PMID- 28951257 OWN - NLM STAT- MEDLINE DCOM- 20171113 LR - 20231213 IS - 1879-1220 (Electronic) IS - 0960-0760 (Linking) VI - 174 DP - 2017 Nov TI - Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration. PG - 201-216 LID - S0960-0760(17)30263-7 [pii] LID - 10.1016/j.jsbmb.2017.09.015 [doi] AB - Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by progressive death of motoneurons. The Wobbler (WR) mouse is a preclinical model sharing neuropathological similarities with human ALS. We have shown that progesterone (PROG) prevents the progression of motoneuron degeneration. We now studied if allopregnanolone (ALLO), a reduced metabolite of PROG endowed with gabaergic activity, also prevents WR neuropathology. Sixty-day old WRs remained untreated or received two steroid treatment regimens in order to evaluate the response of several parameters during early or prolonged steroid administration. ALLO was administered s.c. daily for 5days (4mg/kg) or every other day for 32days (3, 3mg/kg), while another group of WRs received a 20mg PROG pellet s.c. for 18 or 60days. ALLO administration to WRs increased ALLO serum levels without changing PROG and 5 alpha dihydroprogesterone (5alpha-DHP), whereas PROG treatment increased PROG, 5alpha-DHP and ALLO. Untreated WRs showed higher basal levels of serum 5alpha-DHP than controls. In the cervical spinal cord we studied markers of oxidative stress or associated to trophic responses. These included nitric oxide synthase (NOS) activity, motoneuron vacuolation, MnSOD immunoreactivity (IR), brain derived neurotrophic factor (BDNF) and TrkB mRNAs, p75 neurotrophin receptor (p75NTR) and, cell survival or death signals such as pAKT and the stress activated kinase JNK. Untreated WRs showed a reduction of MnSOD-IR and BDNF/TrkB mRNAs, associated to high p75NTR in motoneurons, neuronal and glial NOS hyperactivity and neuronal vacuolation. Also, low pAKT, mainly in young WRs, and a high pJNK in the old stage characterized WRs spinal cord. Except for MnSOD and BDNF, these alterations were prevented by an acute ALLO treatment, while short-term PROG elevated MnSOD. Moreover, after chronic administration both steroids enhanced MnSOD-IR and BDNF mRNA, while attenuated pJNK and NOS in glial cells. Long-term PROG also increased pAKT and reduced neuronal NOS, parameters not modulated by chronic ALLO. Clinically, both steroids improved muscle performance. Thus, ALLO was able to reduce neuropathology in this model. Since high oxidative stress activates p75NTR and pJNK in neurodegeneration, steroid reduction of these molecules may provide adequate neuroprotection. These data yield the first evidence that ALLO, a gabaergic neuroactive steroid, brings neuroprotection in a model of motoneuron degeneration. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Meyer, Maria AU - Meyer M AD - Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina. FAU - Garay, Laura I AU - Garay LI AD - Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina; Depto. de Bioquimica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina. FAU - Kruse, Maria Sol AU - Kruse MS AD - Laboratory of Neurobiology, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina. FAU - Lara, Agustina AU - Lara A AD - Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina. FAU - Gargiulo-Monachelli, Gisella AU - Gargiulo-Monachelli G AD - Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina. FAU - Schumacher, Michael AU - Schumacher M AD - U1195 INSERM and University Paris Sud: "Neuroprotective, Neuroregenerative and Remyelinating Small Molecules", 94276, Kremlin-Bicetre, France. FAU - Guennoun, Rachida AU - Guennoun R AD - U1195 INSERM and University Paris Sud: "Neuroprotective, Neuroregenerative and Remyelinating Small Molecules", 94276, Kremlin-Bicetre, France. FAU - Coirini, Hector AU - Coirini H AD - Laboratory of Neurobiology, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina; Depto. de Bioquimica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina. FAU - De Nicola, Alejandro F AU - De Nicola AF AD - Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina; Depto. de Bioquimica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina. FAU - Gonzalez Deniselle, Maria Claudia AU - Gonzalez Deniselle MC AD - Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina; Depto. de Ciencias Fisiologicas, Facultad de Medicina, Universidad de, Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina. Electronic address: mcgonza@dna.uba.ar. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170922 PL - England TA - J Steroid Biochem Mol Biol JT - The Journal of steroid biochemistry and molecular biology JID - 9015483 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, Nerve Growth Factor) RN - 0 (Ngfr protein, mouse) RN - 4G7DS2Q64Y (Progesterone) RN - BXO86P3XXW (Pregnanolone) RN - EC 1.14.13.39 (Nitric Oxide Synthase) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 2.3.1.6 (Choline O-Acetyltransferase) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Amyotrophic Lateral Sclerosis MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics MH - Choline O-Acetyltransferase/metabolism MH - Disease Models, Animal MH - Female MH - Male MH - Mice MH - Motor Neurons/drug effects/pathology MH - Nerve Degeneration/*drug therapy/genetics/metabolism MH - Neuroprotective Agents/blood/pharmacology/*therapeutic use MH - Nitric Oxide Synthase/metabolism MH - Pregnanolone/blood/pharmacology/*therapeutic use MH - Progesterone/blood/pharmacology/therapeutic use MH - Receptor, trkB/genetics MH - Receptors, Nerve Growth Factor/metabolism MH - Spinal Cord/metabolism/pathology MH - Superoxide Dismutase/metabolism OTO - NOTNLM OT - Allopregnanolone OT - Amyotrophic lateral sclerosis OT - Brain derived neurotrophic factor OT - Motoneuron degeneration OT - Neuroprotection OT - Progesterone OT - Wobbler mouse OT - p75NTR EDAT- 2017/09/28 06:00 MHDA- 2017/11/14 06:00 CRDT- 2017/09/28 06:00 PHST- 2017/04/21 00:00 [received] PHST- 2017/09/08 00:00 [revised] PHST- 2017/09/21 00:00 [accepted] PHST- 2017/09/28 06:00 [pubmed] PHST- 2017/11/14 06:00 [medline] PHST- 2017/09/28 06:00 [entrez] AID - S0960-0760(17)30263-7 [pii] AID - 10.1016/j.jsbmb.2017.09.015 [doi] PST - ppublish SO - J Steroid Biochem Mol Biol. 2017 Nov;174:201-216. doi: 10.1016/j.jsbmb.2017.09.015. Epub 2017 Sep 22.