Neurogenesis is the principal regenerative mechanism to sustain the plasticity potential in adult brains. Decreased neurogenesis parallels the cognition decline with aging, and has been suggested as a common hallmark in the progression of many neurodegeneration diseases. We previously reported that acute exposure to segesterone acetate (ST-1435; Nestorone), alone or in combination with 17β-estradiol (E2), increased human neural stem cells proliferation and survival both in vitro and in vivo. The present study expanded our previous findings to investigate the more clinical related chronic exposure in combination with E2 on the regenerative capacity of adult brain.
To mimic the chronic contraception exposure in women, 3-month old female mice (n = 110) were treated with ST-1435, with or without co-administration of E2, for 4 weeks. Neural cell proliferation and survival, and oligodendrocyte generation were assessed. The involvement of insulin-like growth factor 1 signaling was studied.
Our results demonstrated that chronic ST-1435 and E2 alone or in combination increased neurogenesis by a comparable magnitude, with minimum to no antagonistic or additive effects between ST-1435 and E2. In addition, chronic exposure of ST-1435 or ST-1435 + E2 stimulated oligodendrocyte generation, indicating potential elevated myelination. Insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) were also up-regulated after chronic ST-1435 and E2 exposure, suggesting the involvement of IGF-1 signaling as the potential underlined regulatory pathway transducing ST-1435 effect.
These findings provide preclinical evidence and mechanistic insights for the development of ST-1435 as a neuroregenerative therapy to promote intrinsic regenerative capacity in female brains against aging and neurodegenerative disorders.
1Center for Innovation in Brain Science, University of Arizona, Tucson, AZ
2Department of Pharmacology, University of Arizona, Tucson, AZ
3Department of Neurology, University of Arizona, Tucson, AZ
4Center for Biomedical Research, Population Council, New York, NY.
Address correspondence to: Roberta Diaz Brinton, PhD, Center for Innovation in Brain Science, 1501 North Campbell Avenue, P.O. Box 245126, Tucson, AZ 85724-5126. E-mail: firstname.lastname@example.org
Received 26 February, 2018
Revised 29 March, 2018
Accepted 29 March, 2018
Funding/support: This study was supported by grants from the National Institute of Health (U54 HD029990 PD/PI RSW; Project 1 to R.D.B.).
Financial disclosure/conflicts of interest: None reported.