Testosterone promotes myelin regeneration in the spinal cord of Wobbler mouse, a model of Amyotrophic lateral sclerosis

ESPERANTE, IVÁN; MEYER, M; BANZAN CAROLINA; LIMA, ANALIA; ROIG PAULINA; SCHUMACHER M; GUENNOUN, RACHIDA; DE NICOLA A. F.; GONZALEZ DENISELLE MC

Torino

Simposio; 11th International Meeting of ?Steroids and the Nervous system; 2022

Amyotrophic lateral sclerosis (ALS), the most common motoneuron disease, is characterized by progressive degeneration of upper and lower motoneurons leading to muscle weakness and motor impairment. The Wobbler (WR) mouse, a recognized model of ALS, shows a selective loss of motoneurons, astrocytosis and microgliosis in cervical spinal cord. Clinically, WRs develop forelimb muscle atrophy and gait disturbances. In common with other rodent models and ALS, the WR mouse presents abnormalities of TDP43 (transactive response DNA binding protein) and ubiquitination, upregulation of the tumor necrosis factor alpha and cortical hyperexcitability (Bigini et al. 2008; Dennis and Citron 2009).Epidemiological studies have shown that the incidence of ALS is higher in men than in women until menopause, when incidence increases. This suggests a role of steroid hormones in disease development. We have shown a dysregulation of steroidogenesis in male WR mice. In particular, male WRs (wr/wr) exhibit reduced levels of testosterone in plasma, brain, spinal cord, and testis as well as androstenedione and its metabolite 5α-DHT (Gonzalez Deniselle 2016).These results suggest that the low levels of androgens in WR may participate to the development of the disease. We recently showed that T treatment reduces astrogliosis, microgliosis and improves clinical score and rotarod performance in male WRs (Lara et al, 2021). As T plays major roles in the plasticity of neurons, and regulates myelination of axons (Schumacher, et al., 2021), we now studied myelin parameters in the cervical spinal cord from male WRs at symptomatic stage after T treatment such as the density of mature CC1+ oligodendrocytes, luxol fast blue (LFB) staining and the myelin/axon thick ratio. We also analyzed the immunoreactivity (IR) for glutamine synthetase (GS), an enzyme that prevents glutamate toxicity in the nervous system. Treatment consisted of s.c. of 10 mm silastic tubes containing crystalline testosterone for 2 months. WR mice and controls that remained untreated were implanted with empty 10mm silastic. We showed that T levels in the cervical spinal cord and seminal vesicles weight were higher in WRs+T vs WRs (p