title: Administration of DHA Reduces Endoplasmic Reticulum Stress-Associated Inflammation and Alters Microglial or Macrophage Activation in Traumatic Brain Injury.
abstract: We investigated the effects of the administration of docosahexaenoic acid (DHA) post-traumatic brain injury (TBI) on reducing neuroinflammation. TBI was induced by cortical contusion injury in Sprague Dawley rats. Either DHA (16 mg/kg in dimethyl sulfoxide) or vehicle dimethyl sulfoxide (1 ml/kg) was administered intraperitonially at 5 min after TBI, followed by a daily dose for 3 to 21 days. TBI triggered activation of microglia or macrophages, detected by an increase of Iba1 positively stained microglia or macrophages in peri-lesion cortical tissues at 3, 7, and 21 days post-TBI. The inflammatory response was further characterized by expression of the proinflammatory marker CD16/32 and the anti-inflammatory marker CD206 in Iba1(+) microglia or macrophages. DHA-treated brains showed significantly fewer CD16/32(+) microglia or macrophages, but an increased CD206(+) phagocytic microglial or macrophage population. Additionally, DHA treatment revealed a shift in microglial or macrophage morphology from the activated, amoeboid-like state into the more permissive, surveillant state. Furthermore, activated Iba1(+) microglial or macrophages were associated with neurons expressing the endoplasmic reticulum (ER) stress marker CHOP at 3 days post-TBI, and the administration of DHA post-TBI concurrently reduced ER stress and the associated activation of Iba1(+) microglial or macrophages. There was a decrease in nuclear translocation of activated nuclear factor kappa-light-chain-enhancer of activated B cells protein at 3 days in DHA-treated tissue and reduced neuronal degeneration in DHA-treated brains at 3, 7, and 21 days after TBI. In summary, our study demonstrated that TBI mediated inflammatory responses are associated with increased neuronal ER stress and subsequent activation of microglia or macrophages. DHA administration reduced neuronal ER stress and subsequent association with microglial or macrophage polarization after TBI, demonstrating its therapeutic potential to ameliorate TBI-induced cellular pathology.
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Lloyd D
authors.initials: LD
authors.lastname: Harvey
authors.affiliation: Department of Neurology, the Second Hospital of Dalian Medical University, Dalian, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Insiya Y
authors.initials: IY
authors.lastname: Attarwala
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Gulnaz
authors.initials: G
authors.lastname: Begum
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Neurosurgery, Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, PA, USA Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
authors.forename: Hong Q
authors.initials: HQ
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, PA, USA Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA sund@upmc.edu.
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D016328:NF-kappa B; D018696:Neuroprotective Agents; D004281:Docosahexaenoic Acids
keywords: cortical contusion injury; docosahexaenoic acid; microglial polarization; neuroinflammation; nuclear factor kappa-light-chain-enhancer of activated B cells; secondary injury