Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson’s Disease Models

Abstract

Gastrointestinal disorders in Parkinson’s disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.

Three-Dimensional Analysis of Sex- and Gonadal Status- Dependent Microglial Activation in a Mouse Model of Parkinson’s Disease

“…In the present study, MPTP caused a loss of striatal TH + intensity in vehicle-treated SHAM male mice compared to the control group. As we reported previously, DUT exerts a protective effect against MPTP toxicity on DA neurons in non-gonadectomized male mice when administered before the lesion [ 55 , 65 , 67 , 68 ]. In GDX males, MPTP caused a decrease of TH intensity, and DUT did not show a protective effect.…”

LHFPL2 Serves as a Potential Biomarker for M2 Polarization of Macrophages in Renal Cell Carcinoma

“…For instance, Olaparib can reprogram TAMs, enhancing their cytotoxicity and phagocytic activity [ 47 ]. Avodart treatment can inhibit the increase in pro-inflammatory macrophage density [ 48 ]. Azelastine can inhibit macrophage chemotaxis and phagocytic activity in vitro [ 49 ].…”

Oral dutasteride is a first‐line treatment for frontal fibrosing alopecia

“…Lastly, dutasteride have shown immunomodulatory effects in vitro. It inhibits the recruitment and polarization of macrophages, reduces the production of proinflammatory cytokines IL‐1beta and IL‐6, and inhibits the cellular production of oxidative stress (ROS) 6 . In any of the previous scenarios, and according to the clinical evidence, the route of administration of dutasteride must be oral in order to have a systemic effect and be effective in FFA.…”