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Cited by 10Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeuroinflammation and Neurodegeneration Mechanisms

Systemically circulating 17β-estradiol enhances the neuroprotective effect of the smoking cessation drug cytisine in female parkinsonian mice

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Zarate, Sara M., Garcia, Roger C., Pandey, Gauri, Srinivasan, Rahul·2025·npj Parkinson's Disease
DOI 10.1038/s41531-024-00855-3PMC PMC11698717
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Abstract

The smoking cessation drug cytisine exerts neuroprotection in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons of female but not male 6-hydroxydopamine (6-OHDA) lesioned parkinsonian mice. To address the important question of whether circulating 17β-estradiol mediates this effect, we employ two mouse models aimed at depleting systemically circulating 17β-estradiol: (i) bilateral ovariectomy (OVX), and (ii) aromatase inhibition with systemically administered letrozole. In both models, depleting systemically circulating 17β-estradiol in female 6-OHDA lesioned parkinsonian mice results in the loss of cytisine-mediated neuroprotection as measured using apomorphine-induced contralateral rotations and SNc DA neurodegeneration. Our experiments also reveal that OVX alone exerts neuroprotection in SNc DA neurons due to compensatory changes not observed in the letrozole model, which underscores the importance of using independent models of 17β-estradiol depletion to study neuroprotection. Taken together, our findings suggest that the smoking cessation drug cytisine is a viable neuroprotective drug for pre-menopausal women with Parkinson's disease.

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  • After unilateral loss of SNc DA neurons, apomorphine activates hypersensitive postsynaptic D1 and D2 dopamine receptors in MSNs within the DLS on the SNc damaged side, resulting in apomorphine-induced contralateral rotations.

    “A known postsynaptic mechanism is that after unilateral loss of SNc DA neurons, apomorphine activates hypersensitive postsynaptic D1 and D2 dopamine postsynaptic receptors in MSNs within the DLS on the SNc damaged side, which results in apomorphine-induced contralateral rotations (Zarate et al. 2025).”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Zarate et al. 2025

    The Discussion (page unavailable) says apomorphine-induced rotations arise from activation of hypersensitive dopamine receptors in striatal medium spiny neurons after a unilateral lesion, and it specifically discusses D1 receptors and contralateral rotations. The Methods identify the lesion site as the DLS. Our copy does not identify D2 receptors as part of this mechanism, so that specificity is unsupported. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Unilateral damage to the SNc can cause contralateral rotations in mice via postsynaptic and/or presynaptic mechanisms.

    “unilateral damage to the SNc can cause contralateral rotations in mice via postsynaptic and/or presynaptic mechanisms.”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Zarate et al. 2025

    The Results report increased rotations after unilateral striatal 6-OHDA lesions, and the Discussion links the rotations to SNc dopamine-neuron loss and describes both striatal receptor sensitivity and dopamine release as influences. However, the measured rotations were induced by apomorphine, and the lesion was made in the striatum, not directly in the SNc; the claim omits those conditions. The supplied passages and indexed results give section labels but no page numbers. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Spontaneous and apomorphine-induced rotational assays detect imbalances in dopamine release and/or changes in dopamine receptor sensitivity in the striatum, leading to contralateral rotational behavior.

    “Spontaneous and apomorphine-induced rotational assays detect imbalances in dopamine release and/or changes in dopamine receptor sensitivity in the striatum, leading to abnormal rotational behavior in mice in a direction that is contralateral to the side with either excessive striatal dopamine release and/or abnormally increased postsynaptic D1 and D2 dopamine receptor activation (Zarate et al. 202”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Zarate et al. 2025

    The Discussion (page unavailable) links apomorphine-induced contralateral rotations to activation of hypersensitive striatal dopamine receptors and describes a possible contribution from dopamine release and D1 activation on the lesioned side. The Methods (page unavailable) describe an apomorphine-induced assay, but the copy does not establish the claim about spontaneous rotations or specifically implicate D2 activation. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Zarate, S. M., Garcia, R. C., Pandey, G., & Srinivasan, R.
Affiliations
Texas A&M University (US)
Corresponding author
Srinivasan, Rahul
ORCID
Srinivasan, Rahul
Venue
npj Parkinson's Disease
Publisher
Springer Science and Business Media LLC
Published
2025-01-03
Volume
11
Issue
1
Pages
6-6
ISSN
2373-8057 (ISSN-L)
DOI
10.1038/s41531-024-00855-3
PMC
PMC11698717
OpenAlex
W4406026626
Cited by
10
References
3
Citations by year
2026: 9 · 2025: 1
FWCI
5.49
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Parkinson s Disease (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS115809)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
estradiol, cytisine, Parkinson's disease, neuroprotection, substantia nigra pars compacta, dopaminergic neurons, 6-hydroxydopamine lesion, ovariectomy, letrozole, aromatase inhibition, sex differences, smoking cessation drugs, premenopausal women

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