Pregabalin treatment for neuropathic pain may damage intervertebral disc tissue

Karaarslan,Numan; Yilmaz,Ibrahim; Si̇rin,Duygu Yasar; Ozbek,Hanefi; Kaplan,Necati; Kaya,Yasin  Emre; Akyuva,Yener; Gurbuz,Mehmet  Sabri; Oznam,Kadir; Ates,Ozkan

doi:10.3892/etm.2018.6289

Pregabalin treatment for neuropathic pain may damage intervertebral disc tissue

Authors:
- Numan Karaarslan
- Ibrahim Yilmaz
- Duygu Yasar Si̇rin
- Hanefi Ozbek
- Necati Kaplan
- Yasin Emre Kaya
- Yener Akyuva
- Mehmet Sabri Gurbuz
- Kadir Oznam
- Ozkan Ates
View Affiliations

Affiliations: Department of Neurosurgery, Namik Kemal University School of Medicine, Tekirdag 59100, Turkey, Department of Medical Pharmacology, Istanbul Medipol University School of Medicine, Istanbul 34810, Turkey, Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Namik Kemal University, Tekirdag 59030, Turkey, Department of Neurosurgery, Istanbul Rumeli University, Corlu Reyap Hospital, Tekirdag 59860, Turkey, Department of Orthopedic and Traumatology, Abant Izzet Basal University School of Medicine, Bolu 14000, Turkey, Department of Neurosurgery, Gaziosmanpasa Taksim Training and Research Hospital, Istanbul 34433, Turkey, Department of Neurosurgery, Istanbul Medeniyet University School of Medicine, Istanbul 34730, Turkey, Department of Orthopedic and Traumatology, Istanbul Medipol University School of Medicine, Istanbul 34214, Turkey, Department of Neurosurgery, Istanbul Esenyurt University, Esencan Hospital, Istanbul 34517, Turkey
Published online on: June 12, 2018 https://doi.org/10.3892/etm.2018.6289
Pages: 1259-1265
Copyright: © Karaarslan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to determine whether pharmaceutical preparations with pregabalin (PGB) as an active ingredient, which are widely prescribed by clinicians, exert toxic effects on human primary nucleus pulposus (NP) and annulus fibrosis (AF). Primary human cell cultures were obtained from intact (n=6) and degenerated (n=6) tissues resected from the two groups of patients. Different doses of PGB were applied to these cultures and cells were subjected to molecular analyses at 0, 24 and 48 h. Cell vitality, toxicity and proliferation were assessed using a spectrophotometer. The expression of chondroadherin (CHAD), a (member of the NP‑specific protein family), hypoxia‑inducible factor‑1α (HIF‑1α) and type II collagen (COL2A1) was measured using reverse transcription‑quantitative polymerase chain reaction. The results revealed that cell intensity increased in a time‑dependent manner and cell vitality continued in the cultures without pharmaceuticals. Cell proliferation was suppressed in the PGB‑treated cultures independent from the dose and duration of application. PGB was demonstrated to suppress the expression of CHAD and HIF‑1α. In contrast, COL2A1 gene expression was not revealed in any experimental group. The present study utilized an in vitro model and the PGB active ingredient used herein may not be representative of clinical applications; however, the results demonstrated that PGB has a toxic effect on NP/AF cell cultures containing primary human intervertebral disc tissue. In summary, the use of pharmacological agents containing PGB may suppress the proliferation and differentiation of NP/AF cells and/or tissues, which should be considered when deciding on an appropriate treatment regime.

View Figures

View References

1	Goodman CW and Brett AS: Gabapentin and pregabalin for pain-is increased prescribing a cause for concern? N Engl J Med. 377:411–414. 2017. View Article : Google Scholar : PubMed/NCBI
2	Bian F, Li Z, Offord J, Davis MD, McCormick J, Taylor CP and Walker LC: Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: An ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice. Brain Res. 1075:68–80. 2006. View Article : Google Scholar : PubMed/NCBI
3	Blommel ML and Blommel AL: Pregabalin: An antiepileptic agent useful for neuropathic pain. Am J Health Syst Pharm. 64:1475–1482. 2007. View Article : Google Scholar : PubMed/NCBI
4	Zarei M, Najafi A, Mansouri P, Sadeghi-Yazdankhah S, Saberi H, Moradi M and Farzan M: Management of postoperative pain after lumbar surgery-pregabalin for one day and 14 days-a randomized, triple-blinded, placebo-controlled study. Clin Neurol Neurosurg. 151:37–42. 2016. View Article : Google Scholar : PubMed/NCBI
5	Roth T, Arnold LM, Garcia-Borreguero D, Resnick M and Clair AG: A review of the effects of pregabalin on sleep disturbance across multiple clinical conditions. Sleep Med Rev. 18:261–271. 2014. View Article : Google Scholar : PubMed/NCBI
6	Foroutan N and Nikvarz N: Role of pregabalin in management of pruritus: A literature review. J Pharm Pharm Sci. 19:465–474. 2016. View Article : Google Scholar : PubMed/NCBI
7	Gazulla J, Ruiz-Gazulla C and Tintore M: GABAergic pharmacotherapy in the treatment of motor disorders of the central nervous system. Curr Pharm Des. 21:4989–4995. 2015. View Article : Google Scholar : PubMed/NCBI
8	Akyuva Y, Karaarslan N, Yilmaz I, Ozbek H, Sirin DY, Gurbuz MS, Kaya YE, Kaplan N and Ates O: How scaffolds, which are polymeric drug delivery systems allowing controlled release, can be tested in human primary nucleus pulposus and annulus fibrosus cell cultures? Merit Res J Med Med Sci. 5:477–487. 2017.
9	Karaarslan N, Yilmaz I, Ozbek H, Yasar Sirin D, Kaplan N, Akyuva Y, Gonultas A and Ates O: Are specific gene expressions of extracellular matrix and nucleus pulposus affected by primary cell cultures prepared from intact or degenerative intervertebral disc tissue? Turk Neurosurg. Jan 22–2018.(Epub ahead of print). View Article : Google Scholar
10	Komur B, Akyuva Y, Karaslan N, Isyar M, Gumustas SA, Yilmaz I, Akkaya S, Sirin DY, Mutlu CA, Batmaz AG, et al: Can a biodegradable implanted bilayered drug delivery system loaded with BMP-2/BMP-12 take an effective role in the biological repair process of bone-tendon injuries? A preliminary report. J Pharm (Cairo). 2017:74578652017.PubMed/NCBI
11	Oznam K, Sirin DY, Yilmaz I, Kaya YE, Isyar M, Gumustas SA, Ozbek H, Akkaya S, Kayhan A and Mahirogullari M: Iopromide- and gadopentetic acid-derived preparates used in MR arthrography may be harmful to chondrocytes. J Orthop Surg Res. 12:982017. View Article : Google Scholar : PubMed/NCBI
12	Gumustas F, Yilmaz I, Sirin DY, Gumustas SA, Batmaz AG, Isyar M, Akkaya S and Mahirogullari M: Chondrocyte proliferation, viability and differentiation is declined following administration of methylphenidate utilized for the treatment of attention-deficit/hyperactivity disorder. Hum Exp Toxicol. 36:981–992. 2017. View Article : Google Scholar : PubMed/NCBI
13	Rosenzweig DH, Gravel Tremblay J, Bisson D, Ouellet JA, Weber MH and Haglund L: Comparative analysis in continuous expansion of bovine and human primary nucleus pulposuscells for tissue repair applications. Eur Cell Mater. 33:240–251. 2017. View Article : Google Scholar : PubMed/NCBI
14	Ehlicke F, Freimark D, Heil B, Dorresteijn A and Czermak P: Intervertebral disc regeneration: Influence of growth factors on differentiation of human mesenchymal stem cells (hMSC). Int J Artif Organs. 33:244–252. 2010. View Article : Google Scholar : PubMed/NCBI
15	Zhou X, Tao Y, Liang C, Zhang Y, Li H and Chen Q: BMP3 alone and together with TGF-β promote the differentiation of human mesenchymal stem cells into a nucleus pulposus-like phenotype. Int J Mol Sci. 16:20344–20359. 2015. View Article : Google Scholar : PubMed/NCBI
16	Feng G, Jin X, Hu J, Ma H, Gupte MJ, Liu H and Ma PX: Effects of hypoxias and scaffold architecture on rabbit mesenchymal stem cell differentiation towards a nucleus pulposus-like phenotype. Biomaterials. 32:8182–8189. 2011. View Article : Google Scholar : PubMed/NCBI
17	Li XC, Wu YH, Bai XD, Ji W, Guo ZM, Wang CF, He Q and Ruan DK: BMP7-Based functionalized self-assembling peptides protect nucleus pulposus-derived stem cells from apoptosis ın vitro. Tissue Eng Part A. 22:1218–1228. 2016. View Article : Google Scholar : PubMed/NCBI
18	Emanuel KS, Vergroesen PP, Peeters M, Holewijn RM, Kingma I and Smit TH: Poroelastic behaviour of the degenerating human intervertebral disc: A ten-day study in a loaded disc culture system. Eur Cell Mater. 29:330–340. 2015. View Article : Google Scholar : PubMed/NCBI
19	Risbud MV and Shapiro IM: Notochordal cells in the adult intervertebral disc: New perspective on an old question. Crit Rev Eukaryot Gene Expr. 21:29–41. 2011. View Article : Google Scholar : PubMed/NCBI
20	Van den Akker GG, Surtel DA, Cremers A, Rodrigues-Pinto R, Richardson SM, Hoyland JA, van Rhijn LW, Welting TJ and Voncken JW: Novel immortal human cell lines reveal subpopulations in the nucleus pulposus. Arthritis Res Ther. 16:R1352014. View Article : Google Scholar : PubMed/NCBI
21	Imabuchi R, Ohmiya Y, Kwon HJ, Onodera S, Kitamura N, Kurokawa T, Gong JP and Yasuda K: Gene expression profile of the cartilage tissue spontaneously regenerated in vivo by using a novel double-network gel: Comparisons with the normal articular cartilage. BMC Musculoskelet Disord. 12:2132011. View Article : Google Scholar : PubMed/NCBI
22	Zeng Y, Danielson KG, Albert TJ, Shapiro IM and Risbud MV: HIF-1 alpha is a regulator of galectin-3 expression in the intervertebral disc. J Bone Miner Res. 22:1851–1861. 2007. View Article : Google Scholar : PubMed/NCBI
23	Risbud MV, Schipani E and Shapiro IM: Hypoxic regulation of nucleus pulposus cell survival: From niche to notch. Am J Pathol. 176:1577–1583. 2010. View Article : Google Scholar : PubMed/NCBI
24	Hanley EN Jr and McCulloch JA: Surgical indication and techniques international society for the study of the lumbar spine: The lumbar spinethe lumbar spine 2nd edition. WB Saunders; Philadelphia, PA: pp. 492–524. 1996
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Taylor CP, Angelotti T and Fauman E: Pharmacology And mechanism of action of pregabalin: The calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 73:137–150. 2007. View Article : Google Scholar : PubMed/NCBI
27	Salat K, Librowski T, Nawiesniak B and Gluch-Lutwin M: Evaluation of analgesic, antioxidant, cytotoxic and metabolic effects of pregabalin for the use in neuropathic pain. Neurol Res. 35:948–958. 2013. View Article : Google Scholar : PubMed/NCBI
28	Kim JS, Ahmadinia K, Li X, Hamilton JL, Andrews S, Haralampus CA, Xiao G, Sohn HM, You JW, Seo YS, et al: Development of an experimental animal model for lower back pain by percutaneous injury-induced lumbar facet joint osteoarthritis. J Cell Physiol. 230:2837–2847. 2015. View Article : Google Scholar : PubMed/NCBI
29	Jang Y, Song HK, Yeom MY and Jeong DC: The immunomodulatory effect of pregabalin on spleen cells in neuropathic mice. Anesth Analg. 115:830–836. 2012. View Article : Google Scholar : PubMed/NCBI
30	Kalaf Growney EA, Flores R, Bledsoe JG and Sell SA: Characterization of slow-gelling alginate hydrogels for intervertebral disc tissue-engineering applications. Mater Sci Eng C Mater Biol Appl. 63:198–210. 2016. View Article : Google Scholar : PubMed/NCBI
31	Liu MC, Chen WH, Wu LC, Hsu WC, Lo WC, Yeh SD, Wang MF, Zeng R and Deng WP: Establishment of a promising human nucleus pulposus cell line for intervertebral disc tissue engineering. Tissue Eng Part C Methods. 20:1–10. 2014. View Article : Google Scholar : PubMed/NCBI
32	Gumustas SA, Yilmaz I, Isyar M, Sirin DY, Batmaz AG, Ugras AA, Oznam K, Ciftci Z and Mahirogullari M: Assessing the negative impact of phenyl alkanoic acid derivative, a frequently prescribed drug for the suppression of pain and inflammation, on the differentiation and proliferation of chondrocytes. J Orthop Surg Res. 11:702016. View Article : Google Scholar : PubMed/NCBI
33	Isyar M, Yilmaz I, Sirin Yasar D, Yalcin S, Guler O and Mahirogullari M: A practical way to prepare primer human chondrocyte culture. J Orthop. 13:162–167. 2016. View Article : Google Scholar : PubMed/NCBI
34	Guzelant AY, Isyar M, Yilmaz I, Sirin DY, Cakmak S and Mahirogullari M: Are chondrocytes damaged when rheumatologic inflammation is suppressed? Drug Chem Toxicol. 40:13–23. 2017. View Article : Google Scholar : PubMed/NCBI