Abstract
More than half of diabetic patients suffer from intractable neuropathic pain. As inflammation plays an important role in diabetic neuropathic pain, anti-inflammatory drugs might have therapeutic potentials for neuropathic pain. Salidroside (SAL), a phenylpropanoid glucoside, modulates a variety of cell functions, including inflammation. Here, we explored anti-nociceptive and anti-inflammatory effects of SAL on Zucker diabetic fatty rats with type 2 diabetes (DM rats). DM rats were tested for mechanical and thermal hyperalgesia using von Frey filament and plantar hot box test, respectively. The anti-nociceptive effect of chronic SAL (25–100 mg/kg, per oral) treatment was tested. The expression of inflammatory cytokines (TNF-α and IL-1β) and P2X7 receptors in spinal cord and sciatic nerve were measured with ELISA. SAL alleviated mechanical and thermal hyperalgesia and reduced TNF-α and IL-1β in sciatic nerve and spinal cord in DM rats. Furthermore, SAL reduced P2X7 receptor upregulation in spinal cord of DM rats and directly inhibited P2X7 receptors expressed in HEK293 cells. This study provides evidence that SAL attenuated nociception in diabetic neuropathic pain rat models probably through inhibiting neuroinflammation and P2X7 receptors.
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References
Alotaibi NA, Slater NK, Rahmoune H (2016) Salidroside as a novel protective agent to improve red blood cell cryopreservation. PLoS One 11:e0162748. doi:10.1371/journal.pone.0162748
Brussee V et al (2008) Distal degenerative sensory neuropathy in a long-term type 2 diabetes rat model. Diabetes 57:1664–1673. doi:10.2337/db07-1737
Carroll WA, Donnelly-Roberts D, Jarvis MF (2009) Selective P2X(7) receptor antagonists for chronic inflammation and pain. Purinergic Signal 5:63–73. doi:10.1007/s11302-008-9110-6
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63
Chessell IP et al (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114:386–396. doi:10.1016/j.pain.2005.01.002
Collaboration NCDRF (2016) Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 387:1513–1530. doi:10.1016/S0140-6736(16)00618-8
Dixon WJ (1991) Staircase bioassay: the up-and-down method. Neurosci Biobehav Rev 15:47–50
Ellis A, Bennett DL (2013) Neuroinflammation and the generation of neuropathic pain. Br J Anaesth 111:26–37. doi:10.1093/bja/aet128
Finnerup NB et al (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14:162–173. doi:10.1016/S1474-4422(14)70251-0
Ji RR, Chamessian A, Zhang YQ (2016) Pain regulation by non-neuronal cells and inflammation. Science 354:572–577. doi:10.1126/science.aaf8924
Kawamura N, Dyck PJ, Schmeichel AM, Engelstad JK, Low PA, Dyck PJ (2008) Inflammatory mediators in diabetic and non-diabetic lumbosacral radiculoplexus neuropathy. Acta Neuropathol 115:231–239. doi:10.1007/s00401-007-0326-2
Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 28:5189–5194. doi:10.1523/JNEUROSCI.3338-07.2008
Leung L, Cahill CM (2010) TNF-alpha and neuropathic pain--a review. J Neuroinflammation 7:27. doi:10.1186/1742-2094-7-27
Li F, Abatan OI, Kim H, Burnett D, Larkin D, Obrosova IG, Stevens MJ (2006) Taurine reverses neurological and neurovascular deficits in Zucker diabetic fatty rats. Neurobiol Dis 22:669–676. doi:10.1016/j.nbd.2006.01.012
Lim AK, Tesch GH (2012) Inflammation in diabetic nephropathy. Mediat Inflamm 2012:146154. doi:10.1155/2012/146154
Lister MF, Sharkey J, Sawatzky DA, Hodgkiss JP, Davidson DJ, Rossi AG, Finlayson K (2007) The role of the purinergic P2X7 receptor in inflammation. J Inflamm (Lond) 4:5. doi:10.1186/1476-9255-4-5
Liu S et al (2016) LncRNA NONRATT021972 siRNA regulates neuropathic pain behaviors in type 2 diabetic rats through the P2X7 receptor in dorsal root ganglia. Mol Brain 9:44. doi:10.1186/s13041-016-0226-2
O'Brien PD, Sakowski SA, Feldman EL (2014) Mouse models of diabetic neuropathy. ILAR J 54:259–272. doi:10.1093/ilar/ilt052
Schulz A, Walther C, Morrison H, Bauer R (2014) In vivo electrophysiological measurements on mouse sciatic nerves. J Vis Exp. doi:10.3791/51181
Sperlagh B, Illes P (2014) P2X7 receptor: an emerging target in central nervous system diseases. Trends Pharmacol Sci 35:537–547. doi:10.1016/j.tips.2014.08.002
Sperlagh B, Vizi ES, Wirkner K, Illes P (2006) P2X7 receptors in the nervous system. Prog Neurobiol 78:327–346. doi:10.1016/j.pneurobio.2006.03.007
Tesfaye S, Selvarajah D (2012) Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev 28(Suppl 1):8–14. doi:10.1002/dmrr.2239
Ursu D et al (2014) Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain. Mol Pain 10:37. doi:10.1186/1744-8069-10-37
Wang M et al (2016) Salidroside improves glucose homeostasis in obese mice by repressing inflammation in white adipose tissues and improving leptin sensitivity in hypothalamus. Sci Rep 6:25399. doi:10.1038/srep25399
Wang Y, Xiao C, Indersmitten T, Freedman R, Leonard S, Lester HA (2014) The duplicated alpha7 subunits assemble and form functional nicotinic receptors with the full-length alpha7. J Biol Chem 289:26451–26463. doi:10.1074/jbc.M114.582858
Zhang JM, An J (2007) Cytokines, inflammation, and pain. Int Anesthesiol Clin 45:27–37. doi:10.1097/AIA.0b013e318034194e
Zheng T et al (2015) Salidroside ameliorates insulin resistance through activation of a mitochondria-associated AMPK/PI3K/Akt/GSK3beta pathway. Br J Pharmacol 172:3284–3301. doi:10.1111/bph.13120
Zhou C, Luo ZD (2014) Electrophysiological characterization of spinal neuron sensitization by elevated calcium channel alpha-2-delta-1 subunit protein. Eur J Pain 18:649–658. doi:10.1002/j.1532-2149.2013.00416.x
Acknowledgments
This work was supported by Zhejiang Provincial Science and Technology Department of Public Welfare Technology Application Project (2017C37124). We thank Professor Shucai Ling for his valuable suggestions on this paper.
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All animal care and experimental protocols were approved by Animal care and research committee in the First People’s Hospital of Linhai City. All applicable international, national, and institutional guidelines for the care and use of animals were followed.
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Ni, GL., Cui, R., Shao, AM. et al. Salidroside Ameliorates Diabetic Neuropathic Pain in Rats by Inhibiting Neuroinflammation. J Mol Neurosci 63, 9–16 (2017). https://doi.org/10.1007/s12031-017-0951-8
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DOI: https://doi.org/10.1007/s12031-017-0951-8