Translational Stroke Research

, Volume 10, Issue 1, pp 67–77 | Cite as

The 5α-Reductase Inhibitor Finasteride Exerts Neuroprotection Against Ischemic Brain Injury in Aged Male Rats

  • Motoki TanakaEmail author
  • Takunori Ogaeri
  • Mikhail Samsonov
  • Masahiro SokabeEmail author
Original Article


Progesterone (P4) exerts potent neuroprotection both in young and aged animal models of stroke. The neuroprotection is likely to be mediated by allopregnanolone (ALLO) metabolized from P4 by 5α-reductase, since the neuroprotection is attenuated by the 5α-reductase inhibitor finasteride, which was done only with young animals though. Thus, we do not know the contribution of ALLO to the P4-induced neuroprotection in aged animals. We examined effects of finasteride on the P4-induced neuroprotection in aged (16–18-month-old) male rats subjected to transient focal cerebral ischemia. Transient focal cerebral ischemia was induced by left middle cerebral artery occlusion (MCAO) and occlusion of the bilateral common carotid arteries. MCAO rats were given an 8 mg/kg P4 6 h after MCAO followed by the same treatment once a day for successive 3 days. Finasteride, a 5α-reductase inhibitor, at 20 mg/kg was intraperitoneally injected 30 min prior to the P4-injections. P4 markedly reduced neuronal damage 72 h after MCAO, and the P4-induced neuroprotection was apparently suppressed by finasteride in the aged animals. However, post-ischemic administration of finasteride alone (20 mg/kg) significantly prevented neuronal damage and the impairment of Rotarod performance after MCAO in aged male rats, but not in young ones. The androgen receptor antagonist flutamide markedly suppressed the neuroprotection of finasteride in the cerebral cortex, but not in the striatum, suggesting the androgen receptor-dependent mechanism of the finasteride-induced neuroprotection in the cerebral cortex. Our findings suggested, for the first time, the potential of finasteride as a therapeutic agent in post-ischemic treatment of strokes in aged population.


5α-reductase inhibitor Finasteride Middle cerebral artery occlusion Progesterone Stroke 



This work was supported by the grant for collaborative research between Nagoya University and R-Pharm (2614Dj-02b). We would like to thank Dr. Takayuki Nakajima, PhD, Osaka Prefecture University, for providing detailed surgical information and training on the three vessel occlusion model of focal cerebral ischemia in rats.


This work was supported by the grant for collaborative research between Nagoya University and R-Pharm (2614Dj-02b).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.


  1. 1.
    Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al. Global and regional burden of stroke during 1990-2010: findings from the global burden of disease study 2010. Lancet. 2014;383:245–54.CrossRefGoogle Scholar
  2. 2.
    Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke. 2009;40:2438–41.CrossRefGoogle Scholar
  3. 3.
    Shobha N, Buchan AM, Hill MD. Thrombolysis at 3-4.5 hours after acute ischemic stroke onset—evidence from the Canadian Alteplase for stroke effectiveness study (CASES) registry. Cerebrovasc Dis. 2011;31:223–8.CrossRefGoogle Scholar
  4. 4.
    Cai W, Sokabe M, Chen L. Time-window of progesterone neuroprotection after stroke and its underlying molecular mechanisms. Adv. Preclin. Study Ischemic Stroke. 2012:479–96.Google Scholar
  5. 5.
    Yousuf S, Atif F, Sayeed I, Tang H, Stein DG. Progesterone in transient ischemic stroke: a dose-response study. Psychopharmacology. 2014;231:3313–23.CrossRefGoogle Scholar
  6. 6.
    Wali B, Ishrat T, Won S, Stein DG, Sayeed I. Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study. Brain. 2014;137:486–502.CrossRefGoogle Scholar
  7. 7.
    Wali B, Ishrat T, Stein DG, Sayeed I. Progesterone improves long-term functional and histological outcomes after permanent stroke in older rats. Behav Brain Res. 2016;305:46–56.CrossRefGoogle Scholar
  8. 8.
    Ishihara Y, Fujitani N, Sakurai H, Takemoto T, Ikeda-Ishihara N, Mori-Yasumoto K, et al. Effects of sex steroid hormones and their metabolites on neuronal injury caused by oxygen-glucose deprivation/reoxygenation in organotypic hippocampal slice cultures. Steroids. 2016;113:71–7.CrossRefGoogle Scholar
  9. 9.
    Kokate TG, Banks MK, Magee T, Yamaguchi S, Rogawski MA. Finasteride, a 5alpha-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice. J Pharmacol Exp Ther. 1999;288:679–84.PubMedGoogle Scholar
  10. 10.
    Ciriza I, Carrero P, Frye CA, Garcia-Segura LM. Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective. J Neurobiol. 2006;66:916–28.CrossRefGoogle Scholar
  11. 11.
    Liu QY, Chang YH, Schaffner AE, Smith SV, Barker JL. Allopregnanolone activates GABA(A) receptor/Cl(-) channels in a multiphasic manner in embryonic rat hippocampal neurons. J Neurophysiol. 2002;88:1147–58.CrossRefGoogle Scholar
  12. 12.
    Hosie AM, Wilkins ME, da Silva HM, Smart TG. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature. 2006;444:486–9.CrossRefGoogle Scholar
  13. 13.
    Modgil A, Parakala ML, Ackley MA, Doherty JJ, Moss SJ, Davies PA. Endogenous and synthetic neuroactive steroids evoke sustained increases in the efficacy of GABAergic inhibition via a protein kinase C-dependent mechanism. Neuropharmacology. 2016;113:314–22.CrossRefGoogle Scholar
  14. 14.
    Cheng J, Alkayed NJ, Hurn PD. Deleterious effects of dihydrotestosterone on cerebral ischemic injury. J Cereb Blood Flow Metab. 2007;27:1553–62.CrossRefGoogle Scholar
  15. 15.
    Uchida M, Palmateer JM, Herson PS, DeVries AC, Cheng J, Hurn PD. Dose-dependent effects of androgens on outcome after focal cerebral ischemia in adult male mice. J Cereb Blood Flow Metab. 2009;29:1454–62.CrossRefGoogle Scholar
  16. 16.
    Kimoto T, Ishii H, Higo S, Hojo Y, Kawato S. Semicomprehensive analysis of the postnatal age-related changes in the mRNA expression of sex steroidogenic enzymes and sex steroid receptors in the male rat hippocampus. Endocrinology. 2010;151:5795–806.CrossRefGoogle Scholar
  17. 17.
    Munetomo A, Hojo Y, Higo S, Kato A, Yoshida K, Shirasawa T, et al. Aging-induced changes in sex-steroidogenic enzymes and sex-steroid receptors in the cortex, hypothalamus and cerebellum. J Physiol Sci. 2015;65:253–63.CrossRefGoogle Scholar
  18. 18.
    Nakajima T, Iwabuchi S, Miyazaki H, Okuma Y, Inanami O, Kuwabara M, et al. Relationship between the activation of cyclic AMP responsive element binding protein and ischemic tolerance in the penumbra region of rat cerebral cortex. Neurosci Lett. 2002;331:13–6.CrossRefGoogle Scholar
  19. 19.
    Fanaei H, Karimian SM, Sadeghipour HR, Hassanzade G, Kasaeian A, Attari F, et al. Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats. Brain Res. 2014;1558:74–83.CrossRefGoogle Scholar
  20. 20.
    Dang MT, Yokoi F, McNaught KS, Jengelley TA, Jackson T, Li J, et al. Generation and characterization of Dyt1 DeltaGAG knock-in mouse as a model for early-onset dystonia. Exp Neurol. 2005;196:452–63.CrossRefGoogle Scholar
  21. 21.
    Pelletier G, Luu-The V, Labrie F. Immunocytochemical localization of 5α-reductase in rat brain. Mol Cell Neurosci. 1994;5:394–9.CrossRefGoogle Scholar
  22. 22.
    Castelli MP, Casti A, Casu A, Frau R, Bortolato M, Spiga S, et al. Regional distribution of 5α-reductase type 2 in the adult rat brain: an immunohistochemical analysis. Psychoneuroendocrinology. 2013;38:281–93.CrossRefGoogle Scholar
  23. 23.
    Azzolina B, Ellsworth K, Andersson S, Geissler W, Bull HG, Harris GS. Inhibition of rat alpha-reductases by finasteride: evidence for isozyme differences in the mechanism of inhibition. J Steroid Biochem Mol Biol. 1997;61:55–64.CrossRefGoogle Scholar
  24. 24.
    Mukai Y, Higashi T, Nagura Y, Shimada K. Studies on neurosteroids XXV. Influence of a 5alpha-reductase inhibitor, finasteride, on rat brain neurosteroid levels and metabolism. Biol Pharm Bull. 2008;31:1646–50.CrossRefGoogle Scholar
  25. 25.
    Cheng J, Hu W, Toung TJ, Zhang Z, Parker SM, Roselli CE, et al. Age-dependent effects of testosterone in experimental stroke. J Cereb Blood Flow Metab. 2009;29:486–94.CrossRefGoogle Scholar
  26. 26.
    Liszczak TM, Hedley-Whyte ET, Adams JF, Han DH, Kolluri VS, Vacanti FX, et al. Limitations of tetrazolium salts in delineating infarcted brain. Acta Neuropathol. 1984;65:150–7.CrossRefGoogle Scholar
  27. 27.
    Schmued LC, Albertson C, Slikker W. Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res. 1997;751:37–46.CrossRefGoogle Scholar
  28. 28.
    Ünal-Çevik I, Kilinç M, Gürsoy-Özdemir Y, Gurer G, Dalkara T. Loss of NeuN immunoreactivity after cerebral ischemia does not indicate neuronal cell loss: a cautionary note. Brain Res. 2004;1015:169–74.CrossRefGoogle Scholar
  29. 29.
    Liu F, Schafer DP, McCullough LDTTC, Fluoro-Jade B. NeuN staining confirm evolving phases of infarction induced by middle cerebral artery occlusion. J Neurosci Methods. 2009;179:1–8.CrossRefGoogle Scholar
  30. 30.
    Zille M, Farr TD, Przesdzing I, Müller J, Sommer C, Dirnagl U, et al. Visualizing cell death in experimental focal cerebral ischemia: promises, problems, and perspectives. J Cereb Blood Flow Metab. 2012;32:213–31.CrossRefGoogle Scholar
  31. 31.
    McPhail LT, McBride CB, McGraw J, Steeves JD, Tetzlaff W. Axotomy abolishes NeuN expression in facial but not rubrospinal neurons. Exp Neurol. 2004;185:182–90.CrossRefGoogle Scholar
  32. 32.
    Davoli MA, Fourtounis J, Tam J, Xanthoudakis S, Nicholson D, Robertson GS, et al. Immunohistochemical and biochemical assessment of caspase-3 activation and DNA fragmentation following transient focal ischemia in the rat. Neuroscience. 2002;115:125–36.CrossRefGoogle Scholar
  33. 33.
    Hirayama Y, Ikeda-Matsuo Y, Notomi S, Enaida H, Kinouchi H, Koizumi S. Astrocyte-mediated ischemic tolerance. J Neurosci. 2015;35:3794–805.CrossRefGoogle Scholar
  34. 34.
    Sayeed I, Guo Q, Hoffman SW, Stein DG. Allopregnanolone, a progesterone metabolite, is more effective than progesterone in reducing cortical infarct volume after transient middle cerebral artery occlusion. Ann Emerg Med. 2006;47:381–9.CrossRefGoogle Scholar
  35. 35.
    Sayeed I, Parvez S, Wali B, Siemen DSD. Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism for better neuroprotective effects of allopregnanolone over progesterone. Brain Res. 2009;1263:165–73.CrossRefGoogle Scholar
  36. 36.
    Lee RJ, Kim JK, Chao D, Kuo L, Mally A, McClean ME, et al. Progesterone and allopregnanolone improves stroke outcome in male mice via distinct mechanisms but neither promotes neurogenesis. J Neurochem. 2015;132:32–7.CrossRefGoogle Scholar
  37. 37.
    Chen J, Chopp M, Li Y. Neuroprotective effects of progesterone after transient middle cerebral artery occlusion in rat. J Neurol Sci. 1999;171:24–30.CrossRefGoogle Scholar
  38. 38.
    Paba S, Frau R, Godar SC, Devoto P, Marrosu F, Bortolato M. Steroid 5α-reductase as a novel therapeutic target for schizophrenia and other neuropsychiatric disorders. Curr Pharm Des. 2011;17:151–67.CrossRefGoogle Scholar
  39. 39.
    Bortolato M, Frau R, Godar SC, Mosher LJ, Paba S, Marrosu F, et al. The implication of neuroactive steroids in Tourette’s syndrome pathogenesis: a role for 5α-reductase? J Neuroendocr. 2013;25:1196–208.CrossRefGoogle Scholar
  40. 40.
    Frau R, Abbiati F, Bini V, Casti A, Caruso D, Devoto P, et al. Targeting neurosteroid synthesis as a therapy for schizophrenia-related alterations induced by early psychosocial stress. Schizophr Res. 2015;168:640–8.CrossRefGoogle Scholar
  41. 41.
    Mladenović D, Hrnčić D, Petronijević N, Jevtić G, Radosavljević T, Rašić-Marković A, et al. Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2014;307:G931–40.CrossRefGoogle Scholar
  42. 42.
    Mladenović D, Petronijević N, Stojković T, Velimirović M, Jevtić G, Hrnčić D, et al. Finasteride has regionally different effects on brain oxidative stress and acetylcholinesterase activity in acute thioacetamide-induced hepatic encephalopathy in rats. PLoS One. 2015;10:1–14.CrossRefGoogle Scholar
  43. 43.
    Litim N, Bourque M, Al Sweidi S, Morissette M, Di Paolo T. The 5α-reductase inhibitor Dutasteride but not Finasteride protects dopamine neurons in the MPTP mouse model of Parkinson’s disease. Neuropharmacology. 2015;97:86–94.CrossRefGoogle Scholar
  44. 44.
    Feng Y, Weijdegård B, Wang T, Egecioglu E, Fernandez-Rodriguez J, Huhtaniemi I, et al. Spatiotemporal expression of androgen receptors in the female rat brain during the oestrous cycle and the impact of exogenous androgen administration: a comparison with gonadally intact males. Mol Cell Endocrinol. 2010;321:161–74.CrossRefGoogle Scholar
  45. 45.
    Kritzer M. The distribution of immunoreactivity for intracellular androgen receptors in the cerebral cortex of hormonally intact adult male and female rats: localization in pyramidal neurons making corticocortical connections. Cereb Cortex. 2004;14:268–80.CrossRefGoogle Scholar
  46. 46.
    Li X, Bertics PJ, Karavolas HJ. Regional distribution of cytosolic and particulate 5alpha-dihydroprogesterone 3alpha-hydroxysteroid oxidoreductases in female rat brain. J Steroid Biochem Mol Biol. 1997;60:311–8.CrossRefGoogle Scholar
  47. 47.
    Frye CA, McCormick CM. Androgens are neuroprotective in the dentate gyrus of adrenalectomized female rats. Stress. 2000;3:185–94.CrossRefGoogle Scholar
  48. 48.
    Gormley GJ, Stoner E, Bruskewitz RC, Imperato-Mcginley J, Walsh PC, JD MC, et al. The effect of finasteride in men with benign prostatic hyperplasia. J Urol. 2002;167:1102–7.CrossRefGoogle Scholar
  49. 49.
    Roberts JL, Fiedler V, Imperato-McGinley J, Whiting D, Olsen E, Shupack J, et al. Clinical dose ranging studies with finasteride, a type 2 5alpha-reductase inhibitor, in men with male pattern hair loss. J Am Acad Dermatol. 1999;41:555–63.PubMedGoogle Scholar
  50. 50.
    Leyden J, Dunlap F, Miller B, Winters P, Lebwohl M, Hecker D, et al. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol. 1999;40:930–7.CrossRefGoogle Scholar
  51. 51.
    Irwig MS. Persistent sexual side effects of finasteride: could they be permanent? J Sex Med. 2012;9:2927–32.CrossRefGoogle Scholar
  52. 52.
    Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A. Finasteride induced depression: a prospective study. BMC Clin Pharmacol. 2006;6:7.CrossRefGoogle Scholar
  53. 53.
    Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012;73:1220–3.CrossRefGoogle Scholar
  54. 54.
    Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215–24.CrossRefGoogle Scholar
  55. 55.
    Theoret MR, Ning YM, Zhang JJ, Justice R, Keegan P, Pazdur R. The risks and benefits of 5α-reductase inhibitors for prostate-cancer prevention. N Engl J Med. 2011;365:97–9.CrossRefGoogle Scholar
  56. 56.
    Thompson IM Jr, Goodman PJ, Tangen CM, Parnes HL, Minasian LM, Godley PA, et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med. 2013;369:603–10.CrossRefGoogle Scholar
  57. 57.
    Kumazaki M, Ando H, Ushijima K, Maekawa T, Motosugi Y, Takada M, et al. Influence of dosing time on the efficacy and safety of finasteride in rats. J Pharmacol Exp Ther. 2011;338:718–23.CrossRefGoogle Scholar
  58. 58.
    Back T, Hemmen T, Schüler OG. Lesion evolution in cerebral ischemia. J Neurol. 2004;251:388–97.CrossRefGoogle Scholar
  59. 59.
    Do Rego JL, Seong JY, Burel D, Leprince J, Luu-The V, Tsutsui K, et al. Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front Neuroendocrinol. 2009;30:259–301.CrossRefGoogle Scholar
  60. 60.
    Liu A, Margaill I, Zhang S, Labombarda F, Coqueran B, Delespierre B, et al. Progesterone receptors: a key for neuroprotection in experimental stroke. Endocrinology. 2012;153:3747–57.CrossRefGoogle Scholar
  61. 61.
    Ma YL, Qin P, Li Y, Shen L, Wang SQ, Dong HL, et al. The effects of different doses of estradiol (E2) on cerebral ischemia in an in vitro model of oxygen and glucose deprivation and reperfusion and in a rat model of middle carotid artery occlusion. BMC Neurosci. 2013;14:118.CrossRefGoogle Scholar
  62. 62.
    Carpenter RS, Iwuchukwu I, Hinkson CL, Reitz S, Lee W, Kukino A, et al. High-dose estrogen treatment at reperfusion reduces lesion volume and accelerates recovery of sensorimotor function after experimental ischemic stroke. Brain Res. 2016;1639:200–13.CrossRefGoogle Scholar
  63. 63.
    Soskić V, Klemm M, Proikas-Cezanne T, Schwall GP, Poznanović S, Stegmann W, et al. A connection between the mitochondrial permeability transition pore, autophagy, and cerebral amyloidogenesis. J Proteome Res. 2008;7:2262–9.CrossRefGoogle Scholar
  64. 64.
    Albers GW, Goldstein LB, Hess DC, Wechsler LR, Furie KL, Gorelick PB, et al. Stroke treatment academic industry roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke. 2011;42:2645–50.CrossRefGoogle Scholar
  65. 65.
    Samba Reddy D, Ramanathan G. Finasteride inhibits the disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis. Epilepsy Behav. 2012;25:92–7.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Mechanobiology Laboratory, Nagoya University Graduate School of MedicineNagoyaJapan
  2. 2.R-PharmMoscowRussia

Personalised recommendations