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OMEGA-3 FATTY ACIDS FOR NEUROTRAUMA
ADINA MICHAEL-TITUS
PROFESSOR OF NEUROSCIENCECENTRE LEAD
Centre for Neuroscience and Trauma
Blizard Institute
Queen Mary University of London
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Royal London Hospital - >2,000 trauma patients/yearNeurotrauma in a context of polytrauma
WHY ARE WE INTERESTED IN CLINICAL TRANSLATION IN NEUROTRAUMA?
Intervention in the “golden hour”
Level One Trauma Centre
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PRESENTATION OF TRAUMATIC BRAIN INJURY
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Having suffered a TBI, annual mortality remains increased up to seven fold for at least 13 years.
THE IMPACT OF TBI
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PUBLIC HEALTH IMPACT
5
In the US, the annual burden of TBI has been estimated at over $ 70 billion.
In patients with severe TBI, the life time cost per case is estimated at over $ 400,000, with disability and lost productivity cost outweighing medical and rehabilitation costs by a factor of 4.
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HUMAN TBI IS VERY HETEROGENEOUS
(Maas et al., 2017)
What regime of treatment for what type of brain injury?
(Stocchetti et al., 2017)
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THE PATIENT CARE PATH IN TBIWHEN WOULD OMEGA-3 BE ADMINISTERED?
(Maas et al 2017)
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SECONDARY INJURY PATHWAYS IN TBI • Trauma affects neurons and non-
neuronal cells and triggers a cascade of processes which continue for years after the primary injury event
(Load and Faden 2010)
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TBI AS A CHRONIC CONDITIONPERSISTENT NEUROINFLAMMATION SIGNAL
(Schwab et al 2006)
Imaging of the translocator protein ( TSPO ) reveals neuroinflammatory changes more than a decade after injury
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CHRONIC CONSEQUENCES OF TBITHE TERTIARY INJURY
(Wilson et al., 2017)
Chronic traumatic encephalopathy
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PRIORITIES FOR TBI RESEARCH
Neuroprotection in the acute phase
Develop biomarkers predictive of severity and of response to treatment
Regeneration and restoration of circuitry
Prevent complications (e.g. post-traumatic stress disorder, personality changes, secondary epilepsy)
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THE TRANSLATIONAL PATH FROM PRECLINICAL RESEARCH TO THE CLINIC
$2.5-3 billion; 10-15 years
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DOCOSAHEXAENOIC ACID HAS MULTIPLE CELLULAR TARGETS AND ACTIVE METABOLITES
• Targets: ion channels (dual pore mechano-activated background potassium channels - TREK-1), voltage-gated sodium channels, retinoid receptors (RXR), peroxisome proliferator receptors (PPAR), GPCRs…
• Active metabolites (resolvins, protectins…)
(Michael-Titus and Priestley, 2013)
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EXPERIMENTAL EVIDENCE OF EFFICACY OF OMEGA-3 FATTY ACIDS IN NEUROLOGICAL INJURY MODELS
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SO, SHOULD OMEGA-3 FATTY ACIDS BE IN THE NEUROTRAUMA CLINIC NOW?
academics clinicians
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THE TRANSLATIONAL FAILURE LESSONS
THE EXAMPLE OF PROGESTERONE
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MILD TBI – CONCUSSIONFIRST STEPS TOWARDS THERAPEUTIC USE
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CONCUSSION CHANGES BRAIN CONNECTIVITY
(Hocke et al., 2018)
Connectivity evaluated using functionalinfrared spectroscopy
PPCS = persistent post-concussion symptoms
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OMEGA-3 FATTY ACIDS AND NEUROPLASTICITYTHE RESTORATION OF CONNECTIVITY POST-NEUROTRAUMA
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PROTECTION BY DHA IN SPORTS CONCUSSION
Disruption of the axonal cytoskeleton post-injuryRelease of Neurofilament L reflects the neuronal damage
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DHA ONLY OR DHA PLUS …?
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PHOSPHOLIPIDS DECREASE IN TBISIMILAR OBSERVATIONS IN EXPERIMENTAL AND HUMAN TBI
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(2014)
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TBI AND DEMENTIASPECIALISED NUTRITION CONTAINING OMEGA-3
FATTY ACIDS AS PROPHYLAXIS
(Thau-Zuchman et al., 2018)
Multinutrient in Mouse Experimental TBI
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NEXT STEPS FOR OMEGA-3 FATTY ACIDS IN TBI
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LOOKING INTO THE FUTURE
• TBI is increasingly recognised as a public health issue with massive impact
• There have been significant advances in the characterization of omega-3 fatty acids as neuroactive substances with unique structural and signalling roles
• There is increasing evidence of therapeutic potential of omega-3 fatty acids from the acute to the chronic phase post-trauma
• There are promising steps towards generation of clinically relevant data in pilot studies
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