Adverse effects of methamphetamine on vital organs of male rats: Histopathological and immunohistochemical investigations

Document Type : Original Article

Authors

1 Department of Pathobiology, School of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran

2 Pathology and Stem Cell Research Center, Pathology Department, Afzalipour Kerman Medical School, Kerman, Iran

Abstract

Objective(s): Methamphetamine (named crystal, ice, and crank), is a strong psychostimulant drug with addictive and neurotoxic properties. It is absorbed by various organs and induces tissue damage in abusers. Most METH studies have focused on the central nervous system and its effects on other organs have been neglected. Experimental investigations of animal models are used to provide significant additional information. We have studied the histopathological effects of methamphetamine in the brains, hearts, livers, testes, and kidneys of rats. 
Materials and Methods: Methamphetamine (0.5 mg/kg) was administered subcutaneously for 21 days. Immunohistochemistry was carried out with markers including glial fibrillary acidic protein (GFAP) for reactive astrocytes, vimentin as an intermediate filament in different cells, and CD45 marker for the detection of reactive microglia in the brain. Also, some samples were taken from livers, kidneys, hearts, and testes.
Results: Degenerative changes and necrosis were the most common histopathological effects in the liver, kidneys, heart, testes, and brains of rats treated with methamphetamine. Immunohistochemical analyses by vimentin and GFAP markers revealed reactive microglia and astrocytes with the appearance of swollen cell bodies and also short, thickened, and irregular processes. Moreover, the number of CD45-positive cells was higher in this group. Reactive cells were more noticeable in the peduncles and subcortical white matter of the cerebellum.  
Conclusion: Our results showed the toxic effects of methamphetamine on the vital organs and induction of neurotoxicity, cardiomyopathy, renal damage, and infertility in male rats. We could not attribute observed hepatic changes to METH and further evaluation is needed.

Keywords

References

1. Lappin JM, Darke S, Farrell M. Methamphetamine use and future risk for Parkinson’s disease: evidence and clinical implications. Drug Alcohol Depend 2018;187:134-140.
2. Logan BK. Methamphetamine effects on human performance and behavior. Forensic Sci Rev 2002;14:133-151.
3. Newton TF, De La Garza R, Kalechstein AD, Tziortzis D, Jacobsen CA. Theories of addiction: methamphetamine users ‘explanations for continuing drug use and relapse. Am J Addict 2009;18:294-300.
4. Cruickshank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine. Addiction 2009;104: 1085-1099.
5. Barati M, Ahmadpanah M, Soltanian AR. Prevalence and factors associated with methamphetamine use among adult substance abusers. J Res Health Sci 2014;14:221-226. 
6. Karila L, Petit A, Cottencin O, Reynaud M. Methamphetamine dependence: Consequences and complications. Press Med 2010;39:1246-1253.
7. Hobkirk AL, Watt MH, Myers B, Skinner D, Meade CS. A qualitative study of methamphetamine initiation in Cape Town, South Africa. Int J Drug Policy 2015;30: 99-106.
8. Moratalla R, Khairnar A, Simola N, Granado N, Garcia-Montes JR, Porceddu PF, Tizabi Y, Costa G, Morelli M. Amphetamine-related drugs neurotoxicity in humans and in experimental animals: main mechanisms. Prog Neurobiol 2017;155:149-170.
9. Volkow ND, Fowler JS, Wang GJ, Shumay E, Telang F, Thanos PK, Alexoff D. Distribution and pharmacokinetics of methamphetamine in the human body: Clinical implications. PLoS One 2010;5:e15269.
10. Taslimi Z, Komaki A, Haghparast A, Sarihi A. Effects of acute and chronic restraint stress on reinstatement of extinguished methamphetamine-induced conditioned place preference in rats. Basic Clin Neurosci 2018;9:157-166.
11. Johnsen SG. Testicular biopsy score count- a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones 1970;1:2-25.
12. Kajihara T, Okagaki R, Ishihara O. LPS-induced transient testicular dysfunction accompanied by apoptosis of testicular germ cells in mice. Med Mol Morphol 2006;39:203-208.
13. Azizollahi S, Babaei H, Derakhshanfar A, Oloumi MM. Effects of co-administration of dopamine and vitamin C on ischemia-reperfusion injury after experimental testicular torsion-detorsion in rats. Andrologia 2011;43:100-105.
14. Halpin LE, Collins SA, Yamamoto BK. Neurotoxicity of methamphetamine and 3,4 methylenedioxymethamphetamine. Life Sci 2014;97:37-44. 
15. Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS. A role for oxytocin and 5- HT (1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine (“ecstasy”). Neurosci 2007;146:509-514.
16. Movassaghi S, Yousefi Oudarji A, Sharifi ZN. Effect of pentoxifylline on apoptosis of kidney’s cells following acute methamphetamine administration in male Wistar rats. Galen M J 2016; 5:131-138.
17. Friend DM, Keefe KA. Glial reactivity in resistance to methamphetamine-induced neurotoxicity. J Neurochem 2013;125:566-574.
18. Lafuente JV, Sharma A, Muresanu DF, Ozkizilcik A, Tian ZR, Patnaik R, Sharma HS. Repeated forced swim exacerbates methamphetamine-induced neurotoxicity: neuroprotective effects of nanowired delivery of 5-ht3 receptor antagonist ondansetron. Mol Neurobiol 2017;55:322-33.4
19. Zhang Z, Gong Q, Feng X, Zhang D, Quan L. Astrocytic clasmatodendrosis in the cerebral cortex of methamphetamine Abusers. Forensic Sci Res 2017;2:139-144.
20. Sharma HS, Kiyatkin EA. Rapid morphological brain abnormalities during acute methamphetamine intoxication in the rat. an experimental study using light and electron microscopy. J Chem Neuroanat 2009;37:18-32.
21. O’Callaghan JP, Miller DB. Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse. J Pharmacol Exp Therap 1994;270:741-751.
22. Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci 2004;5:146-156.
23. Kulik T, Kusano Y, Aronhime S, Sandler AL, Winn HR. Regulation of cerebral vasculature in normal and ischemic brain. Neuropharmacol 2008;55:281-288.
24. Dietrich JB. Alteration of blood-brain barrier function by methamphetamine and cocaine. Cell Tissue Res 2009;336:385–392.
25. Paulin D, Jakob H, Jacob F, Weber K, Osborn M. In vitro differentiation of mouse teratocarcinoma cells monitored by intermediate filament expression. Differentiation 1982;22: 90-99
26. Boyne LJ, Fischer I, Shea TB. Role of vimentin in early stages of neuritogenesis in cultured hippocampal neurons. Int J Dev Neurosci 1996;14:739-748.
27. Izmiryan A, Franco CA, Paulin D, Li Z, Xue Z. Synemin isoforms during mouse development: multiplicity of partners in vascular and neuronal systems. Exp Cell Res 2009;315:769-783.
28. Calvo JL, Carbonell AL Boya J. Co-expression of glial fibrillary acidic protein and vimentin in reactive astrocytes following brain injury in rats. Brain Res 1991;566:333-336.
29. Graeber MB, Kreutzberg GW. Delayed astrocyte reaction following facial nerve axotomy. J Neurocytol 1988;17:209-220.
30. Halliday GM, Stevens CH. Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord 2011;26:6-17.
31. Proescholdt MG, Chakravarty S, Foster JA, Foti SB, Briley EM, Herkenham M. Intracerebroventricular but not intravenous interleukin-1β induces widespread vascular mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neurosci 2002;112:731-749.
32. Stevens SL, Bao J, Hollis J, Lessov NS, Clark WM, Stenzel-Poore MP. The use of flow cytometry to evaluate temporal changes in inflammatory cells following focal cerebral ischemia in mice. Brain Res 2002;932:110-119.
33. Rothman RB, Baumann MH. Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 2003;479:23-40.
34. Hansen JP. Ten keys to successful NCQA accreditation: a health plan perspective. J Healthc Qual 2002;24: 39-42. 
35. Dawson TM, Dawson VL. Mitochondrial mechanisms of neuronal cell death: potential therapeutics. Annu Rev Pharmacol Toxicol 2017;57:437-454.
36. Beer SM, Taylor ER, Brown SE, Dahm CC, Costa NJ, Runswick MJ, Murphy MP. Glutaredoxin 2 catalyzes the reversible oxidation and glutathionylation of mitochondrial membrane thiol proteins: implications for mitochondrial redox regulation and anti-oxidant defense. J Biol Chem 2004;279:47939-47951.
37. Panenka WJ, Procyshyn RM, Lecomte T, MacEwan GW, Flynn SW, Honer WG, Barr AM. Methamphetamine use: a comprehensive review of molecular, preclinical and clinical findings. Drug Alcohol Depend 2013;129:167-179.
38. Ishigami A, Tokunaga I, Gotohda T, Kubo S. Immunohistochemical study of myoglobin and oxidative injury related markers in the kidney of methamphetamine abusers. Legal Med (Tokyo) 2003;5:42-48.
39. Tokunaga I, Kubo S, Ishigami A, Gotohda T, Kitamura O. Changes in renal function and oxidative damage in methamphetamine-treated rat. Legal Med 2006;8:16-21.
40. Ambruzs JM, Serrell PB, Rahim N, Larsen CP. Thrombotic microangiopathy and acute kidney injury associated with intravenous abuse of an oral extended-release formulation of oxymorphone hydrochloride: kidney biopsy findings and report of 3 cases. Am J Kidney Dis 2014;63:1022-1026.
41. Carrasco R, Salinas M, Rossel V. Rhabdomyolysis and acute renal failure after cocaine overdose: report of one case. Rev Med Chil 2011;139:480-483.
42. Islam MN, Jesmine K, Kong Sn Molh A, Hasnan J. Histopathological studies of cardiac lesions after long term administration of methamphetamine in high dosage: part II. Leg Med (Tokyo) Suppl 2009;1:S147–150.
43. Lord KC, Shenouda SK, McIlwain E, Charalampidis D, Lucchesi PA, Varner KJ. Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction. Cardiovasc Res 2010;87:111-118.
44. Akhgari M, Mobaraki H, Etemadi-Aleagha A. Histopathological study of cardiac lesions in methamphetamine poisoning-related deaths. Daru 2017;25:5
45. Won S, Hong RA, Shohet RV, Seto TB, Parikh NI. Methamphetamine-associated cardiomyopathy. Clin Cardiol 2013;36:737-742.
46. Bruno VD, Duggan S, Capoun R, Ascione R. Methamphetamine-induced cardiomyopathy causing severe mitral valve regurgitation. Arch Med Sci 2014;10:630-631.
47. Yeo KK, Wijetunga M, Ito H, Efird JT, Tay K, Seto TB, Alimineti K, Kimata C, Schatz IJ. The association of methamphetamine use and cardiomyopathy in young patients. Am J Med 2007;120:165-171.
48. Paratz ED, Cunningham NJ, MacIsaac AI. The cardiac complications of methamphetamines. Heart Lung Circ 2016; 25:325-332. 
49. Yamamoto Y, Yamamoto, Abiru H, Fukui Y, Shiota K. Effects of methamphetamine on rat embryos cultured in vitro. Biol Neonate 1995; 68:33-38. 
50. Saberi A, Sepehri G, Safi Z, Razavi B, Jahandari F, Divsalar K, Salarkia E. Effects of methamphetamine on testes histopathology and spermatogenesis indices of adult male rats. Addict Health 2017;9:199-205.
51. Lin JF, Lin YH, Liao PC, Lin YC, Tsai TF, Chou KY, Chen HE, Tsai SC, Hwang TI. Induction of testicular damage by daily methamphetamine administration in rats. Chinese J Physiol 2014;57:19-30. 
52. Nudmamud-Thanoi S, Tangsrisakda N, Thanoi S. Changes of androgen receptor expression in stages VII-VIII seminiferous tubules of rat testis after exposure to methamphetamine. Songklanakarin J Sci Technol 2016;38:275-279.
53. Kaewman P, Nudmamud-Thanoi S, Thanoi S. Gabaergic alterations in the rat testis after methamphetamine exposure. Int J Med Sci 2018;15:1349-1354
54. Yang L, Shen J, Chen J, Li W, Xie X. Reduced glycolysis contributed to inhibition of testis spermatogenesis in rats after chronic methamphetamine exposure. Med Sci Monit 2019;25:5453-5464.
55. Halpin L, Yamamoto BK. Peripheral ammonia as a mediator of methamphetamine neurotoxicity. J Neurosci 2012;32:13155-13163. 
56. Wang Q, Wei LW, Xiao HQ, Xue Y, Du SH, Liu YG, Xie XL. Methamphetamine induces hepatotoxicity via inhibiting cell division, arresting cell cycle and activating apoptosis: In vivo and in vitro studies. Food Chem Toxicol 2017;105:61-72.
57. Kamijo Y, Soma K, Nishida M, Namera A, Ohwada T. Acute liver failure following intravenous methamphetamine. Vet Human Toxicol 2002;44: 216 –217.
58. Merchant K, Schammel C, Fulcher J. Acute methamphetamine-induced hepatic and pancreatic ischemia. Am J Forensic Med Pathol 2019; l40: 285-288.
59. da Silva D, Carmo H, Lynch A, Silva E. An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis. Arch Toxicol 2013;87:2165-2185.
60. da Silva DD, Silva E, Carmo H. Combination effects of amphetamines under hyperthermia – the role played by oxidative stress. J Appl Toxicol 2013;34:637-650.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 5
May 2023
Pages 549-557

Files

Share

How to cite

Statistics