Allopregnanolone decreases neuropathology in a mouse model of motoneuron degeneration

GONZALEZ DENISELLE, MARIA CLAUDIA; RACHIDA GUENNOUN; MICHEL SCHUMACHER; COIRINI H; G. GARGIULO MONACHELLI; MARIA SOL KRUSE; LAURA GARAY; MEYER MARIA; AGUSTINA LARA; GONZALEZ DENISELLE, MARIA CLAUDIA

Torino

Congreso; 9th International 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 sharesseveral similarities with ALS neuropathology (2). Previously, we demonstratedthat progesterone prevents the progression of WR mice motoneuron degeneration(3). Here, we studied if allopregnanolone (ALLO), a reduced metabolite ofprogesterone endowed with gabaergic activity, also prevents neuropathology in thecervical spinal cord from WR mice. WR mice received short or long-termtreatment with ALLO s.c. daily for 5 days (4mg/kg) or every two days for 32days (3,3 mg/kg) respectively. After ALLO treatment, ALLO serum levels,determined by gas chromatography and mass spectrometry (GC/MS), weresignificantly elevated in WRs compared to its untreated counterpart, withoutchanging the concentration of progesterone and 5 alpha dihydroprogesterone (5alpha-DHPROG). Untreated WRs showed increased serum levels of progesterone, 5alpha-DHPROG and ALLO in comparison to control animals. Parameters deeply influenced by degenerative process were measured in the spinalcord such as: brain derived neurotrophic factor (BDNF) mRNA, p75NTR and TrkBreceptors, the phosphorylation of the downstream AKT and the stress activatedkinase JNK. Untreated WRs showed a reduction of the mRNA for BDNF and TrkB inlarge neurons of the ventral horn associated to an enhancement of p75NTRimmunoreactivity on motoneurons positive for choline acetyl transferase (ChAT).Also, low pAKT/AKT ratio with an elevation of pJNK characterized the spinalcord of this experimental model. With the exception of BDNF, these alterationswere prevented by an acute ALLO treatment. On the other hand, chronicadministration of ALLO enhanced BDNF mRNA and attenuated pJNK. Thus, exogenousadministration of ALLO decreased motoneuron pathology in this model. Given thatp75NTR has also been implicated in neurodegeneration, its down regulation mayprovide adequate neuroprotection at early stages of the disease. Sincelong-term steroid treatment also increased BDNF mRNA and reduced pJNK, prolongALLO-treatment should be useful in order to provide neuroprotection inmotoneuron disease. In the animal model, our data shows that the reducedderivative ALLO endowed with gabaergic activity might directly delay theprogression of neuropathology in the Wobbler disease, without being metabolizedinto progesterone receptor agonists, 5 alpha-DHPROG and progesterone.