the hpa-axis and neuroinflammation
TRANSCRIPT
Nina BaileyBSc (Hons) MSc PhD ANutr
Stress, the HPA-axis and neuroinflammation
Acute stressors occur rapidly and have an obvious onset and offset; chronic stressors are ongoing and may not have a clear endpoint
Brief, predictable stressors are generally beneficial in terms of enhancing cognition, emotion and neurobiological systems such as the immune system
Chronic, sustained stressors are considered to be the most deleterious, contributing to immune and endocrine dysfunction, altered mood, and several neurobiological and psychological diseases
Many physical illnesses are associated with behavioural changes - such as decreased appetite, weight loss, fatigue, sleep disturbances, impaired cognitive abilities and depressed mood
• These symptoms appear to result from immune activation and are mediated by inflammatory cytokines (i.e. IL-1, IL-6 and TNF-α) and named ‘sickness behaviour’
Similar symptoms (to sickness behaviour) can be induced artificially by the administration of bacterial endotoxin and IFN-α (given therapeutically for hepatitis C)
• These IFN-α -induced symptoms can be successfully treated with SSRI antidepressants, suggesting that the production of inflammatory cytokines may also underpin the development of depressive illness
An excessive level of cortisol is neurotoxic, especially for hippocampal neurones which play a predominant role in memory and learning
Patients with Cushing's disease (exposed to excessive release of cortisol over long periods) present with reductions in hippocampal volume that correlate to deficits in cognitive function and memory (Andela et al. 2013)
Depression, anxiety and cognitive dysfunction, decreased libido, disrupted sleep are also common in patients with Cushing's disease
In a 1997 study - 66% of Cushing’s patients exhibited psychopathology, consisting mainly of atypical and major depression as well as anxiety disorder and increased suicide risk
After three months following treatment (surgery) for hypercortisolemia, this dropped significantly to 54% and further decreased to 24% after 12 months
Starkman 2013; Dorn et al. 1997
Elevated cortisol levels and decreased hippocampal volume
The neurotoxic effects of cortisol on the hippocampus may depend on at least three factors:
the developmental stage of the structure (the hippocampus glucocorticoid receptors density may change throughout development)
the level and sustainability of cortisol released
the severity and/or duration of the stressful event/s
Bremner 1999
Psychological stress
Psychological stressors fall into different categories, depending on the individual's age during stress exposure, severity and chronicity of the stressor, and the subjectively perceived threat:
Altered mother-infant interaction (i.e. foster care)
Chronic abuse (physical and mental)
Life-threatening situation (rape, combat situation, natural disaster)
Chronic stressors in adult life (such as loss, financial issues, etc)
Early life stress
Stress early in life may induce a vulnerability to stress later in life, resulting in an increased risk for anxiety, depression and post traumatic stress disorder (PTSD)
In the pathogenesis of PTSD, fear memory becomes excessively consolidated and extinction learning doesn’t progress with high comorbidity between PTSD and depression
Childhood physical abuse predisposes for PTSD development of anxiety disorders and depression in adulthood and influences its clinical course and predicts a poorer treatment outcome
Women with a history of childhood abuse are more than twice as likely to develop depression as non-abused women
Juruena et al. 2015
Changes in brain structure in mood disorders
Dysregulation of the HPA-axis/elevated cortisol is strongly implicated in the pathology of major depressive disorder and are also key features in neurodegenerative disease
MRI scans and post mortem studies show that depression is related to changes in regions of the brain relating to mood (i.e. the temporal lobes, medulla and hippocampus)
Levels of neurotrophins such as Brain-Derived Neurotrophic Factor (BDNF) involved in neuronal survival and synaptic plasticity, are lower in patients with major depression, bi-polar depression and animal models of depression
Du & Pang 2015
Cortisol and long-chain omega-3 fatty acids
Studies have found a modulating effect of HPA-axis activity on long-chain fatty acid metabolism
Cortisol influences mobilisation, oxidation and synthesis of fatty acids
For example, cortisol inhibits Δ5- and Δ6-desaturase-activity enzymes responsible for unsaturation of fatty acid chains
High cortisol concentrations are therefore associated with a decrease in omega-3 EPA and DHA concentrations
Mocking 2013DHA
EPA
ETA
SDA
ALA
Δ -6 desaturase
Elongase/desaturase
Δ -5 desaturase
Elongase
Bosma-den Boer et al. 2012
RBC membrane content of AA versus circulating TNF-α and IL-6 concentrations in healthy adults
Flock et al. 2014
Primary structural function & anti-inflammatory docosanoid
production
Anti-inflammatory eicosanoid production
REDUCED INFLAMMATION
DHAEPA
Pro-inflammatory eicosanoid production
INFLAMMATION
AA
AA to EPA ratiodirect antagonism
The relationship between the omega-3 index and the AA to EPA ratio
Omega-3 index
There is now an extensive body of data showing that depression is associated with both a chronic low-grade inflammatory response and activation of cell-mediated immunity
High AA and low EPA increases the inflammatory ‘potential’
Meta-analyses of 14 studies comparing PUFA levels between depressive and control subjects omega-3 levels significantly lower in depressed subjects
compared to controls Differences in the levels of omega-3 were more pronounced for
individuals with severe depression
Low omega-3 index and a high AA to EPA ratio are associated with the severity of depression
Conklin et al. 2007; Lin et al. 2010
Elevated cytokines are associated with depression
Meta-analysis (18 studies) found significantly increased levels of IL-1β, IL-6, and TNF-α in post mortem brain samples of suicide victims compared with brain samples of healthy control individuals who did not die by suicide
Levels of IL-1β and IL-6 were robustly associated with suicidality
Higher levels of the systemic inflammatory marker IL-6 in childhood (9 years) are associated with and increased risk of developing depression and psychosis in young adulthood (18 years)
Black et al. 2014; Khandaker et al. 2014
Cytokine-induced depression
Intravenous administration of IFN-α for seven days in healthy males– Volunteers became feverish, fatigued and lacked appetite before becoming socially withdrawn, slow to answer questions, losing interest in their surroundings, sleeping most of the day
(Rohatiner et al. 1983)
IFN-α affects HPA-axis activity – Increased cortisol brought about by IFN-α administration significantly correlates with depression and fatigue
(Raison et al. 2010)
Serotonin
TDOIDO
IFN-, TNF-, IL-1, IL-6
Kynurenine
Quinolinic acidNMDA agonist
3-Hydroxykynurenine
+
+
+
KMO
5-HTP
Neuronal damage Depression
Kynurenic acidNMDA antagonist
NMDA receptor
Tryptophan
Cortisol
IDO
Sleep disturbance
IFN-, TNF-, IL-1, IL-6
+
Omega-3 modulates neurotrophins
High omega-3 intake is associated with higher levels of BDNF and is associated with increased/greater grey matter volume (hippocampus & amygdala) in healthy individuals (Conklin et al. 2007; Ferreira et al. 2014)
Omega-3 deprivation [animal model] decreases frontal cortex omega-3 content and reduces frontal cortex BDNF expression (Rao et al. 2007)
A potential role of omega-3 in brain trauma
Production of inflammatory cytokines
and catecholamines
Increased activity of HPA-axis
Increased secretion of cortisol
Decreased dendritic branching atrophy/death of neurones
Normal growth and survival of dendritic
neurones
STRESS
Low omega-3 intake
Reduced omega-3 metabolism(via ∆ 5 & ∆ 6, desaturase)
5-HIAA/serotonin ratio
After exerting its action in the postsynaptic neuron, serotonin is transported back to presynaptic neuron by specific transporters (SERT)
The serotonin is incorporated again into vesicles and metabolised to form 5HIAA
When SERT activity is increased, more serotonin is metabolised to 5HIAA
Therefore, the 5HIAA/serotonin ratio would be higher
Serotonin recycling and degradation
The depletion of tryptophan and subsequent decrease in serotonin production is a well-established feature of mood disorders pathophysiology (Oxenkrug 2010)
SERT activity is increased by certain pro-inflammatory cytokines, thus reducing overall serotonin activity (Jazayeri et al.,2010; Song et al. 2007)
Rats fed omega-3-free diets were associated with greater RBC membrane AA composition and increased plasma IL-6, TNF-α and CRP compared to controls
Both AA levels and AA to EPA ratio are positively correlated with plasma IL-6, TNF-α, and CRP levels
The 5-HIAA/5-HT ratio is significantly greater in frontal cortex, hypothalamus, and ventral striatum of omega-3 deficient rats relative to controls
(McNamara et al., 2010)
• Increased HPA-axis activity• Increased cortisol production• Increased IDO/TMO/KMO activity • The kynurenine (KYN)/tryptophan ratio • Increased SERT activity/low serotonin
• Decreased neurotrophins• Decreased neurogenesis• Increased hippocampal atrophy• Decreased delta-6 desaturase activity • Increased COX-2, PLA2 & PGE2 activity
Neuroinflammation in mood disorders
High AA to EPA ratioLow omega-3 status
CytokinesCortisol
2012 meta-analysis of 10 studies (including 2,280 subjects)
- EPA and total n-3 PUFAs were decreased in patients with dementia
- levels of EPA, but not DHA or other PUFAs, were significantly lower in patients with pre-dementia syndrome
- EPA may act as a disease-state marker AND a risk factor for cognitive impairment (Lin et al. 2012)
EPA intake is more advantageous than DHA in reducing "brain effort" relative to cognitive performance (in young adults) (Bauer et al. 2014)
22
Omega-3 and dementia risk
Omega-3 increases blood flow to the brain supplying oxygen and fuel delivery, are essential for neurotransmitter production and function, memory, learning, cognition, and brain and neurone cell structure
Benefits restricted to those with sub-optimal omega-3 intake!!
Increased interest in the use of omega-3 in military settings to reduce/prevent PTSD and suicide rates
Low EPA and a high AA to EPA ratio is associated with the severity of the PTSD symptoms in Croatian war veterans (Kalinić et al. 2014)
Subjects with PTSD had significantly higher pro-inflammatory scores (IL-1b, IL-6, TNF-, INF-and CRP) compared to combat-exposed subjects without PTSD (Lindqvist et al. 2014)
PTSD in severely injured patients
Significant numbers of accident–injured individuals worldwide who are admitted to intensive care units develop PTSD
1 in 4 patients will develop full-blown or partial PTSD
Hippocampus is crucial for converting short-term memory into long-term
In the pathogenesis of PTSD, fear memory becomes excessively consolidated and extinction learning doesn’t progress with high comorbidity between PTSD and depression
Promoting adult neurogenesis by omega-3 supplementation early in the post trauma period might facilitate the clearance of fear memory from the hippocampus and consequently minimise PTSD symptoms
DHA for the prevention of PTSD in severely injured patients
110 accident-injured patients
3-month daily dose of 1,470mg DHA and 147mg EPA
Primary outcome was total score on the Clinical-Administered PTSD Scale
Secondary outcome included PTSD diagnosis (full-blown or partial)
Specific effect of DHA on BDNF levels
(Matsuoka et al. 2015a; Matsuoka et al. 2015b)
DHA for the prevention of PTSD in severely injured patients
No significant differences in CAPS total score at 3-months (DHA 10.78 vs Placebo 9.22)
11.1% of the DHA group and 5.5% of the placebo group developed PTSD RBC omega-3 DHA and EPA in the DHA group significantly elevated compared to the placebo group (p <0.01)Changes in BDNF levels at week 12 were inversely associated with depression severity but with no specific effect of DHA on either BDNF level
(Matsuoka et al. 2015a; Matsuoka et al. 2015b)
DHA group PlaceboBaseline 3-months Baseline 3-months
AA to EPA ratio 10.0 6.5 9.3 8.8Omega-3 index 7.63 10.58 7.78 8.00
AA 12.33 10.9 11.94 11.58EPA 1.23 1.64 1.29 1.32DHA 6.40 8.94 6.29 6.68
Matsuoka et al. 2015a
RBC membrane fatty acid composition was determined in first-episode bipolar manic or mixed (n=40) and healthy (n=40) subjects
At baseline bipolar subjects exhibited significantly lower RBC DHA levels compared with healthy subjects
EPA , DPA and AA were not different
McNamara et al. 2015
First-episode bipolar disorder is associated with erythrocyte membrane docosahexaenoic acid deficits
Bipolar Healthy controlsAA to EPA ratio 65.9 58.9Omega-3 index 3.1 3.9
AA 17.5 17.6EPA 0.28 0.33DHA 3.1 3.6
McNamara et al. 2015
First-episode bipolar disorder is associated with erythrocyte membrane docosahexaenoic acid deficits
Fatty acid intervention is dependent on
• Omega-3 status
• EPA vs DHA requirements
• AA to EPA ratio ( inflammation)
Omega-3 intervention studies meta-analysis findings
•2009 meta-analysis (28 studies) clarified ‘EPA but not DHA to be responsible for the efficacy of omega-3 long-chain polyunsaturated fatty acid supplementation in depression (Martins 2009)
•Only those supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against primary depression (15 studies) (Sublette et al. 2011)
•It is the EPA in excess of DHA within a supplement that exerts therapeutic effects (Sublette et al. 2011)
•Meta-analysis of 8 RCTs (high EPA to DHA ration in 7 of the 8) indicate a beneficial effect of omega-3 monotherapy on depressed mood in women compared with placebo (Yang et al. 2015)
Hamilton Depression Rating Scale (HDRS) total scores after a 12 week treatment with 1g daily DHA, docosahexaenoic acid or EPA, eicosapentaenoic acid. *p<0.001.
1g pure EPA more effective than 1g DHA in treating depressive symptoms
(Mozaffari-Khosravi et al. 2012)
Pure EPA vs pure DHA in the treatment of clinical depression
The effect of EPA supplements in combination with fluoxetine
• Sixty outpatients with a diagnosis of major depressive disorder based on DSM-IV criteria and a score >or=15 in the 17-item Hamilton Depression Rating Scale (HDRS) were randomly allocated to receive daily either 1g EPA or 20 mg fluoxetine, or their combination for 8 weeks
– Response rates (>or=50% decrease in baseline HDRS) were 50%, 56% and 81% in the fluoxetine, EPA and combination groups, respectively (Jazayeri et al. 2008)
– EPA alone or in combination with fluoxetine, as well as fluoxetine alone decreased serum cortisol after 8 weeks
(Jazayeri et al. 2008; Jazayeri et al. 2010)
Why is EPA so effective in managing the symptoms of depression?
EPA to DHA ratio of oils may affect the anti-inflammatory ‘potential’ and there is evidence to suggest that EPA may be more effective than DHA in reducing levels of the inflammatory cytokines TNF-a, IL-6 and IL-1β (Bhattacharya et al. 2007)
Oils with a high ratio of EPA to DHA appear to be more effective in treating depression and may explain some of the neutral findings reported in some studies
Improves symptoms in treatment-resistant
depression
Bypasses delta-6 desaturase
Reduces activation of PLA2 and the release of
AA and PGE2
Reduces hippocampal atrophy
Normalisation of BDNF levels
Improved cell survival via increased neurotrophin
receptor expression
Decreased pro-inflammatory cytokine
production
Lowers cortisol levels
EPA
Increased production of pro resolving mediators & anti-inflammatory eicosanoids
In patients with hepatitis C treated with IFN-α up to 45% will develop depression
IFN-α treatment in hepatitis C patients was associated with an increase in depressive symptoms and serum kynurenine concentrations and a decrease in serum concentrations of tryptophan and serotonin
Low omega-3 and high AA to omega-3 ratio predicts depression induced by IFN-α treatment
Bonaccorso et al. 2002; Lotrich et al. 2013
A 2-week intervention with EPA, DHA or placebo followed by 24 weeks of IFN-α treatment (n=52)
Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHA-treated patients (10% and 28%, respectively, versus 30% for placebo, p = .037)
Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p = .002)
EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels
Su et al. 2014
EPA’s effects: high vs low inflammatory markers
155 subjects diagnosed with major depressive disorder (as defined by the Hamilton Depression Rating Scale - HAM-D-17) ≥ 15 were randomised to 8-weeks of a double-blind treatment with EPA (1060mg) or DHA (900mg) or placebo
Outcomes were determined using mixed model repeated measures analysis for ‘high’ and ‘low’ inflammation groups based on individual or combined biomarkers (IL-1ra, IL-6, CRP, leptin and adiponectin)
Rapaport 2015
EPA’s effects: high vs low inflammatory markers
Although overall group differences were negligible, subjects with any ‘high’ inflammation responded more to EPA than placebo or DHA and less to DHA than placebo
Subjects identified as being high on any of the five biomarkers were more likely to respond to EPA than to placebo with DHA and the EPA placebo separation increasing with increasing numbers of markers of high inflammation
EPA supplements are more likely to be ‘effective’ where there is pre-existing inflammation
Rapaport 2015
Biomarkers for personalising omega-3 fatty acid dosing
Omega-3 index an early cardiovascular risk indicatorOmega-6 to omega-3 ratio an established marker of long-term health and chronic illnessAA to EPA ratio a measure of ’silent’ or chronic inflammation
A personalised plan aims to achieve:an omega-3 index of more than 8% an omega-6 to omega-3 ratio of between 3 and 4an AA to EPA ratio of between 1.5 and 3
‘RESTORE’ pure EPA
‘MAINTAIN’EPA, DHA and GLAMinimum 3-6 months
AA to EPA ratio Inflammatory regulation Symptoms of inflammatory illness Optimum brain, cell, heart, immune
and CNS function Optimum wellbeing
Omega-3 index AA to EPA ratio Long-term general and cellular health Heart, brain and eye health Reduce risk of chronic illness and help
protect against inflammatory disease
Therapeutic role of Pharmepa®RESTORE & MAINTAIN™
• Increased HPA-axis activity• Increased cortisol production• Increased IDO/TMO/KMO activity • The kynurenine (KYN)/tryptophan ratio • Increased SERT activity/low serotonin
• Decreased neurotrophins• Decreased neurogenesis• Increased hippocampal atrophy• Decreased delta-6 desaturase activity • Increased COX-2, PLA2 & PGE2 activity
Neuroinflammation in mood disorders
High AA to EPA ratioLow omega-3 status
CytokinesCortisol
SAMe – metabolism of neurotransmitters serotonin, melatonin and dopamine
cysteine and glutathione – vital for antioxidant protection and detoxification processes
DNA – cell cycle, genetic replication, growth and development
carnitine, choline and CoQ10 – energy metabolism and mitochondrial function
myelin proteins – nerve transmission and CNS communication
A healthy methylation cycle – necessary for the production of:
Highly bioavailable (‘body-ready’) micronutrient activesFormulated at proven dosages for enhanced efficacyStrong benefits supported with strong health claimsOffers benefits for cardiovascular health, brain function and mood balanceSynergistic benefits alongside the Igennus clinical omega-3 range Small, easy-to-swallow tablets optimised for split-dosingSplit-dosing overcomes bioavailability issues related to vitamin B12 intake and maintains optimal blood levels of key B-vitaminsSuitable for vegetarians & vegans Suitable for adults and children aged 7+
Nutritional information Per dose % RI*Vitamin C (ascorbic acid) 160 mg 200Vitamin B3 (niacin) 48 mg 300Vitamin B5 (pantothenic acid) 36 mg 600Vitamin B1 (thiamine ) 20 mg 1818Vitamin B6 (pyridoxal-5-phosphate) 20 mg 1429Vitamin B2 (riboflavin-5-phosphate 14 mg 1000Vitamin B12 (methylcobalamin) 900 g 36000Folate ([6S]-5-methyltetrahydrofolate) 400 g 200Vitamin B7 (biotin) 300 g 600
Super B-Complex
Igennus MindCare® is the first comprehensive range of targeted brain nutrition supplements based on four identified consumer need-states.
EPA & DHA +vitamins E & D
EPA & DHA +vitamins E & D
EPA & DHA +vitamins E & D
EPA & DHA +vitamins E & D
Magnesium glycinate, L-Theanine &
micronutrients
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caffeine & micronutrients
5-HTP, Magnesium glycinate &
micronutrients
N-Acetyl L-Cysteine, alpha-lipoic acid,
resveratrol & micronutrients
Education Technical
Sophie TullyNutrition Education Manager
Dr Nina Bailey Head of Nutrition
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