Repurposing sex steroids and related drugs as potential treatment for Parkinson's disease

Bourque, Mélanie; Morissette, Marc; Paolo, Thérèse Di

doi:10.1016/j.neuropharm.2018.04.005

Cited by 52 publications

(55 citation statements)

References 191 publications

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“…However, because of their wide distribution and strong impact throughout the body systems, steroids are difficult to control and thus result in significant side effects. Studies are numerous on its dysfunction [1,2] and its influence on growth [3], cancer [4], neuroendocrinology [5,6], Alzheimers disease [7], and Parkinson's disease [8].…”

Section: Introductionmentioning

confidence: 99%

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Schaper¹

2020

Preprint

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Steroid hormones, such as cortisol, testosterone and estrogen, have powerful control over human physiology, growth, and reproduction, but efforts to deploy its potential, such as with glucocorticoids, a first-line defense of inflammation, are often met with severe side effects. Unfortunately, much is unknown about the basic interaction of steroid molecules with DNA, including its receptors, activators, factors, and the gene transcription procedure. In this research article, a remarkable finding is shown for the first time, in which it is illustrated through structural analysis that the base pairings of the four DNA nucleotides, adenine with thymine (A-T) and cytosine with guanine (C-G), form perfectly the classic four ring structure of the steroid molecule, which indicates the profound result put forth in this article that steroid molecules bind directly to DNA for the purpose of gene transcription. Further, critical to a basic understanding of DNA, it is resolved here of the location of the unusual ``missing" hydrogen bond of the A-T and T-A pairings, which has only two internal hydrogen bonds whereas C-G and G-C have three hydrogen bonds. It is shown that the third hydrogen bond for A-T and T-A is formed when the A-T and T-A nucleotides are coupled with corticosteroids, such as cortisol, which has an oxygen functional group that is perfectly positioned to form a hydrogen bond with the accessible oxygen-based functional group of thymine. In addition, to facilitate the binding process, it is shown that Ca$^{2+}$ ions, which are associated with the ligand binding domain of the steroid receptor prior to its association with DNA, couple the oxygen-based functional groups at each end of the steroid molecule with the PO$_4^-$ ions of adjacent nucleotides and thus bind the steroid molecule directly to the nucleic acid. Additionally, the basis of initiating the transcription process is described in which the energy stabilization due to the binding of the ion-steroid complex to DNA is dissipated through the DNA molecule to initiate strand separation locally by increasing the length of hydrogen bonds, thus allowing RNA polymerase action. The results are further amplified by analysis of the cortisol hormone and the ligand binding domain of the glucocorticoid receptor in its interaction with the A-T nucleotide pairing.

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Section: Introductionmentioning

confidence: 99%

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Schaper¹

2020

Preprint

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“…Furthermore, prospective and casecontrol studies have demonstrated that estrogen mitigates PD symptoms in women (Blanchet et al, 1999;Tsang et al, 2000). Most epidemiological studies evaluating exogenous estrogen use and risk of PD among women showed decreased risk (Dye et al, 2012;Bourque et al, 2019). However, efficacy of estrogen therapy in PD has been debated in light of detrimental peripheral side effects, such as stroke and breast cancer (Rossouw et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Female Sex and Brain-Selective Estrogen Benefit α-Synuclein Tetramerization and the PD-like Motor Syndrome in 3K Transgenic Mice

et al. 2019

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Many studies report a higher risk for Parkinson's disease (PD) and younger age of onset in men. This, and the fact that the neuropathological process underlying PD symptoms may begin before menopause, suggests that estrogen-based hormone therapy could modify this higher risk in males. However, the effects of female sex or estrogen on ␣-synuclein (␣S) homeostasis and related PD neuropathology remain unknown. Here, we used an ␣S tetramer-abrogating mouse model of PD (3K) that amplifies the familial E46K PD mutation to investigate the effects of female sex and brain-selective estrogen treatment on ␣S tetramerization and solubility, formation of vesicle-rich ␣S ϩ aggregates, dopaminergic and cortical fiber integrity, and associated motor deficits. In male 3K mice, the motor phenotype became apparent at ϳ10 weeks and increased to age 6 months, paralleled by PD-like neuropathology, whereas 3K females showed a significant delay in onset. At 6 months, this beneficial phenotypic effect in 3K females was associated with a higher ␣S tetramer-to-monomer ratio and less decrease in dopaminergic and cortical fiber length and quantity. Brain-selective estrogen treatment in symptomatic 3K mice significantly increased the tetramer-to-monomer ratio, turnover by autophagy of aggregate-prone monomers, and neurite complexity of surviving DAergic and cortical neurons, in parallel with benefits in motor performance. Our findings support an upstream role for ␣S tetramer loss in PD phenotypes and a role for estrogen in mitigating PD-like neuropathology in vivo. Brain-selective estrogen therapy may be useful in delaying or reducing PD symptoms in men and postmenopausal women.

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“…17,18 E 2 receptors α and β (ERα and ERβ) are ligand-activated transcription factors able to reduce mitochondrial ROS production and increase oxidative phosphorylation, 19,20 leading to substantial interest in the potential clinical use of selective ERα or ERβ agonists in postmenopausal women 22 or in the context of neurodegenerative disorders. 23,24 ERα and ERβ are expressed in the central and peripheral nervous system. In the brain cortex, ERα mediates neuroprotection during hypoxic/ischemic insults.…”

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confidence: 99%

Roles of oestradiol receptor alpha and beta against hypertension and brain mitochondrial dysfunction under intermittent hypoxia in female rats

et al. 2019

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Aim Chronic intermittent hypoxia (CIH) induces systemic (hypertension) and central alterations (mitochondrial dysfunction underlying cognitive deficits). We hypothesized that agonists of oestradiol receptors (ER) α and β prevent CIH‐induced hypertension and brain mitochondrial dysfunction. Methods Ovariectomized female rats were implanted with osmotic pumps delivering vehicle (Veh), the ERα agonist propylpyraoletriol (PPT — 30 μg/kg/day) or the ERβ agonist diarylpropionitril (DPN — 100 μg/kg/day). Animals were exposed to CIH (21%‐10% FIO2 — 10 cycles/hour – 8 hours/day – 7 days) or normoxia. Arterial blood pressure was measured after CIH or normoxia exposures. Mitochondrial respiration and H2O2 production were measured in brain cortex with high‐resolution respirometry, as well as activity of complex I and IV of the electron transport chain, citrate synthase, pyruvate, and lactate dehydrogenase (PDH and LDH). Results Propylpyraoletriol but not DPN prevented the rise of arterial pressure induced by CIH. CIH exposures decreased O2 consumption, complex I activity, and increased H2O2 production. CIH had no effect on citrate synthase activity, but decreased PDH activity and increased LDH activity indicating higher anaerobic glycolysis. Propylpyraoletriol and DPN treatments prevented all these alterations. Conclusions We conclude that in OVX female rats, the ERα agonist prevents from CIH‐induced hypertension while both ERα and ERβ agonists prevent the brain mitochondrial dysfunction and metabolic switch induced by CIH. These findings may have implications for menopausal women suffering of sleep apnoea regarding hormonal therapy.

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Repurposing sex steroids and related drugs as potential treatment for Parkinson's disease

Cited by 52 publications

References 191 publications

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Female Sex and Brain-Selective Estrogen Benefit α-Synuclein Tetramerization and the PD-like Motor Syndrome in 3K Transgenic Mice

Roles of oestradiol receptor alpha and beta against hypertension and brain mitochondrial dysfunction under intermittent hypoxia in female rats

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