Anti‑inflammatory actions of gabapentin and pregabalin on the substance P‑induced mitogen‑activated protein kinase activation in U373 MG human glioblastoma astrocytoma cells

Yamaguchi,Keisuke; Kumakura,Seiichiro; Someya,Akimasa; Iseki,Masako; Inada,Eiichi; Nagaoka,Isao

doi:10.3892/mmr.2017.7368

Anti‑inflammatory actions of gabapentin and pregabalin on the substance P‑induced mitogen‑activated protein kinase activation in U373 MG human glioblastoma astrocytoma cells

Authors:
- Keisuke Yamaguchi
- Seiichiro Kumakura
- Akimasa Someya
- Masako Iseki
- Eiichi Inada
- Isao Nagaoka
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Affiliations: Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, Tokyo 113‑8421, Japan, Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113‑8421, Japan
Published online on: August 28, 2017 https://doi.org/10.3892/mmr.2017.7368
Pages: 6109-6115

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Abstract

Gabapentin (GBP) and pregabalin (PGB) exert antinociceptive effects on chronic nociceptive responses with neuropathic or inflammatory conditions. Furthermore, it is considered that GBP and PGB exhibit anti‑inflammatory effects by modulating the substance P (SP)‑mediated neurokinin‑1 receptor (NK1R; a SP receptor) response. Thus, in the present study, the effects of GBP and PGB on SP‑induced activation were investigated in the human glioblastoma astrocytoma U373 MG cell line, which expresses high levels of functional high‑affinity NK1R, and produces interleukin (IL)‑6 and IL‑8 in response to SP. The results indicated that GBP and PGB suppressed the SP‑induced production of IL‑6, and IL‑8 in U373 MG cells. Furthermore, GBP and PGB inhibited the SP‑induced phosphorylation of p38 mitogen‑activated protein kinase (MAPK) and nuclear factor (NF)‑κB, and the nuclear translocation of NF‑κB in U373 MG cells. Together, these observations suggest that GBP and PGB likely prevent SP‑induced IL‑6 and IL‑8 production in U373 MG cells via the inhibition of signaling molecules, including p38 MAPK and NF‑κB, thereby exhibiting antineuroinflammatory effects.

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1	Samsam M, Coveñas R, Ahangari R, Yajeya J, Narváez JA and Tramu G: Simultaneous depletion of neurokinin A substance P and calcitonin gene-related peptide from the caudal trigeminal nucleus of the rat during electrical stimulation of the trigeminal ganglion. Pain. 84:389–395. 2000. View Article : Google Scholar : PubMed/NCBI
2	Johnson MB, Young AD and Marriott I: The therapeutic potential of targeting substance P/NK-1R interactions in inflammatory CNS disorders. Front Cell Neurosci. 10:2962017. View Article : Google Scholar : PubMed/NCBI
3	Muñoz M and Coveñas R: Involvement of substance P and the NK-1 receptor in cancer progression. Peptides. 48:1–9. 2013. View Article : Google Scholar : PubMed/NCBI
4	Ebner K and Singewald N: The role of substance P in stress and anxiety responses. Amino Acids. 31:251–272. 2006. View Article : Google Scholar : PubMed/NCBI
5	Garcia-Recio S and Gascón P: Biological and pharmacological aspects of the NK1-receptor. Biomed Res Int. 2015:4957042015. View Article : Google Scholar : PubMed/NCBI
6	Lieb K, Schaller H, Bauer J, Berger M, Schulze-Osthoff K and Fiebich BL: Substance P and histamine induce interleukin-6 expression in human astrocytoma cells by a mechanism involving protein kinase C and nuclear factor-IL-6. J Neurochem. 70:1577–1583. 1998. View Article : Google Scholar : PubMed/NCBI
7	Lieb K, Fiebich BL, Berger M, Bauer J and Schulze-Osthoff K: The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells. J Immunol. 159:4952–4958. 1997.PubMed/NCBI
8	Horuk R, Martin AW, Wang Z, Schweitzer L, Gerassimides A, Guo H, Lu Z, Hesselgesser J, Perez HD, Kim J, et al: Expression of chemokine receptors by subsets of neurons in the central nervous system. J Immunol. 158:2882–2890. 1997.PubMed/NCBI
9	Kim SY, Bae JC, Kim JY, Lee HL, Lee KM, Kim DS and Cho HJ: Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport. 13:2483–2486. 2002. View Article : Google Scholar : PubMed/NCBI
10	Ji RR, Befort K, Brenner GJ and Woolf CJ: ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci. 22:478–585. 2002.PubMed/NCBI
11	Jin SX, Zhuang ZY, Woolf CJ and Ji RR: p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci. 23:4017–4022. 2003.PubMed/NCBI
12	Bryans JS and Wustrow DJ: 3-substituted GABA analogs with central nervous system activity: a review. Med Res Rev. 19:149–177. 1999. View Article : Google Scholar : PubMed/NCBI
13	Taylor CP, Gee NS, Su TZ, Kocsis JD, Welty DF, Brown JP, Dooley DJ, Boden P and Singh L: A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res. 29:233–249. 1998. View Article : Google Scholar : PubMed/NCBI
14	Maneuf YP, Gonzalez MI, Sutton KS, Chung FZ, Pinnock RD and Lee K: Cellular and molecular action of the putative GABA-mimetic, gabapentin. Cell Mol Life Sci. 60:742–750. 2003. View Article : Google Scholar : PubMed/NCBI
15	Brown JT and Randall A: Gabapentin fails to alter P/Q-type Ca²⁺ channel-mediated synaptic transmission in the hippocampus in vitro. Synapse. 55:262–269. 2005. View Article : Google Scholar : PubMed/NCBI
16	SILLS G: The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol. 6:108–113. 2006. View Article : Google Scholar : PubMed/NCBI
17	Maneuf YP, Hughes J and McKnight AT: Gabapentin inhibits the substance P-facilitated K (+)-evoked release of [(3)H]glutamate from rat caudial trigeminal nucleus slices. Pain. 93:191–196. 2001. View Article : Google Scholar : PubMed/NCBI
18	Cunningham MO, Woodhall GL, Thompson SE, Dooley DJ and Jones RSG: Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. Eur J Neurosci. 20:1566–1576. 2004. View Article : Google Scholar : PubMed/NCBI
19	Dooley DJ, Mieske CA and Borosky SA: Inhibition of K(+)-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett. 280:107–110. 2000. View Article : Google Scholar : PubMed/NCBI
20	Rosenberg JM, Harrell C, Ristic H, Werner RA and de Rosayro AM: The effect of gabapentin on neuropathic pain. Clin J Pain. 13:251–255. 1997. View Article : Google Scholar : PubMed/NCBI
21	Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L and Garofalo E: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA. 280:1831–1836. 1998. View Article : Google Scholar : PubMed/NCBI
22	Rowbotham M, Harden N, Stacey B, Bernstein P and Magnus-Miller L: Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial. JAMA. 280:1837–1842. 1998. View Article : Google Scholar : PubMed/NCBI
23	Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H and Dahl JB: A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology. 97:560–564. 2002. View Article : Google Scholar : PubMed/NCBI
24	Serpell MG; Neuropathic pain study group, : Gabapentin in neuropathic pain syndromes: A randomised, double-blind, placebo-controlled trial. Pain. 99:557–566. 2002. View Article : Google Scholar : PubMed/NCBI
25	Werner MU, Perkins FM, Holte K, Pedersen JL and Kehlet H: Effects of gabapentin in acute inflammatory pain in humans. Reg Anesth Pain Med. 26:322–328. View Article : Google Scholar : PubMed/NCBI
26	Field MJ, Holloman EF, McCleary S, Hughes J and Singh L: Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain. J Pharmacol Exp Ther. 282:1242–1246. 1997.PubMed/NCBI
27	Houghton AK, Lu Y and Westlund KN: S-(+)-3-isobutylgaba and its stereoisomer reduces the amount of inflammation and hyperalgesia in an acute arthritis model in the rat. J Pharmacol Exp Ther. 285:533–538. 1998.PubMed/NCBI
28	Partridge BJ, Chaplan SR, Sakamoto E and Yaksh TL: Characterization of the effects of gabapentin and 3-isobutyl-gamma-aminobutyric acid on substance P-induced thermal hyperalgesia. Anesthesiology. 88:196–205. 1998. View Article : Google Scholar : PubMed/NCBI
29	Chen SR, Xu Z and Pan HL: Stereospecific effect of pregabalin on ectopic afferent discharges and neuropathic pain induced by sciatic nerve ligation in rats. Anesthesiology. 95:1473–1479. 2001. View Article : Google Scholar : PubMed/NCBI
30	Takasaki I, Andoh T, Nojima H, Shiraki K and Kuraishi Y: Gabapentin antinociception in mice with acute herpetic pain induced by herpes simplex virus infection. J Pharmacol Exp Ther. 296:270–275. 2001.PubMed/NCBI
31	Hunter JC, Gogas KR, Hedley LR, Jacobson LO, Kassotakis L, Thompson J and Fontana DJ: The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain. Eur J Pharmacol. 324:153–160. 1997. View Article : Google Scholar : PubMed/NCBI
32	Stanfa LC, Singh L, Williams RG and Dickenson AH: Gabapentin, ineffective in normal rats, markedly reduces C-fibre evoked responses after inflammation. Neuroreport. 8:587–590. 1997. View Article : Google Scholar : PubMed/NCBI
33	Oku R, Satoh M and Takagi H: Release of substance P from the spinal dorsal horn is enhanced in polyarthritic rats. Neurosci Lett. 74:315–319. 1987. View Article : Google Scholar : PubMed/NCBI
34	Fehrenbacher JC, Taylor CP and Vasko MR: Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain. 105:133–141. 2003. View Article : Google Scholar : PubMed/NCBI
35	Heuillet E, Ménager J, Fardin V, Flamand O, Bock M, Garret C, Crespo A, Fallourd AM and Doble A: Characterization of a human NK1 tachykinin receptor in the astrocytoma cell line U 373 MG. J Neurochem. 60:868–876. 1993. View Article : Google Scholar : PubMed/NCBI
36	Bahrami G and Mohammadi B: Sensitive microanalysis of gabapentin by high-performance liquid chromatography in human serum using pre-column derivatization with 4-chloro-7-nitrobenzofurazan: Application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci. 837:24–28. 2006. View Article : Google Scholar : PubMed/NCBI
37	Jalalizadeh H, Souri E, Tehrani MB and Jahangiri A: Validated HPLC method for the determination of gabapentin in human plasma using pre-column derivatization with 1-fluoro-2,4-dinitrobenzene and its application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 854:43–47. 2007. View Article : Google Scholar : PubMed/NCBI
38	Park S, Ahn ES, Han DW, Lee JH, Min KT, Kim H and Hong YW: Pregabalin and gabapentin inhibit substance P-induced NF-kappaB activation in neuroblastoma and glioma cells. J Cell Biochem. 105:414–423. 2008. View Article : Google Scholar : PubMed/NCBI
39	Tremont-Lukats IW, Megeff C and Backonja MM: Anticonvulsants for neuropathic pain syndromes: Mechanisms of action and place in therapy. Drugs. 60:1029–1052. 2000. View Article : Google Scholar : PubMed/NCBI
40	Mao J and Chen LL: Gabapentin in pain management. Anesth Analg. 91:680–687. 2000. View Article : Google Scholar : PubMed/NCBI
41	Patel S, Naeem S, Kesingland A, Froestl W, Capogna M, Urban L and Fox A: The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat. Pain. 90:217–226. 2001. View Article : Google Scholar : PubMed/NCBI
42	Field MJ, Oles RJ, Lewis AS, McCleary S, Hughes J and Singh L: Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents. Br J Pharmacol. 121:1513–1522. 1997. View Article : Google Scholar : PubMed/NCBI
43	Shimoyama N, Shimoyama M, Davis AM, Inturrisi CE and Elliott KJ: Spinal gabapentin is antinociceptive in the rat formalin test. Neurosci Lett. 222:65–67. 1997. View Article : Google Scholar : PubMed/NCBI
44	Kaneko M, Mestre C, Sánchez EH and Hammond DL: Intrathecally administered gabapentin inhibits formalin-evoked nociception and the expression of Fos-like immunoreactivity in the spinal cord of the rat. J Pharmacol Exp Ther. 292:743–751. 2000.PubMed/NCBI
45	Field MJ, McCleary S, Hughes J and Singh L: Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat. Pain. 80:391–398. 1999. View Article : Google Scholar : PubMed/NCBI
46	Gajraj NM: Pregabalin: Its pharmacology and use in pain management. Anesth Analg. 105:1805–1815. 2007. View Article : Google Scholar : PubMed/NCBI
47	Davies A, Hendrich J, Van Minh AT, Wratten J, Douglas L and Dolphin AC: Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci. 28:220–228. 2007. View Article : Google Scholar : PubMed/NCBI
48	Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME and Yaksh TL: Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci. 21:1868–1875. 2001.PubMed/NCBI
49	Fiebich BL, Schleicher S, Butcher RD, Craig A and Lieb K: The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B. J Immunol. 165:5606–5611. 2000. View Article : Google Scholar : PubMed/NCBI
50	Hu P, Bembrick AL, Keay KA and McLachlan EM: Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun. 21:599–616. 2007. View Article : Google Scholar : PubMed/NCBI
51	Scholz J, Abele A, Marian C, Häussler A, Herbert TA, Woolf CJ and Tegeder I: Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats. Pain. 138:130–142. 2008. View Article : Google Scholar : PubMed/NCBI
52	Cao H and Zhang YQ: Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev. 32:972–983. 2008. View Article : Google Scholar : PubMed/NCBI
53	Obata K and Noguchi K: MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci. 74:2643–2653. 2004. View Article : Google Scholar : PubMed/NCBI
54	Arruda JL, Colburn RW, Rickman AJ, Rutkowski MD and DeLeo JA: Increase of interleukin-6 mRNA in the spinal cord following peripheral nerve injury in the rat: Potential role of IL-6 in neuropathic pain. Brain Res Mol Brain Res. 62:228–235. 1998. View Article : Google Scholar : PubMed/NCBI
55	Lee HL, Lee KM, Son SJ, Hwang SH and Cho HJ: Temporal expression of cytokines and their receptors mRNAs in a neuropathic pain model. Neuroreport. 15:2807–2811. 2004.PubMed/NCBI
56	Wang XM, Hamza M, Wu TX and Dionne RA: Upregulation of IL-6, IL-8 and CCL2 gene expression after acute inflammation: Correlation to clinical pain. Pain. 142:275–283. 2009. View Article : Google Scholar : PubMed/NCBI
57	Wang F, Xu S, Shen X, Guo X, Peng Y and Yang J: Spinal macrophage migration inhibitory factor is a major contributor to rodent neuropathic pain-like hypersensitivity. Anesthesiology. 114:643–659. 2011. View Article : Google Scholar : PubMed/NCBI