Effect of sex and gonadectomy on brain MPTP toxicity and response to dutasteride treatment in mice

Isenbrandt, Amandine; Morissette, Marc; Bourque, Mélanie; Lamontagne‐Proulx, Jérôme; Coulombe, Katherine; Soulet, Denis; Paolo, Thérèse Di

doi:10.1016/j.neuropharm.2021.108784

Cited by 14 publications

(27 citation statements)

References 91 publications

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“…Six-to eight-week-old male C57BL/6 mice were purchased from Hunan Sja Laboratory Animal Co., Ltd. Male mice were selected to rule out the neuroprotective activities of estrogens, progesterone and certain other neuroactive steroids on mesencephalic DA neurons (Isenbrandt et al, 2021). The animals were fed in a controlled environment and provided standard rodent chow and water.…”

Section: Animals and Treatmentmentioning

confidence: 99%

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

Huang

Yan

et al. 2021

Front. Neurosci.

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Parkinson’s disease is a neurodegenerative disorder with an inflammatory response as the core pathogenic mechanism. Previous human genetics findings support the view that the loss of TREM2 function will aggravate neurodegeneration, and TREM2 is one of the most highly expressed receptors in microglia. However, the role of TREM2 in the inflammatory mechanism of PD is not clear. In our study, it was found both in vivo and in vitro that the activation of microglia not only promoted the secretion of inflammatory factors but also decreased the level of TREM2 and inhibited the occurrence of autophagy. In contrast, an increase in the level of TREM2 decreased the expression of inflammatory factors and enhanced the level of autophagy through the p38 MAPK/mTOR pathway. Moreover, increased TREM2 expression significantly decreased the apoptosis of dopaminergic (DA) neurons and improved the motor ability of PD mice. In summary, TREM2 is an important link between the pathogenesis of PD and inflammation. Our study provides a new view for the mechanism of TREM2 in PD and reveals TREM2 as a potential therapeutic target for PD.

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Section: Animals and Treatmentmentioning

confidence: 99%

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

Huang

Yan

et al. 2021

Front. Neurosci.

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“…Recently, a study with a Mendelian randomization approach showed that the later onset of menopause was associated with lowering PD risk in women, highlighting again the potential neuroprotective role of sex hormones and other factors related to the menopausal state [ 51 ]. Sex differences have already been reported for 6-hydroxydopamine (6-OHDA) [ 52 , 53 ] and MPTP [ 53 , 54 , 55 ] animal models of PD with protection in females.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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Parkinson’s disease (PD) is characterized by neurodegeneration and neuroinflammation. PD prevalence and incidence are higher in men than in women and modulation of gonadal hormones could have an impact on the disease course. This was investigated in male and female gonadectomized (GDX) and SHAM operated (SHAM) mice. Dutasteride (DUT), a 5α-reductase inhibitor, was administered to these mice for 10 days to modulate their gonadal sex hormones. On the fifth day of DUT treatment, mice received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model PD. We have previously shown in these mice the toxic effect of MPTP in SHAM and GDX males and in GDX females on dopamine markers and astrogliosis whereas SHAM females were protected by their female sex hormones. In SHAM males, DUT protected against MPTP toxicity. In the present study, microglial density and the number of doublets, representative of a microglial proliferation, were increased by the MPTP lesion only in male mice and prevented by DUT in SHAM males. A three-dimensional morphological microglial analysis showed that MPTP changed microglial morphology from quiescent to activated only in male mice and was not prevented by DUT. In conclusion, microgliosis can be modulated by sex hormone-dependent and independent factors in a mice model of PD.

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“…In the MPTP mouse model, higher brain neurotoxicity was observed in male than female mice, suggesting that estrogen levels influence susceptibility to the toxin (Miller et al, 1998;Isenbrandt et al, 2021). Other studies have also shown a beneficial therapeutic effect of female sex steroids on CNS-damaged DA neurons in MPTP mice (Bourque et al, 2013;Bourque et al, 2014;Bourque et al, 2015;Bourque et al, 2016;Isenbrandt et al, 2021;Thadathil et al, 2021). In addition to its neuroprotective role, there is evidence that estrogen is also involved in the regulation of the immune system (Kovats, 2015).…”

Section: Introductionmentioning

confidence: 98%

“…It has been suggested that estrogen could be used as a neuroprotective agent since hormonal therapies have been associated with a decreased risk of PD (Song et al, 2020). In the MPTP mouse model, higher brain neurotoxicity was observed in male than female mice, suggesting that estrogen levels influence susceptibility to the toxin (Miller et al, 1998;Isenbrandt et al, 2021). Other studies have also shown a beneficial therapeutic effect of female sex steroids on CNS-damaged DA neurons in MPTP mice (Bourque et al, 2013;Bourque et al, 2014;Bourque et al, 2015;Bourque et al, 2016;Isenbrandt et al, 2021;Thadathil et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Of great interest, in MPTP-treated animals, Isenbrandt et al have shown that the dutasteride-mediated neuroprotection observed in sham male mice was not seen in gonadectomized male mice. Thus, the 5α-reductase inhibition may require the presence of sex hormones to be neuroprotective (Isenbrandt et al, 2021). Interestingly, a report by Soskić et al (2008) suggested an association between mitochondrial functions and neuroprotection against calcium overload by finasteride and dutasteride.…”

Section: Introductionmentioning

confidence: 99%

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

Poirier

Côté²,

Jarras³

et al. 2022

Front. Pharmacol.

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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.

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Effect of sex and gonadectomy on brain MPTP toxicity and response to dutasteride treatment in mice

Cited by 14 publications

References 91 publications

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

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

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

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