Progress in progestin-based therapies for neurological disorders. (March 2021)

• Record Type: Journal Article
• Authors: Sitruk-Ware, Regine; Bonsack, Brooke; Brinton, Roberta; Schumacher, Michael; Kumar, Narender; Lee, Jea-Young; Castelli, Vanessa; Corey, Sydney; Coats, Alexandreya; Sadanandan, Nadia; Gonzales-Portillo, Bella; Heyck, Matt; Shear, Alex; Blaise, Cozene; Zhang, Henry; Sheyner, Michael; García-Sánchez, Julián; Navarro, Lisset; El-Etr, Martine; De Nicola, Alejandro F.; Borlongan, Cesar V.
• Is Part Of: Neuroscience and biobehavioral reviews. Volume 122(2021)
• Page Start: 38
• Page End: 65
• Publication Date: 2021-03
• Subjects: AKR1C aldo-keto reductase 1C family enzyme -- ALS amyotrophic lateral sclerosis -- ALS-CSF rats rats injected with cerebrospinal fluid from human sporadic ALS patients -- AR androgen receptors -- BBB blood-brain barrier -- BDNF brain-derived neurotrophic factor -- CAII carbonic anhydrase type II -- CEE conjugated equine estrogens -- ChAT choline acetyltransferase -- CNS central nervous system -- DRSP drospirenone -- E2 estradiol -- E2-V estradiol valerate -- EAE experimental autoimmune encephalomyelitis -- EE ethinyl estradiol -- ER estrogen receptors -- ERK extracellular signal-regulated kinase -- GABA γ-aminobutyric acid -- GABAa GABA type A -- GAP growth-associated protein -- GFAP glial fibrillary acidic protein -- GLT-1 glutamate transporter 1 -- GR glucocorticoid receptors -- GS glutamine synthase -- HPA hypothalamic-pituitary-adrenal -- HT hemorrhagic transformation -- Iba1 ionized calcium-binding adaptor molecule 1 -- IFN interferon -- IGF-1 insulin-like growth factor-1 -- IL interleukin -- IL-1R1 IL-1 receptor type 1 -- iNOS inducible nitric oxide synthase -- iPSCs induced pluripotent stem cells -- LNG Levonorgestrel -- LNG-IUS LNG-releasing intrauterine system -- MAPK mitogen-activated protein kinase -- MBP myelin basic protein -- MCAO middle cerebral artery occlusion -- MPA medroxyprogesterone acetate -- MS multiple sclerosis -- NFκB nuclear factor-κB -- NG2 neural/glial antigen 2 -- NMDA N-methyl-D-aspartate -- OGD/R oxygen-glucose deprivation and reoxygenation -- Olig2 oligodendrocyte transcription factor 2 -- OPC oligodendrocyte progenitor cell -- p-p90RSK phospho-ribosomal S6 kinase -- PI3-K phosphoinositide-3 kinase -- PLP proteolipid protein -- PR progesterone receptors -- PR-/- PR knock out -- PRNesCre transgenic mice lacking PR gene expression in neural cells by way of the Cre-lox strategy -- PROG progesterone -- RAB Ras related protein -- rNPC rat neural progenitor cells -- ROS reactive oxygen species -- SCI spinal cord injury -- SOD1 superoxide dismutase 1 -- T testosterone -- TBI traumatic brain injury -- TDP-43 transactive response DNA binding protein -- TGF transforming growth factor -- Th T helper -- TLR4 toll-like receptor 4 -- TNF tumor necrosis factor -- TRkB tropomyosin receptor kinase B -- tPA tissue plasminogen activator -- VEGF vascular endothelial growth factor; Progesterone -- Nestorone -- Multiple sclerosis -- Amyotrophic lateral sclerosis -- Spinal cord injury -- Stroke; Psychophysiology -- Periodicals; Human behavior -- Periodicals; Animal behavior -- Periodicals; Neurology -- Periodicals; Behavior -- Periodicals; Ethology -- Periodicals; Neurology -- Periodicals; Psychophysiologie -- Périodiques; Comportement humain -- Périodiques; Animaux -- Mœurs et comportement -- Périodiques; Neurologie -- Périodiques; Animal behavior; Human behavior; Neurology; Psychophysiology; Periodicals; Electronic journals; 573.8
• DOI: 10.1016/j.neubiorev.2020.12.007
• Languages: English
• ISSNs: 0149-7634

Abstract

Highlights: Therapeutic options for central nervous system (CNS) disorders are limited warranting the need for novel treatments. Hormone therapy represents an innovative regenerative medicine approach for CNS disorders. The progestin Nestorone stands as a potent therapeutic via its neurogenetic, remyelinating, and anti-inflammatory effects. A review of preclinical and clinical evidence reveals advantages and disadvantages of progesterone, progestins, and Nestorone in CNS disorders. Translational studies towards optimization of the drug will guide Nestorone's entry into clinical trials. Abstract: Hormone therapy, primarily progesterone and progestins, for central nervous system (CNS) disorders represents an emerging field of regenerative medicine. Following a failed clinical trial of progesterone for traumatic brain injury treatment, attention has shifted to the progestin Nestorone for its ability to potently and selectively transactivate progesterone receptors at relatively low doses, resulting in robust neurogenetic, remyelinating, and anti-inflammatory effects. That CNS disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), and stroke, develop via demyelinating, cell death, and/or inflammatory pathological pathways advances Nestorone as an auspicious candidate for these disorders. Here, we assess the scientific and clinical progress over decades of research into progesterone, progestins, and Nestorone as neuroprotective agents in MS, ALS, SCI, and stroke. We also offer recommendations for optimizing timing, dosage, and route of the drug regimen, and identifying candidate patient populations, in advancing Nestorone to the clinic.