Norethindrone and progesterone effects in the degenerative spinal cord of a murine model of Amyotrophic Lateral Sclerosis (ALS).

GARGIULO MONACHELLI GISELLA; GARAY LAURA I; DE NICOLA AF; MEYER M; LIMA A; GONZALEZ DENISELLE MC; LARA AGUSTINA; ROIG P

Torino

Simposio; 10th International Meeting in ?Steroids and the Nervous System?; 2019

Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by progressive death of motoneurons. One preclinical murine model of ALS is the Wobbler (WR) mouse, a mutant that shares several similarities with ALS neuropathology. Current pharmacological treatments for ALS patients are still partially effective. This encouraged us to investigate if the synthetic progestin norethindrone (NOR), showing higher potency than PROG might also afford neuroprotection. Previously, we demonstrated that progesterone prevents the progression of WR mice motoneuron degeneration. Two-month-old Wr mice (wr/wr) were left untreated or received either a 20mg pellet of PROG or a 1mg pellet of NOR for 18 days. Untreated control NFR/NFR mice (background strain for Wobbler) were also employed. Wobblers showed forelimb abnormalities associated to upper and lower motoneuron degeneration. While most of these abnormalities were normalized with PROG treatment, NOR showed differential effects. The treatment with this synthetic progestin did not increase the immunoreactive area for choline-acetyltransferase in motoneurons, drastically decreased GFAP+ astrogliosis, favored proinflammatory mediators, promoted the inflammatory phenotype of IBA1+ microglia and increased the receptor for advanced glycation end products (RAGE) mRNA expression and nitric oxide synthase (NOS)/NADPH diaphorase activity. Additionally, NOR treatment produced atrophy of the thymus and developed negative effects on clinical assessments (forelimb atrophy and rotarod performance). The latter effect suggests a detrimental outcome on muscle trophism and motor function. These findings reinforce the evidence that the type of progestin used for contraception, endometriosis or replacement therapy, may condition the outcome of preclinical and clinical studies targeting neurodegenerative diseases.