title: Autophagy activation and neuroprotection by progesterone in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis.
abstract: Progesterone (PG) exerts neuroprotective effects under conditions such as brain ischemia, traumatic brain injury, and spinal cord injury. Previously, we reported that PG activates autophagy, a potential neuroprotective mechanism, in cortical astrocytes. In the present study, we explored the possibility that PG, by activating autophagy in spinal cord cells, protects against motoneuron degeneration in transgenic (Tg) mice expressing the human G93A-SOD1 (superoxide dismutase 1) mutant, a model of amyotrophic lateral sclerosis. PG treatment increased autophagic flux in G93A-SOD1 Tg spinal cord astrocyte cultures and mice. In addition, PG treatment reduced mutant SOD1 protein levels and motoneuronal death. Inhibition of autophagy with 3-methyladenine (3MA) reversed these PG effects, indicating that activation of autophagy contributed to the PG neuroprotection. PG effects in vivo were tested by intraperitoneally injecting male G93A-SOD1 Tg mice with different doses of PG (2, 4, or 8mg/kg) or vehicle from 70days of age until death. Measurements of motor functions using rota-rod tests showed that the onset of symptoms was not different among groups, but the progression of motor dysfunction was significantly delayed in the PG-treated group compared with the vehicle control group. The average lifespan was also prolonged in the PG-injected group. Histological examinations revealed that PG treatment substantially reduced the death of spinal motoneurons at 14weeks of age with a concomitant decrease in mutant SOD1 levels. Our results demonstrated that PG delays neurodegenerative progress in G93A-SOD1 transgenic mice, possibly through activation of autophagy in the spinal cord.
authors.affiliation: Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Jean
authors.initials: J
authors.lastname: Kim
authors.forename: Tae-Youn
authors.initials: TY
authors.lastname: Kim
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Cho
authors.forename: Ha Na
authors.initials: HN
authors.lastname: Kim
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002452:Cell Count; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011374:Progesterone / Q000627:therapeutic use*; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics; D016019:Survival Analysis; D013997:Time Factors; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C490981:Gtf2h1 protein, mouse; D018696:Neuroprotective Agents; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D011374:Progesterone; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: ALS; LC3; Spinal cord; Steroid hormone; hSOD1