that several flavonoids attenuate different peripheral neuropathic pain conditions at behavioral, electrophysiological, biochemical and molecular biological levels in different murine models. Therefore, the flavonoids hold future promise and can be effectively used in treating or mitigating peripheral neuropathic conditions. Thus, future studies should focus on the structure-activity relationships among different categories of flavonoids and develop therapeutic products that enhance their antineuropathic effects.

scholarly journals Decrease in neuronal nicotinic acetylcholine receptor subunit and PSD-93 transcript levels in the male mouse MPG after cavernous nerve injury or explant culture

2013 ◽  
Vol 305 (10) ◽  
pp. F1504-F1512 ◽  
Author(s):  
Beatrice M. Girard ◽  
Laura A. Merriam ◽  
John D. Tompkins ◽  
Margaret A. Vizzard ◽  
Rodney L. Parsons
Keyword(s):  
Nerve Injury ◽  
Neural Control ◽  
Explant Culture ◽  
Nachr Subunit ◽  
Nerve Crush ◽  
Transcript Levels ◽  
Cavernous Nerve ◽  
Induced Currents ◽  
Cavernous Nerve Injury

Quantitative real-time PCR was used to test whether cavernous nerve injury leads to a decrease in major pelvic ganglia (MPG) neuronal nicotinic ACh receptor (nAChR) subunit and postsynaptic density (PSD)-93 transcript levels. Subunits α3, β4, and α7, commonly expressed in the MPG, were selected for analysis. After 72 h in explant culture, MPG transcript levels for α3, β4, α7, and PSD-93 were significantly depressed. Three days after cavernous nerve axotomy or crush in vivo, transcript levels for α3, β4, and PSD-93, but not for α7, were significantly depressed. Three days after dissection of the cavernous nerve free of underlying tissue and application of a 5-mm lateral stretch (manipulation), transcript levels for α3and PSD-93 were also significantly decreased. Seven days after all three surgical procedures, α3transcript levels remained depressed, but PSD-93 transcript levels were still decreased only after axotomy or nerve crush. At 30 days postsurgery, transcript levels for the nAChR subunits and PSD-93 had recovered. ACh-induced currents were significantly smaller in MPG neurons dissociated from 3-day explant cultured ganglia than from those recorded in neurons dissociated from acutely isolated ganglia; this observation provides direct evidence showing that a decrease in nAChR function was coincident with a decrease in nAChR subunit transcript levels. We conclude that a downregulation of nAChR subunit and PSD-93 expression after cavernous nerve injury, or even manipulation, could interrupt synaptic transmission within the MPG and thus contribute to the loss of neural control of urogenital organs after pelvic surgeries.

scholarly journals Promoting axon regeneration by enhancing the non-coding function of the injury-responsive coding gene Gpr151

2021 ◽  
Author(s):  
Bohm Lee ◽  
Jinyoung Lee ◽  
Yewon Jeon ◽  
Hyemin Kim ◽  
Minjae Kwon ◽  
...  
Keyword(s):  
Nerve Injury ◽  
Rna Binding ◽  
Axon Regeneration ◽  
Rna Binding Proteins ◽  
Nerve Repair ◽  
Coding Regions ◽  
Protein Functions ◽  
Injury Models

AbstractGene expression profiling in response to nerve injury has been mainly focused on protein functions of coding genes to understand mechanisms of axon regeneration and to identify targets of potential therapeutics for nerve repair. However, the protein functions of several highly injury-induced genes including Gpr151 for regulating the regenerative ability remain unclear. Here we present an alternative approach focused on non-coding functions of the coding genes, which led to the identification of the non-coding function of Gpr151 RNA interacting with RNA-binding proteins such as CSDE1. Gpr151 promotes axon regeneration by the function of its 5’-untranslated region (5’UTR) and expression of an engineered form of the 5’UTR improves regenerative capacity in vitro and in vivo in both sciatic nerve and optic nerve injury models. Our data suggest that searching injury-induced coding genes potentially functioning by their non-coding regions is required for the RNA-based gene therapy for improving axon regeneration.

scholarly journals Sensory Axon Regeneration: A Review from an in vivo Imaging Perspective

2012 ◽  
Vol 21 (3) ◽  
pp. 83-93 ◽  
Author(s):  
Seung Baek Han ◽  
Hyukmin Kim ◽  
Andrew Skuba ◽  
Alan Tessler ◽  
Toby Ferguson ◽  
...  
Keyword(s):  
In Vivo Imaging ◽  
Axon Regeneration ◽  
Sensory Axon ◽  
Imaging Perspective

scholarly journals Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling

2016 ◽  
Vol 113 (7) ◽  
pp. 1937-1942 ◽  
Author(s):  
Songshan Li ◽  
Chao Yang ◽  
Li Zhang ◽  
Xin Gao ◽  
Xuejie Wang ◽  
...  
Keyword(s):  
Axonal Regeneration ◽  
Axon Regeneration ◽  
Ganglion Cells ◽  
Mammalian Target Of Rapamycin ◽  
Light Response ◽  
Cns Injury ◽  
Nerve Crush ◽  
Gpcr Signaling ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Cell-type–specific G protein-coupled receptor (GPCR) signaling regulates distinct neuronal responses to various stimuli and is essential for axon guidance and targeting during development. However, its function in axonal regeneration in the mature CNS remains elusive. We found that subtypes of intrinsically photosensitive retinal ganglion cells (ipRGCs) in mice maintained high mammalian target of rapamycin (mTOR) levels after axotomy and that the light-sensitive GPCR melanopsin mediated this sustained expression. Melanopsin overexpression in the RGCs stimulated axonal regeneration after optic nerve crush by up-regulating mTOR complex 1 (mTORC1). The extent of the regeneration was comparable to that observed after phosphatase and tensin homolog (Pten) knockdown. Both the axon regeneration and mTOR activity that were enhanced by melanopsin required light stimulation and Gq/11 signaling. Specifically, activating Gq in RGCs elevated mTOR activation and promoted axonal regeneration. Melanopsin overexpression in RGCs enhanced the amplitude and duration of their light response, and silencing them with Kir2.1 significantly suppressed the increased mTOR signaling and axon regeneration that were induced by melanopsin. Thus, our results provide a strategy to promote axon regeneration after CNS injury by modulating neuronal activity through GPCR signaling.

MicroRNA-210 promotes sensory axon regeneration of adult mice in vivo and in vitro

2016 ◽  
Vol 622 ◽  
pp. 61-66 ◽  
Author(s):  
Yi-Wen Hu ◽  
Jing-Jing Jiang ◽  
Yan-Gao ◽  
Rui-Ying Wang ◽  
Guan-Jun Tu
Keyword(s):  
Axon Regeneration ◽  
Sensory Axon ◽  
Adult Mice
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