Valproate reduces CHOP levels and preserves oligodendrocytes and axons after spinal cord injury.
Spinal cord injury (SCI) is a major cause of disability to which there are not yet effective treatments. We previously reported that degeneration of oligodendrocytes and neurons that occurs after SCI is associated with the development of endoplasmic reticulum (ER) stress and the progressive accumulation of the pro-apoptotic factor CHOP. Since following ER stress, the balance between the pro-survival chaperone BiP and CHOP drives the cell destiny, we aimed to find drugs that modulate this ratio in favour of the former. We found that valproate (VPA) induced a significant reduction of CHOP levels after ER stress in an organotypic-based culture of spinal cord in vitro. We then administered different doses of VPA to rats following spinal cord contusion, and found that the treatment caused a marked reduction of CHOP levels early after the lesion. In addition, VPA administration partially prevented cord tissue, myelin and axonal loss, and significantly increased the relative number of surviving oligodendrocytes in the damaged spinal cord. Besides, VPA-treated rats showed better recovery of the locomotor activity than vehicle-treated rats after SCI. Since VPA is a drug already in clinical use, these results open the avenue for its therapeutical use in SCI as well as in demyelinating disorders.
Group of Neuroplasticity and Regeneration, Institute of Neurosciences, Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
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Asensio-Pinilla
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Guzmán-Lenis
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Herrando-Grabulosa
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D000818:Animals; D001369:Axons / Q000473:pathology*; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009186:Myelin Sheath / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051742:Transcription Factor CHOP / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
C497251:Ddit3 protein, rat; D051742:Transcription Factor CHOP; D014635:Valproic Acid