Allopregnanolone decreases neuropathology in a mouse model of motoneuron degeneration.

SCHUMACHER M; KRUSE, MS; LARA AGUSTINA; DE NICOLA A. F.; COIRINI H; GARAY L; GONZALEZ DENISELLE, MC; GUENNOUN, R; GARGIULO MONACHELLI G; MEYER M

Torino

Simposio; 9th Meeting of Steroids and Nervous System; 2017

Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by progressive death of motoneurons (1). One preclinical model of ALS is the Wobbler (WR) mouse, a mutant that shares several similarities with ALS neuropathology (2). Previously, we demonstrated that progesterone prevents the progression of WR mice motoneuron degeneration (3). Here, we studied if allopregnanolone (ALLO), a reduced metabolite of progesterone endowed with gabaergic activity, also prevents neuropathology in the cervical spinal cord from WR mice. WR mice received short or long-term treatment with ALLO s.c. daily for 5 days (4mg/kg) or every two days for 32 days (3,3 mg/kg) respectively. After ALLO treatment, ALLO serum levels, determined by gas chromatography and mass spectrometry (GC/MS), were significantly elevated in WRs compared to its untreated counterpart, without changing the concentration of progesterone and 5 alpha dihydroprogesterone (5 alpha-DHPROG). Untreated WRs showed increased serum levels of progesterone, 5 alpha-DHPROG and ALLO in comparison to control animals. Parameters deeply influenced by degenerative process were measured in the spinal cord such as: brain derived neurotrophic factor (BDNF) mRNA, p75NTR and TrkB receptors, the phosphorylation of the downstream AKT and the stress activated kinase JNK. Untreated WRs showed a reduction of the mRNA for BDNF and TrkB in large neurons of the ventral horn associated to an enhancement of p75NTR immunoreactivity on motoneurons positive for choline acetyl transferase (ChAT). Also, low pAKT/AKT ratio with an elevation of pJNK characterized the spinal cord of this experimental model. With the exception of BDNF, these alterations were prevented by an acute ALLO treatment. On the other hand, chronic administration of ALLO enhanced BDNF mRNA and attenuated pJNK. Thus, exogenous administration of ALLO decreased motoneuron pathology in this model. Given that p75NTR has also been implicated in neurodegeneration, its down regulation may provide adequate neuroprotection at early stages of the disease. Since long-term steroid treatment also increased BDNF mRNA and reduced pJNK, prolong ALLO-treatment should be useful in order to provide neuroprotection in motoneuron disease. In the animal model, our data shows that the reduced derivative ALLO endowed with gabaergic activity might directly delay the progression of neuropathology in the Wobbler disease, without being metabolized into progesterone receptor agonists, 5 alpha-DHPROG and progesterone.