Comparative effects of progesterone and the synthetic progestin norethindrone on neuroprotection in a model of spontaneous motoneuron degeneration

LARA, AGUSTINA; ROIG, PAULINA; MEYER, MARIA; LIMA, ANALIA; GONZALEZ DENISELLE, MARIA CLAUDIA; GARGIULO-MONACHELLI, GISELLA; GARAY, LAURA; DE NICOLA, ALEJANDRO F.

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2019 vol. 192 p. 105385 - 105386

0960-0760

The Wobbler mouse has been proposed as an experimental model of the sporadic form of amyotrophic lateralsclerosis (ALS). The administration of natural progesterone (PROG) to Wobbler mice attenuates neuropathology,inhibits oxidative stress, enhances the expression of genes involved in motoneuron function, increases survivaland restores axonal transport. However, current pharmacological treatments for ALS patients are still partiallyeffective. This encouraged us to investigate if the synthetic progestin norethindrone (NOR), showing higherpotency than PROG and used for birth control and hormone therapy might also afford neuroprotection. Twomonth-old Wobbler mice (wr/wr) were left untreated or received either a 20 mg pellet of PROG or a 1 mg pelletof NOR for 18 days. Untreated control NFR/NFR mice (background strain for Wobbler) were also employed.Wobblers showed typical clinical and spinal cord abnormalities, while these abnormalities were normalized withPROG treatment. Surprisingly, we found that NOR did not increase immunoreactivity and gene expression forcholine-acetyltransferase, drastically decreased GFAP+astrogliosis, favored proinflammatory mediators, promotedthe inflammatory phenotype of IBA1+ microglia, increased the receptor for advanced glycation endproducts (RAGE) mRNA and protein expression and the activity of nitric oxide synthase (NOS)/NADPH diaphorasein the cervical spinal cord. Additionally, NOR treatment produced atrophy of the thymus. The combinednegative effects of NOR on clinical assessments (forelimb atrophy and rotarod performance) suggest a detrimentaleffect on muscle trophism and motor function. These findings reinforce the evidence that the type ofprogestin used for contraception, endometriosis or replacement therapy, may condition the outcome of preclinicaland clinical studies targeting neurodegenerative diseases.