The Korean Journal of Pain

The Korean Pain Society (대한통증학회)
권호 표지
DOI QR코드

DOI QR Code

The efficacy of GABAergic precursor cells transplantation in alleviating neuropathic pain in animal models: a systematic review and meta-analysis

  • Received : 2021.08.03
  • Accepted : 2021.10.14
  • Published : 2022.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Current therapies are quite unsuccessful in the management of neuropathic pain. Therefore, considering the inhibitory characteristics of GABA mediators, the present systematic review and meta-analysis aimed to determine the efficacy of GABAergic neural precursor cells on neuropathic pain management. Methods: Search was conducted on Medline, Embase, Scopus, and Web of Science databases. A search strategy was designed based on the keywords related to GABAergic cells combined with neuropathic pain. The outcomes were allodynia and hyperalgesia. The results were reported as a pooled standardized mean difference (SMD) with a 95% confidence interval (95% CI). Results: Data of 13 studies were analyzed in the present meta-analysis. The results showed that administration of GABAergic cells improved allodynia (SMD = 1.79; 95% CI: 0.87, 271; P < 0.001) and hyperalgesia (SMD = 1.29; 95% CI: 0.26, 2.32; P = 0.019). Moreover, the analyses demonstrated that the efficacy of GABAergic cells in the management of allodynia and hyperalgesia is only observed in rats. Also, only genetically modified cells are effective in improving both of allodynia, and hyperalgesia. Conclusions: A moderate level of pre-clinical evidence showed that transplantation of genetically-modified GABAergic cells is effective in the management of neuropathic pain. However, it seems that the transplantation efficacy of these cells is only statistically significant in improving pain symptoms in rats. Hence, caution should be exercised regarding the generalizability and the translation of the findings from rats and mice studies to large animal studies and clinical trials.

Keywords

Acknowledgement

This research has been supported by Iran University of Medical Sciences.

References

  1. Whalley K. Pain: transplanted precursors halt neuropathic pain. Nat Rev Neurosci 2012; 13: 447. https://doi.org/10.1038/nrn3283
  2. Tate DG, Forchheimer MB, Karana-Zebari D, Chiodo AE, Kendall Thomas JY. Depression and pain among inpatients with spinal cord injury and spinal cord disease: differences in symptoms and neurological function. Disabil Rehabil 2013; 35: 1204-12. https://doi.org/10.3109/09638288.2012.726692
  3. Kumru H, Soler D, Vidal J, Navarro X, Tormos JM, PascualLeone A, et al. The effects of transcranial direct current stimulation with visual illusion in neuropathic pain due to spinal cord injury: an evoked potentials and quantitative thermal testing study. Eur J Pain 2013; 17: 55-66. https://doi.org/10.1002/j.1532-2149.2012.00167.x
  4. Sharp K, Boroujerdi A, Steward O, Luo ZD. A rat chronic pain model of spinal cord contusion injury. Methods Mol Biol 2012; 851: 195-203. https://doi.org/10.1007/978-1-61779-561-9_14
  5. Finnerup NB. Pain in patients with spinal cord injury. Pain 2013; 154 Suppl 1: S71-6. https://doi.org/10.1016/j.pain.2012.12.007
  6. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005; 118: 289-305. https://doi.org/10.1016/j.pain.2005.08.013
  7. Backonja MM, Irving G, Argoff C. Rational multidrug therapy in the treatment of neuropathic pain. Curr Pain Headache Rep 2006; 10: 34-8. https://doi.org/10.1007/s11916-006-0007-1
  8. Marineo G, Iorno V, Gandini C, Moschini V, Smith TJ. Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: results of a pilot, randomized, controlled trial. J Pain Symptom Manage 2012; 43: 87-95. https://doi.org/10.1016/j.jpainsymman.2011.03.015
  9. Wolfe D, Mata M, Fink DJ. Targeted drug delivery to the peripheral nervous system using gene therapy. Neurosci Lett 2012; 527: 85-9. https://doi.org/10.1016/j.neulet.2012.04.047
  10. Eaton MJ, Martinez MA, Karmally S. A single intrathecal injection of GABA permanently reverses neuropathic pain after nerve injury. Brain Res 1999; 835: 334-9. https://doi.org/10.1016/S0006-8993(99)01564-4
  11. Polgar E, Todd AJ. Tactile allodynia can occur in the spared nerve injury model in the rat without selective loss of GABA or GABA(A) receptors from synapses in laminae I-II of the ipsilateral spinal dorsal horn. Neuroscience 2008; 156: 193-202. https://doi.org/10.1016/j.neuroscience.2008.07.009
  12. McLeod MC, Kobayashi NR, Sen A, Baghbaderani BA, Sadi D, Ulalia R, et al. Transplantation of GABAergic cells derived from bioreactor-expanded human neural precursor cells restores motor and cognitive behavioral deficits in a rodent model of Huntington's disease. Cell Transplant 2013; 22: 2237-56. https://doi.org/10.3727/096368912X658809
  13. Shetty AK, Bates A. Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer's and Parkinson's diseases. Brain Res 2016; 1638(Pt A): 74-87. https://doi.org/10.1016/j.brainres.2015.09.019
  14. Jergova S, Gajavelli S, Pathak N, Sagen J. Recombinant neural progenitor transplants in the spinal dorsal horn alleviate chronic central neuropathic pain. Pain 2016; 157: 977-89. https://doi.org/10.1097/j.pain.0000000000000471
  15. Jergova S, Gajavelli S, Varghese MS, Shekane P, Sagen J. Analgesic effect of recombinant GABAergic cells in a model of peripheral neuropathic pain. Cell Transplant 2016; 25: 629-43. https://doi.org/10.3727/096368916X690782
  16. Hwang I, Hahm SC, Choi KA, Park SH, Jeong H, Yea JH, et al. Intrathecal transplantation of embryonic stem cell-derived spinal GABAergic neural precursor cells attenuates neuropathic pain in a spinal cord injury rat model. Cell Transplant 2016; 25: 593-607. https://doi.org/10.3727/096368915X689460
  17. Sistrom CL, Mergo PJ. A simple method for obtaining original data from published graphs and plots. AJR Am J Roentgenol 2000; 174: 1241-4. https://doi.org/10.2214/ajr.174.5.1741241
  18. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol 2014; 14: 43. https://doi.org/10.1186/1471-2288-14-43
  19. Wei D, Tang K, Wang Q, Estill J, Yao L, Wang X, et al. The use of GRADE approach in systematic reviews of animal studies. J Evid Based Med 2016; 9: 98-104. https://doi.org/10.3969/j.issn.1671-5144.2009.02.019
  20. IntHout J, Ioannidis JP, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol 2014; 14: 25. https://doi.org/10.1186/1471-2288-14-25
  21. Wang D, Mou ZY, Zhai JX, Zong HX, Zhao XD. [Application of Stata software to test heterogeneity in meta-analysis method]. Zhonghua Liu Xing Bing Xue Za Zhi 2008; 29: 726-9. Chinese.
  22. Braz JM, Sharif-Naeini R, Vogt D, Kriegstein A, Alvarez-Buylla A, Rubenstein JL, et al. Forebrain GABAergic neuron precursors integrate into adult spinal cord and reduce injury-induced neuropathic pain. Neuron 2012; 74: 663-75. https://doi.org/10.1016/j.neuron.2012.02.033
  23. Braz JM, Wang X, Guan Z, Rubenstein JL, Basbaum AI. Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity. Pain 2015; 156: 1084-91. https://doi.org/10.1097/j.pain.0000000000000152
  24. Eaton MJ, Berrocal Y, Wolfe SQ. Potential for cell-transplant therapy with human neuronal precursors to treat neuropathic pain in models of PNS and CNS injury: comparison of hNT2.17 and hNT2.19 cell lines. Pain Res Treat 2012; 2012: 356412. https://doi.org/10.1155/2012/356412
  25. Eaton MJ, Plunkett JA, Martinez MA, Lopez T, Karmally S, Cejas P, et al. Transplants of neuronal cells bioengineered to synthesize GABA alleviate chronic neuropathic pain. Cell Transplant 1999; 8: 87-101. https://doi.org/10.1177/096368979900800102
  26. Etlin A, Braz JM, Kuhn JA, Wang X, Hamel KA, Llewellyn-Smith IJ, et al. Functional synaptic integration of forebrain GABAergic precursors into the adult spinal cord. J Neurosci 2016; 36: 11634-45. https://doi.org/10.1523/JNEUROSCI.2301-16.2016
  27. Jergova S, Hentall ID, Gajavelli S, Varghese MS, Sagen J. Intraspinal transplantation of GABAergic neural progenitors attenuates neuropathic pain in rats: a pharmacologic and neurophysiological evaluation. Exp Neurol 2012; 234: 39-49. https://doi.org/10.1016/j.expneurol.2011.12.005
  28. Juarez-Salinas DL, Braz JM, Etlin A, Gee S, Sohal V, Basbaum AI. GABAergic cell transplants in the anterior cingulate cortex reduce neuropathic pain aversiveness. Brain 2019; 142: 2655-69. https://doi.org/10.1093/brain/awz203
  29. Kim DS, Jung SJ, Nam TS, Jeon YH, Lee DR, Lee JS, et al. Transplantation of GABAergic neurons from ESCs attenuates tactile hypersensitivity following spinal cord injury. Stem Cells 2010; 28: 2099-108. https://doi.org/10.1002/stem.526
  30. Mukhida K, Mendez I, McLeod M, Kobayashi N, Haughn C, Milne B, et al. Spinal GABAergic transplants attenuate mechanical allodynia in a rat model of neuropathic pain. Stem Cells 2007; 25: 2874-85. https://doi.org/10.1634/stemcells.2007-0326
  31. Vaysse L, Sol JC, Lazorthes Y, Courtade-Saidi M, Eaton MJ, Jozan S. GABAergic pathway in a rat model of chronic neuropathic pain: modulation after intrathecal transplantation of a human neuronal cell line. Neurosci Res 2011; 69: 111-20. https://doi.org/10.1016/j.neures.2010.10.006
  32. Manion J, Khuong T, Harney D, Littleboy JB, Ruan T, Loo L, et al. Human induced pluripotent stem cell-derived GABAergic interneuron transplants attenuate neuropathic pain. Pain 2020; 161: 379-87. https://doi.org/10.1097/j.pain.0000000000001733
  33. Bao S, Lv Z, Li Y, Ma J, Zhang Y, Li S, et al. Genetic engineering: pros versus cons in deciphering disease mechanism. Sci Insights 2016; 2016: e00258.
  34. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, et al. Neuropathic pain. Nat Rev Dis Primers 2017; 3: 17002. https://doi.org/10.1038/nrdp.2017.2
  35. Meacham K, Shepherd A, Mohapatra DP, Haroutounian S. Neuropathic pain: central vs. peripheral mechanisms. Curr Pain Headache Rep 2017; 21: 28. https://doi.org/10.1007/s11916-017-0629-5