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

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.

Physiopathological role of the enzymatic complex 5α-reductase and 3α/β-hydroxysteroid oxidoreductase in the generation of progesterone and testosterone neuroactive metabolites

“…Inhibitors of 5α-R have been reported to exert male-specific neuroprotective effects in experimental models of neurodegenerative diseases in rodents, like dutasteride in an experimental model of PD (Litim et al, 2015;Litim et al, 2017) or finasteride in ischemic brain injury induced in aged rats (Tanaka et al, 2019). These male-specific effects of 5α-R inhibition are in agreement with the previously discussed sex differences in the neuroprotective actions of PROG and T reduced metabolites.…”

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage

“…The swimming path, frequency of platform crossings, latency of first platform crossing, and frequency of correct quadrant crossings were recorded with a camera and linked to a computer tracking system (Noldus Ethovision, WA, USA). We also utilized the rotarod test to assess sensorimotor coordination and balance [29,30]. The speed of a cylinder was slowly increased from 4 to 40 rpm over 5 min.…”

Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE

“…The Rotarod test was performed by placing the rat pups on a rotating horizontal rod (Columbus Instruments Rotamex, USA), then the times were recorded when the rats fell. The rotation speed started from 5 or 10 rpm separately and accelerated 2 rpm every 5 s. The maximum testing time was 60 s, and any times exceeding 60 s were recorded as 60 s [42].…”