Tacrine alleviates neuropathic pain in mice by mimicking the cell adhesion molecule L1
1Department of Anaesthesiology, Zhujiang Hospital of Southern Medical University, 510282 Guangzhou City, Guangdong, China
DOI: 10.22514/sv.2021.081 Vol.17,Issue 4,July 2021 pp.140-150
Submitted: 04 February 2021 Accepted: 01 March 2021
Published: 08 July 2021
Neuropathic pain, which is caused by nervous system damage or dysfunctions, remains one of the most intractable challenges in modern medicine due to the lack of effective drugs. Tacrine, which is a small organic compound, is known to mimic the beneficial characteristics of the neural cell adhesion molecule L1 (L1CAM, L1) in vitro. Although previous studies indicated that L1 constitutes a viable strategy for promoting regeneration after nervous system injury, it is not clear whether L1 has a definite role in peripheral nerve injury. In this study, we observed that tacrine eased thermal hyperalgesia and mechanical allodynia after sciatic nerve chronic construction injury and restored functional morphological damage. Furthermore, tacrine suppressed the proliferation and activation of glia and reduced the level of IL-1β, IL-6 and TNF-α. Tacrine also inhibited the JAK2/STAT3 signaling pathway, which is involved in neuroinflammation. These observations indicated that tacrine is a promising candidate for an analgesic agent for neuropathic pain.
Neuropathic pain; L1; Tacrine; Neuroinflammation; JAK2/STAT3 pathway
Hua-Li Xu,Shi-Yuan Xu. Tacrine alleviates neuropathic pain in mice by mimicking the cell adhesion molecule L1. Signa Vitae. 2021. 17(4);140-150.
 Torrance N, Ferguson JA, Afolabi E, Bennett MI, Serpell MG, Dunn KM, et al. Neuropathic pain in the community: more under-treated than refractory? Pain. 2013; 154: 690–699.
 Sandkühler J. Models and mechanisms of hyperalgesia and allodynia. Physiological Reviews. 2009; 89: 707–758.
 Matsuo H, Uchida K, Nakajima H, Guerrero AR, Watanabe S, Takeura N, et al. Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain. Pain. 2014; 155: 1888–1901.
 Gao Y, Ji R. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacology & Therapeutics. 2010; 126: 56–68.
 Nicolas C, Peineau S, Amici M, Csaba Z, Fafouri A, Javalet C, et al. The JAK/STAT pathway is involved in synaptic plasticity. Neuron. 2012; 73: 374–390.
 Singh Jaggi A, Singh N. Therapeutic targets for the management of peripheral nerve injury-induced neuropathic pain. CNS & Neurological Disorders-Drug Targets. 2011; 10: 589–609.
 Wood P, Schachner M, Bunge R. Inhibition of Schwann cell myelination in vitro by antibody to the L1 adhesion molecule. Journal of Neuroscience. 1990; 10: 3635–3645.
 Hoschouer EL, Yin FQ, Jakeman LB. L1 cell adhesion molecule is essential for the maintenance of hyperalgesia after spinal cord injury. Experimental Neurology. 2009; 216: 22–34.
 Yamanaka H, Obata K, Kobayashi K, Dai Y, Fukuoka T, Noguchi K. Alteration of the cell adhesion molecule L1 expression in a specific subset of primary afferent neurons contributes to neuropathic pain. European Journal of Neuroscience. 2007; 25: 1097–1111.
 Barbin G, Aigrot MS, Charles P, Foucher A, Grumet M, Schachner M, et al. Axonal cell-adhesion molecule L1 in CNS myelination. Neuron Glia Biology. 2004; 1: 65–72.
 Lavdas AA, Papastefanaki F, Thomaidou D, Matsas R. Cell adhesion molecules in gene and cell therapy approaches for nervous system repair. Current Gene Therapy. 2011; 11: 90–100.
 Irintchev A, Schachner M. The injured and regenerating nervous system: immunoglobulin superfamily members as key players. Neuroscientist. 2012; 18: 452–466.
 Skaper SD. Neuronal growth-promoting and inhibitory cues in neuropro-tection and neuroregeneration. Methods in Molecular Biology. 2012; 846: 13–22.
 Kamiguchi H. The mechanism of axon growth: what we have learned from the cell adhesion molecule L1. Molecular Neurobiology. 2003; 28: 219–228.
 Maness PF, Schachner M. Neural recognition molecules of the im-munoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nature Neuroscience. 2007; 10: 19–26.
 Doherty P, Williams G, Williams EJ. CAMs and axonal growth: a critical evaluation of the role of calcium and the MAPK cascade. Molecular and Cellular Neurosciences. 2000; 16: 283–295.
 Loers G, Chen S, Grumet M, Schachner M. Signal transduction pathways implicated in neural recognition molecule L1 triggered neuroprotection and neuritogenesis. Journal of Neurochemistry. 2005; 92: 1463–1476.
 Kataria H, Lutz D, Chaudhary H, Schachner M, Loers G. Small molecule agonists of cell adhesion molecule L1 mimic L1 functions in vivo. Molecular Neurobiology. 2016; 53: 4461–4483.
 Binder A, Baron R. The pharmacological therapy of chronic neuropathic pain. Deutsches Arzteblatt International. 2016; 113: 616–625.
 Nishikawa N, Nomoto M. Management of neuropathic pain. Journal of General and Family Medicine. 2017; 18: 56–60.
 Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. The Tacrine Study Group. The Journal of the American Medical Association. 1994; 271: 985–991.
 Lin H, Li Q, Gu K, Zhu J, Jiang X, Chen Y, et al. Therapeutic agents in Alzheimer’s disease through a multi-targetdirected ligands strategy: recent progress based on tacrine core. Current Topics in Medicinal Chemistry. 2017; 17: 3000–3016.
 Sahu S, Zhang Z, Li R, Hu J, Shen H, Loers G, et al. A small organic compound mimicking the L1 cell adhesion molecule promotes functional recovery after spinal cord injury in zebrafish. Molecular Neurobiology. 2018; 55: 859–878.
 Yi Y, Cai L, Shao Y, Xu M, Yi J. The protective role of tacrine and donepezil in the retina of acetylcholinesterase knockout mice. International Journal of Ophthalmology. 2015; 8: 884–890.
 Nadal X, Baños J, Kieffer BL, Maldonado R. Neuropathic pain is enhanced in delta-opioid receptor knockout mice. European Journal of Neuroscience. 2006; 23: 830–834.
 Xue Z, Shen L, Wang Z, Hui S, Huang Y, Ma C. STAT3 inhibitor WP1066 as a novel therapeutic agent for bCCI neuropathic pain rats. Brain Research. 2014; 1583: 79–88.
 Lin Y, Liu H, Day Y, Chang C, Hsu P, Chen J. Activation of NPFFR2 leads to hyperalgesia through the spinal inflammatory mediator CGRP in mice. Experimental Neurology. 2017; 291: 62–73.
 Malon JT, Cao L. Calcitonin gene-related peptide contributes to peripheral nerve injury-induced mechanical hypersensitivity through CCL5 and p38 pathways. Journal of Neuroimmunology. 2016; 297: 68–75.
 Hulme CH, Brown SJ, Fuller HR, Riddell J, Osman A, Chowdhury J, et al. The developing landscape of diagnostic and prognostic biomarkers for spinal cord injury in cerebrospinal fluid and blood. Spinal Cord. 2017; 55: 114–125.
 Farghaly HSM, Mahmoud AM, Abdel-Sater KA. Effect of dexmedetomi-dine and cold stress in a rat model of neuropathic pain: role of interleukin-6 and tumor necrosis factor-α. European Journal of Pharmacology. 2016; 776: 139–145.
 Sacerdote P, Franchi S, Moretti S, Castelli M, Procacci P, Magnaghi V, et al. Cytokine modulation is necessary for efficacious treatment of experimental neuropathic pain. Journal of Neuroimmune Pharmacology. 2013; 8: 202–211.
 Whitehead KJ, Smith CGS, Delaney S, Curnow SJ, Salmon M, Hughes JP, et al. Dynamic regulation of spinal pro-inflammatory cytokine release in the rat in vivo following peripheral nerve injury. Brain, Behavior, and Immunity. 2010; 24: 569–576.
 Mori T, Miyamoto T, Yoshida H, Asakawa M, Kawasumi M, Kobayashi T, et al. IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in me-diating inflammatory cytokines and RANKL expression in inflammatory arthritis. International Immunology. 2011; 23: 701–712.
 Zhou Y, Liu Z, Liu Z, Chen S, Li M, Shahveranov A, et al. Interleukin-6: an emerging regulator of pathological pain. Journal of Neuroinflammation. 2016; 13: 141.
 Wei X, Na X, Liao G, Chen Q, Cui Y, Chen F, et al. The up-regulation of IL-6 in DRG and spinal dorsal horn contributes to neuropathic pain following L5 ventral root transection. Experimental Neurology. 2013; 241: 159–168.
 Ji R, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy?Pain. 2013; 154: S10–S28.
 Kronschläger MT, Drdla-Schutting R, Gassner M, Honsek SD, Teuch-mann HL, Sandkühler J. Gliogenic LTP spreads widely in nociceptive pathways. Science. 2016; 354: 1144–1148.
 Zhu X, Cao S, Zhu M, Liu J, Chen J, Gao Y. Contribution of chemokine CCL2/CCR2 signaling in the dorsal root ganglion and spinal cord to the maintenance of neuropathic pain in a rat model of lumbar disc herniation. Journal of Pain. 2014; 15: 516–526.
 Komirishetty P, Areti A, Sistla R, Kumar A. Morin mitigates chronic constriction injury (CCI)-induced peripheral neuropathy by inhibiting oxidative stress induced PARP over-activation and neuroinflammation. Neurochemical Research. 2016; 41: 2029–2042.
 Busch-Dienstfertig M, Labuz D, Wolfram T, Vogel NN, Stein C. JAK-STAT1/3-induced expression of signal sequence-encoding proopiome-lanocortin mRNA in lymphocytes reduces inflammatory pain in rats. Molecular Pain. 2012; 8: 83.
 Murray PJ. The JAK-STAT signaling pathway: input and output integration. Journal of Immunology. 2007; 178: 2623–2629.
Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.
Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.
Chemical Abstracts Service Source Index The CAS Source Index (CASSI) Search Tool is an online resource that can quickly identify or confirm journal titles and abbreviations for publications indexed by CAS since 1907, including serial and non-serial scientific and technical publications.
IndexCopernicus The Index Copernicus International (ICI) Journals database’s is an international indexation database of scientific journals. It covered international scientific journals which divided into general information, contents of individual issues, detailed bibliography (references) sections for every publication, as well as full texts of publications in the form of attached files (optional). For now, there are more than 58,000 scientific journals registered at ICI.
Geneva Foundation for Medical Education and Research The Geneva Foundation for Medical Education and Research (GFMER) is a non-profit organization established in 2002 and it works in close collaboration with the World Health Organization (WHO). The overall objectives of the Foundation are to promote and develop health education and research programs.
Scopus: CiteScore 0.5(2019) Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.
Embase Embase (often styled EMBASE for Excerpta Medica dataBASE), produced by Elsevier, is a biomedical and pharmacological database of published literature designed to support information managers and pharmacovigilance in complying with the regulatory requirements of a licensed drug.