NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2020 Apr 2

PMID 32230770

Citations 8

Authors

David Romeo-Guitart

Caty Casas

Affiliations

Soon will be listed here.

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.

Citing Articles

An Overview of the Mechanisms Involved in Neuralgia.

Zhang B, Dong H, Wu Z, Jiang X, Zou W J Inflamm Res. 2023; 16:4087-4101.

PMID: 37745793 PMC: 10516189. DOI: 10.2147/JIR.S425966.

Antimicrobial therapies for chronic pain (part 1): analgesic mechanisms.

Wang E, Karri J, Tontisirin N, Cohen S Korean J Pain. 2023; 36(3):281-298.

PMID: 37394272 PMC: 10322662. DOI: 10.3344/kjp.23129.

The role of KCC2 and NKCC1 in spinal cord injury: From physiology to pathology.

Talifu Z, Pan Y, Gong H, Xu X, Zhang C, Yang D Front Physiol. 2023; 13:1045520.

PMID: 36589461 PMC: 9799334. DOI: 10.3389/fphys.2022.1045520.

The Overexpression of Insulin-Like Growth Factor-1 and Neurotrophin-3 Promote Functional Recovery and Alleviate Spasticity After Spinal Cord Injury.

Talifu Z, Qin C, Xin Z, Chen Y, Liu J, Dangol S Front Neurosci. 2022; 16:863793.

PMID: 35573286 PMC: 9099063. DOI: 10.3389/fnins.2022.863793.

Direct moxibustion exerts an analgesic effect on cervical spondylotic radiculopathy by increasing autophagy via the Act A/Smads signaling pathway.

Cai H, Lin X, Chen H, Zhang X, Lin Y, Pan S Brain Behav. 2022; 12(4):e2545.

PMID: 35315239 PMC: 9014986. DOI: 10.1002/brb3.2545.

References

Berliocchi L, Russo R, Maiaru M, Levato A, Bagetta G, Corasaniti M . Autophagy impairment in a mouse model of neuropathic pain. Mol Pain. 2011; 7:83. PMC: 3234188. DOI: 10.1186/1744-8069-7-83. View

Aurilio C, Pota V, Pace M, Passavanti M, Barbarisi M . Ionic channels and neuropathic pain: physiopathology and applications. J Cell Physiol. 2008; 215(1):8-14. DOI: 10.1002/jcp.21280. View

Cobianchi S, Arbat-Plana A, Lopez-Alvarez V, Navarro X . Neuroprotective Effects of Exercise Treatments After Injury: The Dual Role of Neurotrophic Factors. Curr Neuropharmacol. 2016; 15(4):495-518. PMC: 5543672. DOI: 10.2174/1570159X14666160330105132. View

Romeo-Guitart D, Leiva-Rodriguez T, Fores J, Casas C . Improved Motor Nerve Regeneration by SIRT1/Hif1a-Mediated Autophagy. Cells. 2019; 8(11). PMC: 6912449. DOI: 10.3390/cells8111354. View

Basbaum A, Bautista D, Scherrer G, Julius D . Cellular and molecular mechanisms of pain. Cell. 2009; 139(2):267-84. PMC: 2852643. DOI: 10.1016/j.cell.2009.09.028. View

Piao Y, Gwon D, Kang D, Hwang T, Shin N, Kwon H . TLR4-mediated autophagic impairment contributes to neuropathic pain in chronic constriction injury mice. Mol Brain. 2018; 11(1):11. PMC: 5830083. DOI: 10.1186/s13041-018-0354-y. View

Zhou C, Zhang M, Zhou S, Li H, Gao J, Du L . SIRT1 attenuates neuropathic pain by epigenetic regulation of mGluR1/5 expressions in type 2 diabetic rats. Pain. 2016; 158(1):130-139. DOI: 10.1097/j.pain.0000000000000739. View

Chang K, Lin Y, Lin C, Hong C, Tsai M, Huang W . Leptin is essential for microglial activation and neuropathic pain after preganglionic cervical root avulsion. Life Sci. 2017; 187:31-41. DOI: 10.1016/j.lfs.2017.08.016. View

Piao Z, Wang W, Xu X, Wang Q, Huo X, Han M . Autophagy of neuron axon during regeneration of rat sciatic nerves. Di Yi Jun Yi Da Xue Xue Bao. 2004; 24(4):361-4. View

10.

Guo J, Jing P, Wang J, Zhang R, Jiang B, Gao Y . Increased autophagic activity in dorsal root ganglion attenuates neuropathic pain following peripheral nerve injury. Neurosci Lett. 2015; 599:158-63. DOI: 10.1016/j.neulet.2015.05.046. View

11.

Leiva-Rodriguez T, Romeo-Guitart D, Marmolejo-Martinez-Artesero S, Herrando-Grabulosa M, Bosch A, Fores J . ATG5 overexpression is neuroprotective and attenuates cytoskeletal and vesicle-trafficking alterations in axotomized motoneurons. Cell Death Dis. 2018; 9(6):626. PMC: 5967323. DOI: 10.1038/s41419-018-0682-y. View

12.

Dai J, Wang Q, Su Y, Gu L, Zhao Y, Chen X . Emodin Inhibition of Influenza A Virus Replication and Influenza Viral Pneumonia via the Nrf2, TLR4, p38/JNK and NF-kappaB Pathways. Molecules. 2017; 22(10). PMC: 6151665. DOI: 10.3390/molecules22101754. View

13.

Berger J, Knaepen L, Janssen S, Jaken R, Marcus M, Joosten E . Cellular and molecular insights into neuropathy-induced pain hypersensitivity for mechanism-based treatment approaches. Brain Res Rev. 2011; 67(1-2):282-310. DOI: 10.1016/j.brainresrev.2011.03.003. View

14.

Chan K, Gordon T, Zochodne D, Power H . Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets. Exp Neurol. 2014; 261:826-35. DOI: 10.1016/j.expneurol.2014.09.006. View

15.

Marinelli S, Nazio F, Tinari A, Ciarlo L, DAmelio M, Pieroni L . Schwann cell autophagy counteracts the onset and chronification of neuropathic pain. Pain. 2013; 155(1):93-107. DOI: 10.1016/j.pain.2013.09.013. View

16.

Smith P . BDNF: no gain without pain?. Neuroscience. 2014; 283:107-23. DOI: 10.1016/j.neuroscience.2014.05.044. View

17.

Puskarjov M, Ahmad F, Kaila K, Blaesse P . Activity-dependent cleavage of the K-Cl cotransporter KCC2 mediated by calcium-activated protease calpain. J Neurosci. 2012; 32(33):11356-64. PMC: 6621186. DOI: 10.1523/JNEUROSCI.6265-11.2012. View

18.

Patel M, Kaye A, Urman R . Tanezumab: Therapy targeting nerve growth factor in pain pathogenesis. J Anaesthesiol Clin Pharmacol. 2018; 34(1):111-116. PMC: 5885425. DOI: 10.4103/joacp.JOACP_389_15. View

19.

Ferrini F, Trang T, Mattioli T, Laffray S, Delguidice T, Lorenzo L . Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis. Nat Neurosci. 2013; 16(2):183-92. PMC: 4974077. DOI: 10.1038/nn.3295. View

20.

Casals-Diaz L, Vivo M, Navarro X . Nociceptive responses and spinal plastic changes of afferent C-fibers in three neuropathic pain models induced by sciatic nerve injury in the rat. Exp Neurol. 2009; 217(1):84-95. DOI: 10.1016/j.expneurol.2009.01.014. View