title: A Single Bolus of Docosahexaenoic Acid Promotes Neuroplastic Changes in the Innervation of Spinal Cord Interneurons and Motor Neurons and Improves Functional Recovery after Spinal Cord Injury.
abstract: Docosahexaenoic acid (DHA) is an ω-3 polyunsaturated fatty acid that is essential in brain development and has structural and signaling roles. Acute DHA administration is neuroprotective and promotes functional recovery in animal models of adult spinal cord injury (SCI). However, the mechanisms underlying this recovery have not been fully characterized. Here we investigated the effects of an acute intravenous bolus of DHA delivered after SCI and characterized DHA-induced neuroplasticity within the adult injured spinal cord. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat cervical hemisection SCI model. A mouse pyramidotomy model was used to confirm that this robust sprouting was not species or injury model specific. Furthermore, we demonstrated that corticospinal fibers sprouting to the denervated side of the cord following pyramidotomy contact V2a interneurons. We also demonstrated increased serotonin fibers and synaptophysin in direct contact with motor neurons. DHA also increased synaptophysin in rat cortical cell cultures. A reduction in phosphatase and tensin homolog (PTEN) has been shown to be involved in axonal regeneration and synaptic plasticity. We showed that DHA significantly upregulates miR-21 and downregulates PTEN in corticospinal neurons. Downregulation of PTEN and upregulation of phosphorylated AKT by DHA were also seen in primary cortical neuron cultures and were accompanied by increased neurite outgrowth. In summary, acute DHA induces anatomical and synaptic plasticity in adult injured spinal cord. This study shows that DHA has therapeutic potential in cervical SCI and provides evidence that DHA could exert its beneficial effects in SCI via enhancement of neuroplasticity.
  
  
  CONCLUSIONS
  In this study, we show that an acute intravenous injection of docosahexaenoic acid (DHA) 30 min after spinal cord injury induces neuroplasticity. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat hemisection spinal cord injury model. A mouse pyramidotomy model was used to confirm that the robust sprouting involved V2a interneurons. We show that DHA significantly upregulates miR-21 and phosphorylated AKT, and downregulates phosphatase and tensin homolog (PTEN), which is involved in suppressing anatomical plasticity, in corticospinal neurons and in primary cortical neuron cultures. We conclude that acute DHA can induce anatomical and synaptic plasticity. This provides direct evidence that DHA could exert its beneficial effects in spinal cord injury via neuroplasticity enhancement.
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, London, E1 2AT, United Kingdom, and Chang Gung Medical College and University, Chang Gung Memorial Hospital, Department of Neurosurgery, Linkou, Taiwan, 33305.
authors.forename: Zhuo-Hao
authors.initials: ZH
authors.lastname: Liu
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, London, E1 2AT, United Kingdom, and.
authors.forename: Ping K
authors.initials: PK
authors.lastname: Yip
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, London, E1 2AT, United Kingdom, and.
authors.forename: Louise
authors.identifier: http://orcid.org/0000-0001-7383-2324
authors.initials: L
authors.lastname: Adams
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, London, E1 2AT, United Kingdom, and.
authors.forename: Meirion
authors.initials: M
authors.lastname: Davies
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, London, E1 2AT, United Kingdom, and.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, London, E1 2AT, United Kingdom, and.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Michael
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, London, E1 2AT, United Kingdom, and.
authors.forename: John V
authors.initials: JV
authors.lastname: Priestley
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, London, E1 2AT, United Kingdom, and a.t.michael-titus@qmul.ac.uk.
authors.forename: Adina T
authors.initials: AT
authors.lastname: Michael-Titus
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002574:Cervical Vertebrae; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007275:Injections, Intravenous; D007395:Interneurons / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011712:Pyramidal Tracts / Q000187:drug effects* / Q000293:injuries / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D059326:Serotonergic Neurons / Q000502:physiology / Q000648:ultrastructure; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C546082:mirn21 microRNA, rat; D004281:Docosahexaenoic Acids; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C487216:Pten protein, rat
keywords: docosahexaenoic acid; neuroplasticity; omega-3 polyunsaturated fatty acids; spinal cord injury