Available online 25 April 2024, 101136

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Progesterone and other sex hormones show potential in repairing nerve coverings and preserving nerve health.

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Nestorone®, a progestin closely related to progesterone, has shown brain protective and injury healing effects in animals.

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Nestorone holds promise as a supplementary treatment for multiple sclerosis, stroke and amyotrophic lateral sclerosis.

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Further research is needed to translate Nestorone from the laboratory to the clinic.

Abstract

Nestorone® (segesterone acetate) is a progestin with a chemical structure closely related to progesterone with high affinity and selectivity for the progesterone receptor without significant interaction with other steroid receptors. It has been developed for female and male contraception and is FDA-approved in a first long-acting contraceptive vaginal system for female contraception. Its safety has been extensively demonstrated in both preclinical and clinical studies for contraceptive indications. Nestorone was found to display neuroprotective and neuroregenerative activity in animal models of various central nervous system diseases, including multiple sclerosis, stroke, and amyotrophic lateral sclerosis. Reviewed herein are neuroprotective and myelin- regenerating properties of Nestorone in various animal models and its translational potential as a therapeutic agent for debilitating neurological diseases for which limited therapeutic options are available (Table 1).

Section snippetsSex hormones as neuroactive steroids

Several steroidal sex hormones have shown the ability to regenerate myelin in experimental animal models, most notably progesterone (PROG), estradiol (E2) and testosterone (T). In addition to their reproductive functionality, PROG, E2 and T can play a significant role throughout the central nervous system and exhibit significant neuroprotective efficacy against neurological disorders (Garcia-Ovejero et al., 2014, Berent-Spillson et al., 2015).

Both PROG and its primary active metabolite,

NES as a possible adjunct treatment for MS

MS is an inflammatory autoimmune disorder of the CNS that causes axonal damage, intermittent or chronic demyelination, astrogliosis and neurodegeneration (Ellwardt and Zipp, 2014, Maitin and Cruz, 2018, Fox et al., 2019, Lublin et al., 2020; and Ahn et al., 2021). MS is statistically the most common chronic inflammatory disease of the CNS, mainly affecting young adults between 20 and 40years old (Friese et al., 2014). MS is three times more prevalent in women than in men, and in older

Stroke

Stroke is the second leading cause of death globally (Katan and Luft, 2018) and creates a significant global health and economic burden (Benjamin et al., 2017). In the United States on average, a new victim suffers a stroke every 40 s, and stroke claims a life about every four minutes (Benjamin et al., 2017). Survivors of stroke are often left with long-term disability and few treatment options (Leng and Xiong, 2019). Also known as a cerebrovascular accident, stroke can be caused by a number of

Amyotrophic Lateral Sclerosis (ALS)

Motor neuron diseases comprise the group of neurodegenerative disorders that involve the progressive breakdown of motor neuron cells (Mitchell and Borasio, 2007). The most common and well-known of this group is ALS, sometimes used interchangeably with Lou Gehrig’s disease. After Alzheimer’s and Parkinson’s disease, ALS is the third most common neurodegenerative disease (Renton et al., 2014). Common symptoms include muscle weakness, muscle spasms, muscle atrophy, loss of voluntary movement, and

Mechanism of action of Nestorone- synopsis

In summary, the mechanism of action of Nestorone in the brain and central nervous system has been determined in different models both in vitro and in vivo, and several mechanisms have been identified. The main pathways include: 1. Chronic exposure of NES as a single agent or in combination with E2 stimulates neurogenesis and promotes the generation of OPCs in adult female mouse brains by upregulating the IGF-1 signaling pathway, which is involved in neuronal maturation, positioning and

Translational implications

Because NES is already approved by the FDA for use in humans (approved in a contraceptive vaginal system), studies can focus on the efficacy of the drug in several indications and on the ideal dose that balances side effects while maximizing healing. This may shorten the development process, at least for the first indication such as MS, compared to a new molecular entity with no prior FDA clearance or approval. Moving forward to transitioning NES as a neuroprotective drug in human patients,

Conclusion

Nestorone (segesterone acetate), a progesterone receptor agonist, with high specificity, exerts remyelinating and neuroprotective properties in experimental models. NES appears as a promising therapeutic with substantial preclinical, translational, and clinical data to support clinical studies to optimize dosage and mode of administration for neurological disorders. Optimizing clinical parameters will advance NES as a safe and potentially efficacious therapy for debilitating diseases such as

Uncited references

Bassani et al., 2022, Klistorner and Barnett, 2021, MacKenzie-Graham et al., 2018, Mallon et al., 2002, Sicotte et al., 2007, Singh et al., 2013, Stanczyk et al., 2013, Yuan et al., 2015.

CRediT authorship contribution statement

Regine Sitruk-Ware: Writing – review & editing, Writing – original draft, Conceptualization. Heather Sussman: Writing – review & editing. Roberta Brinton: Writing – review & editing. Michael Schumacher: Writing – review & editing. Patrick Singer: Writing – review & editing. Narender Kumar: Writing – review & editing. Alejandro F. De Nicola: Writing – review & editing. Martine El-Etr: Writing – review & editing. Rachida Guennoun: Writing – review & editing. Cesar V Borlongan: Writing – review &

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References (136)M. El-Etr et al.Hormonal influences in multiple sclerosis: New therapeutic benefits for steroids

Maturitas.

(2011)

E. Ellwardt et al.Molecular mechanisms linking neuroinflammation and neurodegeneration in MS

Experim. Neurol.

(2014)

H.C. Emsley et al.An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis

J. Neuroimmunol.

(2003)

M. Fréchou et al.Intranasal delivery of progesterone after transient ischemic stroke decreases mortality and provides neuroprotection

Neuropharmacology.

(2015)

M. Fréchou et al.Dose-dependent and long-term cerebroprotective effects of intranasal delivery of progesterone after ischemic stroke in male mice

Neuropharmacology

(2020)

L. Garay et al.Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis

J Steroid Biochem Mol Biol.

(2007)

L. Garay et al.Efficacy of the selective progesterone recptor agonist Nestorone for chronic experimental autoimmune encephalomyelitis

J. Neuroimmunol.

(2014)

K. Gemzell-Danielsson et al.Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation

Contraception.

(2019)

F. Gofflot et al.Systematic gene expression mapping clusters nuclear receptors according to their function in the brain

Cell.

(2007)

R. Guennoun et al.Intranasal administration of progesterone: A potential efficient route of delivery for cerebroprotection after acute brain injuries

Neuropharmacology

(2019)

C. Ibanez et al.Steroids and the reversal of age-associated changes in myelination and remyelination

Prog. Neurobiol.

(2003)

M. Jarahi et al.Effects of progesterone on neuropathic pain responses in an experimental animal model for peripheral neuropathy in the rat: a behavioral and electrophysiological study

Neuroscience.

(2014)

N. Kumar et al.Nestorone®: a progestin with a unique pharmacological profile

Steroids.

(2000)

F. Labombarda et al.Progesterone attenuates astro- and microgliosis and enhance oligodendrocyte differentiation following spinal cord injury

Exp. Neurol.

(2011)

F. Labombarda et al.A functional progesterone receptor is required for immunomodulation, reduction of reactive gliosis and survival of oligodendrocyte precursors in the injured spinal cord

J. Steroid Biochem. Mol. Biol.

(2015)

P. McGoldrick et al.Rodent models of amyotrophic lateral sclerosis

Biochim. Biophys. Acta. Mol. Basis. Dis.

(2013)

S.L. Mehta et al.Molecular targets in cerebral ischemia for developing novel therapeutics

Brain. Res. Rev.

(2007)

M. Meyer et al.The progesterone receptor agonist Nestorone holds back proinflammatory mediators and neuropathology in the Wobbler mouse model of motoneuron degeneration

Neuroscience.

(2015)

W. OelkersDrospirenone, a progestogen with antimineralocorticoid properties: a short review

Mol. Cell Endocrinol.

(2004)

P.V. Prasad et al.Single-dose pharmacokinetics of Nestorone, a potential female contraceptive

Steroids

(2010 Mar)

M. Abu-Rub et al.Emerging cellular and molecular strategies for enhancing central nervous system (CNS) remyelination

Brain Sci.

(2018)

O. Adeoye et al.Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years

Stroke.

(2011)

R. Aggarwal et al.Neuroprotective effect of progesterone on acute phase changes induced by partial global cerebral ischemia in mice

J. Pharm. Pharmacol.

(2008)

Ahn J.J., Abu-Rub M., Miller R.H, 2021. B Cells in Neuroinflammation: New Perspectives and Mechanistic Insights. Cells....B.D. Anawalt et al.Combined Nestorone-testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men

Andrology.

(2019)

L.E. Baldassari et al.Developing therapeutic strategies to promote myelin repair in multiple sclerosis

Expert Rev Neurother.

(2019 Jun)

L. Baldassari et al.Therapeutic Advances and Challenges in the Treatment of Progressive Multiple Sclerosis

Drugs.

(2018)

Bassani, T.B., Bartolomeo, C.S., Oliveira, R.B., Ureshino, R.P., 2022. Progestogen-Mediated Neuroprotection in Central...Bebo, B.F. Jr, Fyfe-Johnson, A., Adlard, K., Beam, A.G., Vandenbark, A.A., Offner, H, 2001. Low-dose estrogen therapy...E.J. Benjamin et al.Heart disease and stroke statistics-2017 update: A report from the American Heart Association

Circulation.

(2017)

E.J. Calabrese et al.How does hormesis impact biology, toxicology, and medicine?

NPJ Aging Mech Dis.

(2017)

A. Chamorro et al.The immunology of acute stroke

Nat. Rev. Neurol.

(2012)

S. Chen et al.Therapeutic progestin segesterone acetate promotes neurogenesis: implications for sustaining regeneration in female brain

Menopause.

(2018)

Cho, H., Shukla, S, 2020. Role of Edaravone as a Treatment Option for Patients with Amyotrophic Lateral Sclerosis....C. Confavreux et al.Rate of pregnancy- related relapse in multiple sclerosis

New England J. Med.

(1998)

Costamagna, G., Bonato, S., Corti, .S, Meneri, M, 2023. Advancing Stroke Research on Cerebral Thrombi with Omic...Cunniffe, N., Coles, A, 2021. Promoting remyelination in multiple sclerosis. J. Neurol. 2021 Jan;268(1):30-44. doi:...De Nicola, A.F., Garay, L.I., Meyer, M., Guennoun, R., Sitruk-Ware, R., Schumacher, M., Gonzalez Deniselle, M.C., 2018....De Nicola, A.F., Meyer, M., Garay, L., Kruse, M.S., Schumacher, M., Guennoun, R., Gonzalez Deniselle, M.C, 2022....Douvaras, P., Wang, J., Zimmer, M., Hanchuk, S., O'Bara, M.A., Sadiq, S., Sim, F.J., Goldman, J., Fossati, V, 2014....View full text

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