Norethindrone and progesterone effects in the degenerative spinal cord of a murine model of amyoatrophic lateral sclerosis

G. GARGIULO-MONACHELLI; A LIMA; GONZÁLEZ DENISELLE MARÍA C; GARAY L; A. F. DE NICOLA; M MEYER; P ROIG

Turin

Congreso; 10th International Meeting on Steroids and nervous System; 2019

Amyotrophic lateralsclerosis (ALS) is a devastating disorder characterized by the progressivedeath of motoneurons, accompanied by astrogliosis and microgliosis [5] . Onepreclinical murine model of ALS is the Wobbler mouse, which suffers amutation in the Vps54 gene causing disruption ofaxonal transport. Interestingly, Wobbler mice share several similarities with ALS neuropathology [1]. However, currentpharmacological treatments for ALS patients employing Riluzone or Edaravone arestill partially effective [6].  Previously, we demonstrated that progesterone treatment preventsthe progression of Wobbler mice motoneuron degeneration,  decreases the reactive astrocytes andmicroglia, preserves mitochondrial function, improves motor skills and prolongsthe clinical outcome  [3, 4].Thesefindings encouraged us to investigate if the synthetic progestin norethindrone(NOR), showing about 8 times higher potency than progesterone [ 2 ] might alsoafford neuroprotection. NOR is a progestogen-only pill available for birthcontrol. Two-month-old Wobbler mice(wr/wr) were left untreated or received either a 20mg pellet of progesterone ora 1mg pellet of NOR for 18 days. Control NFR/NFR mice (background strain forWobbler) were also employed. Untreated Wobblers showed forelimb abnormalitiesassociated to upper and lowermotoneuron degeneration. Most neurochemical and histological abnormalities ofWobbler mice were normalized with progesterone treatment; however, NOR showeddifferential effects. Thus, treatment with this synthetic progestin did notincrease the immunoreactive area for choline-acetyltransferase, a marker offunctional motoneurons, drastically decreased GFAP+ astrogliosis, favored theexpression of proinflammatory mediators, promoted an inflammatory morphologicalphenotype in IBA1+ microglia and increased thereceptor for advanced glycation end products (RAGE) mRNA expression. NOR also enhanced the nitricoxide synthase (NOS)/NADPH diaphorase activity, suggesting a NO-mediatedneurotoxicity. Additionally, NOR treated mice showed atrophy of the thymus anddeveloped negative effects on clinical assessments, with increased forelimbatrophy and decreased rotarod performance. The latter effect suggests adetrimental outcome on muscle trophism and motor function. These findingsreinforce the possibility that the type of progestin used for contraception,endometriosis or replacement therapy, may condition the outcome of preclinicaland clinical studies targeting neurodegenerative diseases.