title: Effects of DHA on Hippocampal Autophagy and Lysosome Function After Traumatic Brain Injury.
abstract: Traumatic brain injury (TBI) triggers endoplasmic reticulum (ER) stress and impairs autophagic clearance of damaged organelles and toxic macromolecules. In this study, we investigated the effects of the post-TBI administration of docosahexaenoic acid (DHA) on improving hippocampal autophagy flux and cognitive functions of rats. TBI was induced by cortical contusion injury in Sprague-Dawley rats, which received DHA (16 mg/kg in DMSO, intraperitoneal administration) or vehicle DMSO (1 ml/kg) with an initial dose within 15 min after the injury, followed by a daily dose for 3 or 7 days. First, RT-qPCR reveals that TBI induced a significant elevation in expression of autophagy-related genes in the hippocampus, including SQSTM1/p62 (sequestosome 1), lysosomal-associated membrane proteins 1 and 2 (Lamp1 and Lamp2), and cathepsin D (Ctsd). Upregulation of the corresponding autophagy-related proteins was detected by immunoblotting and immunostaining. In contrast, the DHA-treated rats did not exhibit the TBI-induced autophagy biogenesis and showed restored CTSD protein expression and activity. T2-weighted images and diffusion tensor imaging (DTI) of ex vivo brains showed that DHA reduced both gray matter and white matter damages in cortical and hippocampal tissues. DHA-treated animals performed better than the vehicle control group on the Morris water maze test. Taken together, these findings suggest that TBI triggers sustained stimulation of autophagy biogenesis, autophagy flux, and lysosomal functions in the hippocampus. Swift post-injury DHA administration restores hippocampal lysosomal biogenesis and function, demonstrating its therapeutic potential.
authors.affiliation: Department of Neurology, The Second Hospital of Dalian Medical University, Dalian, 116027, China.|Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Li
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: George
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA.|Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Education and Clinical Center, Pittsburgh, PA, 15213, USA.
authors.forename: Hong Q
authors.initials: HQ
authors.lastname: Yan
authors.affiliation: Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Lesley M
authors.initials: LM
authors.lastname: Foley
authors.affiliation: Department of Biological Science, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Liwia A
authors.initials: LA
authors.lastname: Andrzejczuk
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Insiya Y
authors.initials: IY
authors.lastname: Attarwala
authors.affiliation: Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA.|Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: T Kevin
authors.initials: TK
authors.lastname: Hitchens
authors.affiliation: Department of Biological Science, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Kirill
authors.initials: K
authors.lastname: Kiselyov
authors.affiliation: Department of Neurosurgery, Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA.|Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Education and Clinical Center, Pittsburgh, PA, 15213, USA.
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA. sund@upmc.edu.|Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Education and Clinical Center, Pittsburgh, PA, 15213, USA. sund@upmc.edu.
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004281:Docosahexaenoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D004281:Docosahexaenoic Acids
keywords: Autophagy; Cortical contusion injury; Docosahexaenoic acid; Lysosome; Microglial polarization; Secondary injury