Raloxifene and progesterone neuroprotection in a female mouse model of Parkinson’s disease

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Abstract
Introduction: Parkinson’s disease (PD) main pathological feature involves degeneration of dopamine (DA) neurons in the brain substantia nigra (SN). Female gonadal steroids are shown to be neuroprotective in animal models of PD and tested mainly in male and less in female animals. Since most women with PD are in menopause the present study tested ovariectomized (OVX) female mice as a model of the hormonal condition of menopause. This study sought the neuroprotective effect of the selective estrogen receptor modulator (SERM) raloxifene and progesterone alone and in combination to protect DA neurons in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-lesioned mice as a model of PD. Methods: Mice were treated with vehicle, raloxifene (2.5 mg/kg, b.i.d., subcutaneous), progesterone (1 μg, b.i.d., subcutaneous) and their combination for 10 days and administered MPTP (5.5 mg/kg, intraperitoneal) or saline on the 5th day; brains and uteri were collected thereafter. Results: Raloxifene treatment led to only small increases in uterine weights less than an average of intact mice uterine weights and no effect of progesterone. OVX MPTP-lesioned female mice showed a loss of striatal DA and metabolites content similarly prevented by treatments with raloxifene, progesterone and their combination. By contrast, striatal serotonin and metabolite remained unchanged. Striatal glial fibrillary acidic protein (GFAP), an astrogliosis marker, levels were elevated in MPTP-lesioned mice and this was similarly prevented with the hormonal treatment alone or in combination. Conclusion: Raloxifene and progesterone treatment was neuroprotective without excessive uterine stimulation in OVX mice supporting repurposing of these drugs for PD and their high translational value.

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