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

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Abstract

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.

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Acknowledgements

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.

Funding

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

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Authors and Affiliations

  1. Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan

    Motoki Tanaka, Takunori Ogaeri & Masahiro Sokabe

  2. R-Pharm, Moscow, 123317, Russia

    Mikhail Samsonov

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  1. Motoki Tanaka
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  2. Takunori Ogaeri
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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.

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Tanaka, M., Ogaeri, T., Samsonov, M. et al. The 5α-Reductase Inhibitor Finasteride Exerts Neuroprotection Against Ischemic Brain Injury in Aged Male Rats. Transl. Stroke Res. 10, 67–77 (2019). https://doi.org/10.1007/s12975-018-0624-0

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