title: Docosahexaenoic acid reduces ER stress and abnormal protein accumulation and improves neuronal function following traumatic brain injury.
abstract: In this study, we investigated the development of endoplasmic reticulum (ER) stress after traumatic brain injury (TBI) and the efficacy of post-TBI administration of docosahexaenoic acid (DHA) in reducing ER stress. TBI was induced by cortical contusion injury in Sprague-Dawley rats. Either DHA (16 mg/kg in DMSO) or vehicle DMSO (1 ml/kg) was administered intraperitoneally at 5 min after TBI, followed by a daily dose for 3-21 d. TBI triggered sustained expression of the ER stress marker proteins including phosphorylated eukaryotic initiation factor-2α, activating transcription factor 4, inositol requiring kinase 1, and C/EBP homologous protein in the ipsilateral cortex at 3-21 d after TBI. The prolonged ER stress was accompanied with an accumulation of abnormal ubiquitin aggregates and increased expression of amyloid precursor protein (APP) and phosphorylated tau (p-Tau) in the frontal cortex after TBI. The ER stress marker proteins were colocalized with APP accumulation in the soma. Interestingly, administration of DHA attenuated all ER stress marker proteins and reduced the accumulation of both ubiquitinated proteins and APP/p-Tau proteins. In addition, the DHA-treated animals exhibited early recovery of their sensorimotor function after TBI. In summary, our study demonstrated that TBI induces a prolonged ER stress, which is positively correlated with abnormal APP accumulation. The sustained ER stress may play a role in chronic neuronal damage after TBI. Our findings illustrate that post-TBI administration of DHA has therapeutic potentials in reducing ER stress, abnormal protein accumulation, and neurological deficits.
authors.affiliation: Departments of Neurology and Neurosurgery, Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, Pennsylvania 15213.
authors.forename: Gulnaz
authors.initials: G
authors.lastname: Begum
authors.forename: Hong Q
authors.initials: HQ
authors.lastname: Yan
authors.forename: Liaoliao
authors.initials: L
authors.lastname: Li
authors.forename: Amneet
authors.initials: A
authors.lastname: Singh
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004281:Docosahexaenoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D004281:Docosahexaenoic Acids
keywords: amyloid precursor protein; controlled cortical impact injury; docosahexaenoic acid; phosphorylated tau; unfolded protein response