title: Pharmacological inhibition of spinal cord injury-stimulated ribosomal biogenesis does not affect locomotor outcome.
abstract: After unresolved endoplasmic reticulum stress, recovery of protein synthesis including increased expression of ribosomal components and translation factors may induce cell death. Using a mouse model of moderate contusive spinal cord injury (SCI) at the T9 level, upregulation of ribosomal biogenesis was observed in the injury epicenter at 24h after trauma. Such upregulation coincided with endoplasmic reticulum stress response as previously reported in this model. It was also accompanied by changes in expression of many other genes associated with translational regulation. Systemic treatment with a pharmacological inhibitor of RNA-Polymerase-1, BMH-21 reduced rRNA transcription in the spinal cord. Moreover, in the injury epicenter, treatment with BMH-21 increased expression of oligodendrocyte-specific transcripts including Mbp and Cldn11 at 3days post injury. Although such findings may suggest at least transient reduction of oligodendrocyte death, locomotor outcome was mostly unaffected except slightly accelerated recovery of hindlimb function at week 2 post-injury. Therefore, at least in mice, RNA-Polymerase-1 does not appear to be a robust target for therapies to protect spinal cord tissue after contusion. However, these findings raise an interesting possibility that altered rate of ribosomal biogenesis contributes to the apparent translational reprogramming after contusive SCI. Such a reprogramming could be a major regulator of SCI-induced gene expression.
authors.affiliation: Kentucky Spinal Cord Injury Research Center, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States; The Department of Neurological Surgery, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kilanczyk
authors.affiliation: Kentucky Spinal Cord Injury Research Center, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States; The Department of Neurological Surgery, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States.
authors.forename: Kariena R
authors.initials: KR
authors.lastname: Andres
authors.affiliation: Kentucky Spinal Cord Injury Research Center, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States; The Department of Pharmacology and Toxicology, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States.
authors.forename: Justin
authors.initials: J
authors.lastname: Hallgren
authors.affiliation: Kentucky Spinal Cord Injury Research Center, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States; The Department of Neurological Surgery, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States.
authors.forename: Sujata Saraswat
authors.initials: SS
authors.lastname: Ohri
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD 21218, United States.
authors.forename: Marikki
authors.initials: M
authors.lastname: Laiho
authors.affiliation: Kentucky Spinal Cord Injury Research Center, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States; The Department of Neurological Surgery, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States; The Department of Anatomical Sciences and Neurobiology, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Whittemore
authors.affiliation: Kentucky Spinal Cord Injury Research Center, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States; The Department of Neurological Surgery, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States; The Department of Pharmacology and Toxicology, MD/PhD Program, University of Louisville, Louisville, KY 40292, United States. Electronic address: michal.hetman@louisville.edu.
authors.forename: Michal
authors.initials: M
authors.lastname: Hetman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006614:Hindlimb / Q000503:physiopathology; D051379:Mice; D009043:Motor Activity; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D001678:Organelle Biogenesis; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D012270:Ribosomes / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000503:physiopathology*
chemical_list: D000970:Antineoplastic Agents
keywords: Cell death; Neuroprotection; Pharmacotherapy; Ribosomal biogenesis; Spinal cord injury; White matter loss