Injury to skeletal muscle of mice following acute and sub-acute pregabalin exposure

Document Type: Original Article

Authors

1 Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran

3 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Milad Infertility Center, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

5 Nanotechnology Research Center School of Pharmacy, Mashhad University Medical Sciences, Mashhad, Iran

6 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Pregabalin (PGB) is a new antiepileptic drug that has received FDA approval for patient who suffers from central neuropathic pain, partial seizures, generalized anxiety disorder, fibromyalgia and sleep disorders. This study was undertaken to evaluate the possible adverse effects of PGB on the muscular system of mice.
Materials and Methods: To evaluate the effect of PGB on skeletal muscle, the animals were exposed to a single dose of 1, 2 or 5 g /kg or daily doses of 20, 40 or 80 mg/kg for 21 days, intraperitoneally (IP). Twaenty-four hr after the last drug administration, all animals were sacrificed. The level of fast-twitch skeletal muscle troponin I and CK-MM activity were evaluated in blood as an indicator of muscle injury. Skeletal muscle pathological findings were also reported as scores ranging from 1 to 3 based on the observed lesion.
Results: In the acute and sub-acute toxicity assay IP injection of PGB significantly increased the activity and levels of CK-MM and fsTnI compared to the control group. Sub-acute exposure to PGB caused damages that include muscle atrophy, infiltration of inflammatory cells and cell degeneration.
Conclusion: PGB administration especially in long term care causes muscle atrophy with infiltration of inflammatory cells and cell degeneration. The fsTnI and CK-MM are reliable markers in PGB-related muscle injury. The exact mechanisms behind the muscular damage are unclear and necessitate further investigations.

Keywords


1.   Etemad L, Moshiri M, Mohammadpour AH, Vahdati Mashhadi N, Moallem SA, Teratogenic effects of pregabalin in mice. Iran J Basic Med Sci 2013; 16: 1065-1070.

2.   Freynhagen R, Grond S, Schupfer G, Hagebeuker A, Schmelz M, Ziegler D, et al. Efficacy and safety of pregabalin in treatment refractory patients with various neuropathic pain entities in clinical routine. Int J Clin Pract 2007; 61: 1989-1996.

3.   Sebastian B, Talikoti AT, Nelamangala K, Krishnamurthy D. Effect of oral pregabalin as preemptive analgesic in patients undergoing lower limb orthopedic surgeries under spinal anaesthesia. J Clin Diagn Res 2016; 10: UC01-4.

4.   Etemad L, Jafarian AH, Moallem SA. Pathogenesis of pregabalin-induced limb defects in mouse embryos. J Pharm Pharm Sci 2015; 18: 882-889.

5.   Vassallo JD, Janovitz EB, Wescott DM, Chadwick C, Lowe-Krentz LJ, Lehman-McKeeman LD. Biomarkers of drug-induced skeletal muscle injury in the rat: troponin I and myoglobin. Toxicol Sci 2009; 111: 402-412.

6.   Brazeau GA. Drug induced muscle damage. In: Reznic AZ,  Packer L, Sen CK, Holloszy JO,  Jackson MJ. editors. Oxidative stress in muscle muscle. 1st ed. Springer Basel AG; 1998.p.295-316.

7.   Jones JD, Kirsch HL, Wortmann RL, Pillinger MH. The causes of drug-induced muscle toxicity. Curr Opin Rheumatol 2014; 26: 697-703.

8.   Anonymous, Lyrica Prescribing Information. USA: Pfizer Inc; 2004.

9.   Sorichter S, Mair J, Koller A, Gebert W, Rama D, Calzolari C, et al. Skeletal troponin I as a marker of exercise-induced muscle damage. J Appl Physiol 1997; 83: 1076-1082.

10. Simpson JA, Labugger R, Collier C, Brison RJ, Iscoe S, Van Eyk JE, Fast and slow skeletal troponin I in serum from patients with various skeletal muscle disorders: a pilot study. Clin Chem 2005; 51: 966-972.

11. Apple FS, Tissue specificity of cardiac troponin I, cardiac troponin T and creatine kinase-MB. Clin Chim Acta 1999; 284: 151-159.

12. Sills GJ, The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol 2006; 6: 108-113.

13. Gong HC, Hang J, Kohler W, Li L, Su TZ. Tissue-specific expression and gabapentin-binding properties of calcium channel alpha 2 delta subunit subtypes. J Membr Biol 2001; 184: 35-43.

14. Patel R, Dickenson AH, Mechanisms of the gabapentinoids and alpha 2 delta-1 calcium channel subunit in neuropathic pain. Pharmacol Res Perspect 2016; 4: e00205.

15. Papadimitriou A, Servidei S. Late onset lipid storage myopathy due to multiple acyl CoA dehydrogenase deficiency triggered by valproate. Neuromuscul Disord 1991; 1: 247-252.

16. Silva MF, Aires CC, Luis PB, Ruiter JP, L IJ, Duran M, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis 2008; 31: 205-216.

17. Kaufman MB, Choy M. Pregabalin and simvastatin: first report of a case of rhabdomyolysis. P T 2012; 37: 579-595.