Central modifications of allopregnanolone and β-endorphin following subcutaneous administration of Nestorone

Lenzi, E; Pluchino, Nicola; Begliuomini, Silvia; Casarosa, Elena; Merlini, Sara; Giannini, Andrea; Luisi, M; Kumar, Narender; Sitruk-Ware, Régine; Genazzani, A. R.

doi:10.1016/j.jsbmb.2009.04.004

Cited by 10 publications

(1 citation statement)

References 27 publications

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“…Although our treatment did not improve Purkinje cell survival, we only gave monotherapy and mice normally have circulating levels of all three hormones: 17β-estradiol, progesterone and testosterone. Indeed, consistent with our data, it has recently been shown that dihydrotestosterone replacement in orchidectomised rats does not increase brain steroid concentrations (Pluchino et al 2008), and that effective neuroprotection requires the combination of exogenous oestrogens and progestins (Smith et al 1987; Kipp and Beyer 2009; Lenzi et al 2009). Therefore the failure of individual sex steroids to prevent premature Purkinje cell death post-gonadectomy, further supports the hypothesis that survival of ageing Purkinje cells requires the integrity of the whole circulating sex steroid profile.…”

Section: Discussionsupporting

confidence: 91%

Age-related Purkinje cell death is steroid dependent: RORα haplo-insufficiency impairs plasma and cerebellar steroids and Purkinje cell survival

Janmaat

Akwa

Doulazmi

et al. 2011

AGE

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A major problem of ageing is progressive impairment of neuronal function and ultimately cell death. Since sex steroids are neuroprotective, their decrease with age may underlie age-related neuronal degeneration. To test this, we examined Purkinje cell numbers, plasma sex steroids and cerebellar neurosteroid concentrations during normal ageing (wild-type mice, WT), in our model of precocious ageing (Rora+/sg, heterozygous staggerer mice in which expression of the neuroprotective factor RORα is disrupted) and after long-term hormone insufficiency (WT post-gonadectomy). During normal ageing (WT), circulating sex steroids declined prior to or in parallel with Purkinje cell loss, which began at 18 months of age. Although Purkinje cell death was advanced in WT long-term steroid deficiency, this premature neuronal loss did not begin until 9 months, indicating that vulnerability to sex steroid deficiency is a phenomenon of ageing Purkinje neurons. In precocious ageing (Rora+/sg), circulating sex steroids decreased prematurely, in conjunction with marked Purkinje cell death from 9 months. Although Rora+/sg Purkinje cells are vulnerable through their RORα haplo-insufficiency, it is only as they age (after 9 months) that sex steroid failure becomes critical. Finally, cerebellar neurosteroids did not decrease with age in either genotype or gender; but were profoundly reduced by 3 months in male Rora+/sg cerebella, which may contribute to the fragility of their Purkinje neurons. These data suggest that ageing Purkinje cells are maintained by circulating sex steroids, rather than local neurosteroids, and that in Rora+/sg their age-related death is advanced by premature sex steroid loss induced by RORα haplo-insufficiency.

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