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The More, the Better: High-Dose Omega-3 Fatty Acids Improve Behavioural and Molecular Outcomes in Preclinical Models in Mild Brain Injury

  • Neurotrauma (D. Sandsmark, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Mild traumatic brain injury (mTBI) is a continuing healthcare concern worldwide contributing to significant cognitive and neurological impairment, consequently affecting activities of daily living. While mTBI recovery is becoming well studied, there are no interventions to reduce the known impairments of mTBI. Omega-3 fatty acids (N-3FA) are safe and beneficial for brain health; however, their potential effects in a pathophysiological environment such as that seen post-mTBI are unknown.

Recent Findings

Preclinical studies using rodent models are key to understanding molecular mechanisms underlying improvements post-injury. Studies to date have shown improved outcomes in rodent models following mTBI protocols, but these data have not been quantified using a systematic review and meta-analysis approach.

Summary

Our systematic review assessed 291 studies identified from the literature. Of these studies, 18 studies met inclusion criteria. We conducted a meta-analysis examining the effect of high-dose n-3FA vs placebo on neurological, cognitive and molecular changes following mTBI. Quality of studies was rated as moderate to high quality, and while mostly compliant, some areas of risk of bias were identified. Results showed that preclinical doses of 10–370 mg/kg/day of n-3FA per day in rodents (equivalent to high clinical doses) resulted in improvements in neurological and cognitive performance (pooled effect sizes ranging between 1.52 and 3.55). Similarly, improvements in molecular and inflammatory markers were observed in treated rodents vs control (pooled effect sizes: 3.73–6.55). Overall, these findings highlight the potential for high-dose n-3FA for human clinical studies following mTBI.

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Data Availability

Data is available upon reasonable request.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. McInnes K, Friesen CL, MacKenzie DE, Westwood DA, Boe SG. Mild traumatic brain injury (mTBI) and chronic cognitive impairment: a scoping review. PLoS One. 2017;12(4):e0174847.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Alexander MP. Mild traumatic brain injury. Pathophysiology, natural history, and clinical management. Neurology. 1995;45(7):1253–60.

    Article  CAS  PubMed  Google Scholar 

  3. Yue JK, Upadhyayula PS, Avalos LN, Phelps RRL, Suen CG, Cage TA. Concussion and mild-traumatic brain injury in rural settings: epidemiology and specific health care considerations. J Neurosci Rural Pract. 2020;11(1):23–33.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21(5):375–8.

    Article  PubMed  Google Scholar 

  5. Finch CF, Clapperton AJ, McCrory P. Increasing incidence of hospitalisation for sport-related concussion in Victoria, Australia. Med J Aust. 2013;198(8):427–30.

    Article  PubMed  Google Scholar 

  6. Faul M, Xu L, Wald MM, Coronado VG. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths 2002–2006. Atlanta, GA: US Department of Health and Human Services, CDC; 2010.

  7. Wang K, Cui D, Gao L. Traumatic brain injury: a review of characteristics, molecular basis and management. Front Biosci. 2016;21:890–9.

    Article  CAS  Google Scholar 

  8. McCrory P, Meeuwisse W, Dvorak J, Aubry M, Bailes J, Broglio S, et al. Consensus statement on concussion in sport—the 5th international conference on concussion in sport held in Berlin, October 2016. Brit J Sport Med. 2017;51:838–47.

    Google Scholar 

  9. Dimou S, Lagopoulos J. Toward objective markers of concussion in sport: a review of white matter and neurometabolic changes in the brain after sports-related concussion. J Neurotrauma. 2014;31(5):413–24.

    Article  PubMed  Google Scholar 

  10. Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train. 2001;36(3):228–35.

    PubMed  PubMed Central  Google Scholar 

  11. Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery. 2014;75(suppl_4):S24–33.

    Article  PubMed  Google Scholar 

  12. Romeu-Mejia R, Giza CC, Goldman JT. Concussion pathophysiology and injury biomechanics. Curr Rev Musculoskelet Med. 2019;12(2):105–16.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kara S, Crosswell H, Forch K, Cavadino A, McGeown J, Fulcher M. Less than half of patients recover within 2 weeks of injury after a sports-related mild traumatic brain injury: a 2-year prospective study. Clin J Sport Med. 2020;30(2):96–101.

    Article  PubMed  Google Scholar 

  14. Alosco ML, Tripodis Y, Baucom ZH, Mez J, Stein TD, Martin B, et al. The late contributions of repetitive head impacts and tbi to depression symptoms and cognition. Neurology. 2020;95(7):e793–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413–46.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Barnes DE, Kaup A, Kirby KA, Byers AL, Diaz-Arrastia R, Yaffe K. Traumatic brain injury and risk of dementia in older veterans. Neurology. 2014;83(4):312–9.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Gardner RC, Yaffe K. Epidemiology of mild traumatic brain injury and neurodegenerative disease. Mol Cell Neurosci. 2015;66:75–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rabinowitz AR, Li X, McCauley SR, Wilde EA, Barnes A, Hanten G, et al. Prevalence and predictors of poor recovery from mild traumatic brain injury. J Neurotrauma. 2015;32(19):1488–96.

  19. Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, et al. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery. 2005;57(4):719–26.

    Article  PubMed  Google Scholar 

  20. Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired National Football League players. Neurology. 2012;79(19):1970–4.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Mackay DF, Russell ER, Stewart K, MacLean JA, Pell JP, Stewart W. Neurodegenerative disease mortality among former professional soccer players. N Engl J Med. 2019;381:1801–8.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mcgeown JP, Hume PA, Theadom A, Quarrie KL, Borotkanics R. Nutritional interventions to improve neurophysiological impairments following traumatic brain injury: a systematic review. J Neurosci Res. 2021;99(2):573–603 The authors systematically reviewed the literature and show that n-3 FAs have shown the most promising pre-clinical results for altering neurophysiological outcomes following traumatic brain injury. Our study confirms that no clinical studies have yet been conducted in not only cognitive and neurological outcomes but also neurophysiological.

    Article  CAS  PubMed  Google Scholar 

  23. Lewis M, Ghassemi P, Hibbeln J. Therapeutic use of omega-3 fatty acids in severe head trauma. Am J Emerg Med. 2013;31(1):273. e5–8.

    Article  Google Scholar 

  24. Gomez-Pinilla F. The combined effects of exercise and foods in preventing neurological and cognitive disorders. Prev Med. 2011;52:S75–80.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Patch C, Hill-Yardin E, Ryan L, Daly E, Pearce AJ. Long chain omega-3 fatty acid intervention in ageing adults at risk of dementia following repeated head trauma. Low-level support or an opportunity for an unanswered question? J Prev Alzheimers Dis. 2021;8(1):29–32 This systematic review demonstrated that there are currently no studies that have employed n-3 FAs in humans with post-concussion syndrome. The study suggests that pre-clinical animal data is strong enough to take n-3 FA to trials in humans suffering from post-concussion syndrome.

    CAS  PubMed  Google Scholar 

  26. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wright RW, Brand RA, Dunn W, Spindler KP. How to write a systematic review. Clin Orthop Relat Res. 2007;455:23–9.

    Article  PubMed  Google Scholar 

  28. Percie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, et al. Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 2020;18(7):e3000411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. J Cereb Blood Flow Metab. 2020;40(9):1769–77.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Brit Med J. 2011;343:d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bailes JE, Mills JD. Docosahexaenoic acid reduces traumatic axonal injury in a rodent head injury model. J Neurotrauma. 2010;27(9):1617–24.

    Article  PubMed  Google Scholar 

  32. Begum G, Yan HQ, Li L, Singh A, Dixon CE, Sun D. Docosahexaenoic acid reduces ER stress and abnormal protein accumulation and improves neuronal function following traumatic brain injury. J Neurosci Off J Soc Neurosci. 2014;34(10):3743–55.

    Article  CAS  Google Scholar 

  33. Chen X, Wu S, Chen C, Xie B, Fang Z, Hu W, et al. Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following experimental traumatic brain injury. J Neuroinflammation. 2017;14(1):1–12.

    Article  CAS  Google Scholar 

  34. Chen X, Chen C, Fan S, Wu S, Yang F, Fang Z, et al. Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury. J Neuroinflammation. 2018;15(1):1–15.

    CAS  Google Scholar 

  35. Chen X, Pan Z, Fang Z, Lin W, Wu S, Yang F, et al. Omega-3 polyunsaturated fatty acid attenuates traumatic brain injury-induced neuronal apoptosis by inducing autophagy through the upregulation of SIRT1-mediated deacetylation of Beclin-1. J Neuroinflammation. 2018;15(1):1–15.

    CAS  Google Scholar 

  36. Ghazale H, Ramadan N, Mantash S, Zibara K, El-Sitt S, Darwish H, et al. Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post—Traumatic brain injury. Behav Brain Res. 2018;340:1–13.

    Article  CAS  PubMed  Google Scholar 

  37. Harvey LD, Yin Y, Attarwala IY, Begum G, Deng J, Yan HQ, et al. Administration of DHA reduces endoplasmic reticulum stress-associated inflammation and alters microglial or macrophage activation in traumatic brain injury. ASN Neuro. 2015;7(6):1759091415618969.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Lin C, Chao H, Li Z, Xu X, Liu Y, Bao Z, et al. Omega-3 fatty acids regulate NLRP3 inflammasome activation and prevent behavior deficits after traumatic brain injury. Exp Neurol. 2017;290:115–22.

    Article  CAS  PubMed  Google Scholar 

  39. Lucke-Wold BP, Turner RC, Logsdon AF, Nguyen L, Bailes JE, Lee JM, et al. Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy. J Neurosurg. 2016;124(3):687–702.

    Article  CAS  PubMed  Google Scholar 

  40. Mills JD, Bailes JE, Sedney CL, Hutchins H, Sears B. Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model. J Neurosurg. 2011;114(1):77–84.

    Article  CAS  PubMed  Google Scholar 

  41. Pu H, Jiang X, Wei Z, Hong D, Hassan S, Zhang W, et al. Repetitive and prolonged omega-3 fatty acid treatment after traumatic brain injury enhances long-term tissue restoration and cognitive recovery. Cell Transplant. 2017;26(4):555–69.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tang R, Lin YM, Liu HX, Wang ES. Neuroprotective effect of docosahexaenoic acid in rat traumatic brain injury model via regulation of TLR4/NF-Kappa B signaling pathway. Int J Biochem Cell Biol. 2018;99:64–71.

    Article  CAS  PubMed  Google Scholar 

  43. Thau-Zuchman O, Gomes RN, Dyall SC, Davies M, Priestley JV, Groenendijk M, et al. Brain phospholipid precursors administered post-injury reduce tissue damage and improve neurological outcome in experimental traumatic brain injury. J Neurotrauma. 2019;36(1):25–42 This study in pre-clinical models demonstrated that n−3 FA treatment led to a significantly improved sensorimotor outcome and cognition and reduced lesion size and oligodendrocyte loss, and it restored myelin. It decreased microglia activation and the rise in ß-amyloid precursor protein and restored depressed neurogenesis resulting from TBI.

    Article  PubMed  Google Scholar 

  44. Wu A, Ying Z, Gomez-Pinilla F. The salutary effects of DHA dietary supplementation on cognition, neuroplasticity, and membrane homeostasis after brain trauma. J Neurotrauma. 2011;28:2113–22.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wu A, Ying Z, Gomez-Pinilla F. Dietary strategy to repair plasma membrane after brain trauma: implications for plasticity and cognition. Neurorehabil Neural Repair. 2014;28(1):75–84.

    Article  CAS  PubMed  Google Scholar 

  46. Yin Y, Li E, Sun G, Yan HQ, Foley LM, Andrzejczuk LA, et al. Effects of DHA on hippocampal autophagy and lysosome function after traumatic brain injury. Mol Neurobiol. 2018;55(3):2454–70.

    Article  CAS  PubMed  Google Scholar 

  47. Zhu W, Chi N, Zou P, Chen H, Tang G, Zhao W. Effect of docosahexaenoic acid on traumatic brain injury in rats. Exp Ther Med. 2017;14(5):4411–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhu W, Ding Y, Kong W, Li T, Chen H. Docosahexaenoic acid (DHA) provides neuroprotection in traumatic brain injury models via activating Nrf2-ARE signaling. Inflammation. 2018;41(4):1182–93.

    Article  CAS  PubMed  Google Scholar 

  49. Rohatgi A. WebPlotDigitizer: Version 4.2. https://automeris.io/WebPlotDigitizer/citation.html. 2019.

  50. Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010;1(2):97–111.

    Article  PubMed  Google Scholar 

  51. Cohen J. Statistical Power Analysis for the Behavioral Sciences. Hillsdale: Erlbaum; 1988.

    Google Scholar 

  52. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Brit Med J. 2003;327(7414):557–60.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Germano AF, Dixon CE, d ' Avella D, Hayes RL, Tomasello F. Behavioral deficits following experimental subarachnoid hemorrhage in the rat. J Neurotrauma. 1994;11(3):345–53.

    Article  CAS  PubMed  Google Scholar 

  54. Morris RG. Spatial localization does not require the presence of local cues. Learn Motiv. 1981;12(2):239–60.

    Article  Google Scholar 

  55. Crawley JN. Behavioral phenotyping of rodents. Comp Med. 2003;53(2):140–6.

    CAS  PubMed  Google Scholar 

  56. Goldstein LB, Davis JN. Beam-walking in rats: studies towards developing an animal model of functional recovery after brain injury. J Neurosci Methods. 1990;31(2):101–7.

    Article  CAS  PubMed  Google Scholar 

  57. Bailes JE, Patel V. The potential for DHA to mitigate mild traumatic brain injury. Mil Med. 2014;179(11):112–6.

    Article  PubMed  Google Scholar 

  58. Nair A, Morsy MA, Jacob S. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Dev Res. 2018;79(8):373–82.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. College of Science, Health and Engineering, La Trobe University, Melbourne, Australia

    Craig S. Patch & Alan J. Pearce

  2. School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Australia

    Elisa L. Hill-Yardin

  3. Brain Health Education and Research Institute, Potomac, MD, USA

    Michael Lewis

  4. School of Science and Computing, Galway-Mayo Institute of Technology, Dublin, Ireland

    Lisa Ryan & Ed Daly

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  1. Craig S. Patch
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  2. Elisa L. Hill-Yardin
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  3. Michael Lewis
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  4. Lisa Ryan
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  5. Ed Daly
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  6. Alan J. Pearce
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Contributions

CSP, EYH and AJP conceived the study. AJP completed the data analysis. CSP, EYH and AJP contributed to the writing of the manuscript. All authors contributed to the review and editorial suggestions for the writing of the manuscript.

Corresponding author

Correspondence to Alan J. Pearce.

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Ethics Approval

No ethics approval was required to undertake this systematic review.

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Conflict of Interest

AJP currently receives partial research salary funding from Sports Health Check charity (Australia) and Erasmus+ strategic partnerships program (2019-1-IE01-KA202-051555). AJP has previously received partial research funding from the Australian Football League, Impact Technologies Inc., and Samsung Corporation, and has provided expert reports in concussion legal proceedings. CSP is Director of Feedback Nutrition Pty Ltd which sells and markets a DHA supplement is a shareholder and Non-Executive Director of Sea Dragon Ltd which sells and markets DHA tuna oil ingredients for the food and infant formula market. ML is a medical advisor to Nordic Naturals, Inc. No other author has any declaration of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Patch, C.S., Hill-Yardin, E.L., Lewis, M. et al. The More, the Better: High-Dose Omega-3 Fatty Acids Improve Behavioural and Molecular Outcomes in Preclinical Models in Mild Brain Injury. Curr Neurol Neurosci Rep 21, 45 (2021). https://doi.org/10.1007/s11910-021-01132-z

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