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Artículo

Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration

Meyer, MariaIcon ; Garay, Laura InesIcon ; Kruse, Maria SolIcon ; Lara, Agustina; Gargiulo Monachelli, Gisella MarianaIcon ; Schumacher, Michael; Guennoun, Rachida; Coirini, HectorIcon ; de Nicola, Alejandro FedericoIcon ; Deniselle, Maria Claudia Gonzalez
Fecha de publicación: 11/2017
Editorial: Pergamon-Elsevier Science Ltd.
Revista: Journal of Steroid Biochemistry and Molecular Biology
ISSN: 0960-0760
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Neurociencias; Patología

Resumen

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 5 days (4 mg/kg) or every other day for 32 days (3, 3 mg/kg), while another group of WRs received a 20 mg PROG pellet s.c. for 18 or 60 days. ALLO administration to WRs increased ALLO serum levels without changing PROG and 5 alpha dihydroprogesterone (5α-DHP), whereas PROG treatment increased PROG, 5α-DHP and ALLO. Untreated WRs showed higher basal levels of serum 5α-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 WŔs 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.
Palabras clave: Motoneuron Disease , Neuroprotection , Allopregnenolone , Amyotrophic Lateral Sclerosis
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info:eu-repo/semantics/embargoedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/28865
URL: http://linkinghub.elsevier.com/retrieve/pii/S0960076017302637
DOI: http://dx.doi.org/10.1016/j.jsbmb.2017.09.015
Colecciones
Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Articulos(SEDE CENTRAL)
Articulos de SEDE CENTRAL
Citación
Meyer, Maria; Garay, Laura Ines; Kruse, Maria Sol; Lara, Agustina; Gargiulo Monachelli, Gisella Mariana; et al.; Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration; Pergamon-Elsevier Science Ltd.; Journal of Steroid Biochemistry and Molecular Biology; 174; 11-2017; 201-216
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