The role of neuroinflammation in affective disorders Flashcards
What is an inflammation?
Vital immune response
Attempt to:
- heal after injury
- defend against foreign bodies
- repair tissue
What is the biochemical inflammatory process?
Macrophages release cytokines (proteins) as “emergency signals”
- bringing immune cells, hormones and nutrients to fix problem
What are the steps of the inflammatory response?
Bacteria and other pathogens enter site of injury
- Blood platelets release proteins
- Most cell secretes essential factors to mediate vasodilation and vascular constriction
- > increased delivery of blood plasma and cells - Neutrophils secrete factors that kill, degrade and remove pathogens
= phagocytosis - Inflammatory response continues until foreign materials are removed and injury is repaired
What are the characteristics of inflammation described by Aulus Cornelius Celsus in the 1st century?
Cardinal signs:
- redness and warmth
- swelling
- pain
What is the biological phenomenon underlying the redness and warmth in an inflammation?
- Dilation of small blood vessels
- Increased rate of blood flow
What is the biological phenomenon underlying the swelling in an inflammation?
- Vascular permeability
- Accumulation of plasma fluid outside blood vessels
What is the biological phenomenon underlying the pain caused by inflammation?
- Distortion of tissue
- Pressure of fluids or swelling through nerve endings
- Induced by chemical mediators (e.g. serotonin)
Which sign of inflammation was described in the 19th century by Rudolf Virchow?
Loss of function
What is the biological phenomenon underlying the loss of function caused by inflammation?
- Pain inhibits mobility
- Severe swelling preventing movement
What constitutes acute inflammation?
- Immediate response
- Activation of monocytes and macrophages
- Quick resolution
What constitutes chronic inflammation?
- Delayed response
- Activation of monocytes and macrophages
AND fibroblast, lymphocytes and plasma - Can last for weeks, month or years AND damage tissue
- > may have to terminate inflammatory response
What are the two factors regulating inflammation?
- Hypothalamic pituitary adrenal (HPA) axis
2. Glucocorticoid receptors (GR)
What is the hypothalamic pituitary adrenal (HPA) axis?
- Major neuroendocrine system
- Control of stress response
- Responds to physical and psychological stressors
- Control of inflammation
What is the role of glucocorticoid receptors?
- Negative feedback regulation of HPA axis
- Immunosuppressive and anti-inflammatory effect
What activates the hypothalamic pituitary adrenal (HPA) axis?
Synthesis and secretion of corticotropin releasing hormone (CRF) and vasopressin from paraventricular nucleus of hypothalamus
What are glucocorticoids?
- Final product of HPA axis
- Made of steroid hormones
- Synthesised from cholesterol
What is the role of glucocorticoids?
- Restore and maintain bodily stress-related homeostasis
- Modulate neuroendocrine and immune responses
- Regulate energy metabolism and inflammatory reactions
- Influence cardiovascular function
What is the process of glucocorticoid receptors activation?
- When activated, GRs go from cytoplasm to nucleus
- In nucleus it binds to glucocorticoid response elements (GREs) located on DNA
- > negatively or positively altering gene transcription
-> GR sensitivity to glucocorticoids is crucial to produce appropriate immune response
What determines GR sensitivity to glucocorticoids?
Number, affinity and function of glucocorticoid receptors (GRs)
- binding from cytoplasm to nucleus and other signalling pathways
What is the transactivation of glucocorticoid receptors (GRs)?
When activation of gene expression by GR stimulates the transcription rate of a respective target gene
What is the transrepression of glucocorticoids receptors (GRs)?
When negative alteration of gene expression by GR suppresses other transcription factors activity
What mediates the crucial immunosuppressive and anti0inflammatory role of glucocorticoids?
Mediated by GR dependent transrepression
- targets genes associated with inflammatory cytokines (including interleukins)
What are the disturbances in the activity of the hypothalamic pituitary adrenal (HPA) axis associated to?
Stress related disorders
- hyperactivation or hypoactivation
To which disorders is the hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and hypercorticolism associated to?
- Major depression
- Schizophrenia
- Alzheimer’s disease
To which disorders is the hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and hypocorticolism associated to?
- PTSD
- Chronic fatigue syndrome and fibromyalgia
- Atypical depression
What is fibromyalgia?
Disorder characterised by
- widespread musculoskeletal pain
- accompanied by fatigue, sleep, memory and mood problems
What characterises the disturbance of the hypothalamic pituitary adrenal (HPA) axis in major depression?
HPA hyperactivity - hypercorticolism
> Exaggerated cortisol response to adrenocorticotropic hormone (ACTH)
> Up regulation of HPA axis activity
-> aetiology and pathogenesis of depression
> Increased cortisol concentration in
- saliva, blood, urine, CSF
> Enlarged pituitary and adrenal glands
Why is there no established biological mechanism established underlying the causality and pathogenesis of major depression?
Depression has is complex and heterogeneous
What does the genetic approach to the aetiology of depression propose?
- Heritability of depression is moderate
- Specific associated genes
- Family history
- Environment and major life stressors interact with genetic vulnerability
What does the monoamine-deficiency hypothesis of depression (Schildkraut, 1965) propose?
Depletion of monoamine neurotransmistters
- 5-HT, norepinephrine
What does the macrophage theory of depression (Smith, 1991) propose?
Excessive secretion of macrophage monokines
What does the cytokine hypotheses of depression (Schierpers et al., 2005) propose?
- Psychoneuroimmunology findings
- Neural-immune interaction
- Elevated levels of pro-inflammatory cytokines
What does the hypothalamic-pituitary-cortisol hypothesis of depression (Belmaker and Agam, 2008) propose?
Alteration in cortisol response to stress
What does the inflammatory and neurodegenerative hypothesis of depression (Maes et al., 2009) propose?
Inflammatory processes lead to diminished neurogenesis AND increased neurodegeneration
What are the two opposite biological events taking place in depression?
Raised cortisol concentration (most potent anti-inflammatory hormone)
+
Increased inflammation (observed in CSF and periphery)
Why does the raised cortisol concentration coexist with the increased inflammation in depression?
Glucocorticoid resistance in 80% of patients with major depression
What is the consequence of glucocorticoid receptor resistance in depression?
- Glucocorticoid hormone not effective
- Glucocorticoid receptors show less sensitivity to the hormone and can’t inhibit corticotropin-releasing hormones (CRH)
- > insufficient glucocorticoid signalling
- > unregulated inflammatory response
- > no anti-inflammatory response
- > excessive release of pro-inflammatory cytokines
=> Higher circulating cytokines (including interleukins)
=> Higher clinical biomarkers of inflammation (C-reactive protein - CRP)
=> Association with inflammatory genes
How is depression associated with cardiovascular disease?
High levels of inflammation
-> small increases in C-reactive protein (CRP)
- > increased risk of:
- heart attacks
- angina
- cardiac events
hs-CROP > 3mg/L -> higher risk of cardiovascular disease
> Depression and coronary hear disease are mutual risk factors
Does the blood brain barrier protect from peripheral inflammatory activation levels?
Immunology research findings:
- breakdown of blood brain barrier and consequent abnormal communication leads to inflammatory molecules in brain
- > cytokine can penetrate the brain
What does the deficient blood brain barrier hypotheses propose?
- Communication between cytokine and brain can be facilitated by transport mechanisms
- Positive diffusion at deficient site on blood brain barrier
- > Passive penetration of cytokines into CNS
- through binding of transporter molecules
What is the current hypothesis on the cause of glucocorticoid resistance?
- Chronic stress
- > prolonged exposure to inflammatory cytokines
- Inflammation reduces glucocorticoid receptor (GR) sensitivity
- Reduced sensitivity leads to inflammation
What do animal models show on the effects of inflammation in the brain?
> Excessive cytokine production
= diminished neurotropic support and neurogenesis
> Neuro-inflammatory activation
= enhanced oxidation status in CNS, stimulation of nitric oxide production
- observed in pathophysiology of depression
How does increased inflammation induce depressive symptoms?
- Modifying serotoninergic system
- Affecting kynurenine pathway of tryptophan metabolism
How is the kynurenine pathway of tryptophan metabolism affected by increased inflammation?
- Increased pro-inflammatory cytokines enhance IDO activation (indoleamine 2,3-dioxygenase)
and KMO enzymes (kynurenine 3-monooxygenase) - Which diverts kynurenic pathway into neurotoxic path
- with diversion of kynerine into 3-Hydroxijynurenine (producing quinolinic acid with KYNU enzyme)
- > Reduced peripheral availability of tryptophan, putatively leading to reduced serotonin synthesis
- > Production of neurotoxic tryptophan metabolites
=> pathophysiology of depression
Why should we consider the treatment of neural-endocrine abnormalities and immune activation in depressed patients?
1/3 of depressed patients fail to respond to conventional anti-depressant therapies
What are the ultimate clinical goals for neural-endocrine abnormalities and immune activation?
- Specifically targeting inflammation-induced depression
- Identification of inflammatory biomarkers
- Prevention of future development of depression
- Detection of biomarkers used for monitoring changes in vulnerability
- Inflammation as pharmacological target to develop new antidepressants
What makes the fight-or-flight response potentially inaccurate?
It is controlled by the amygdala which doesn’t distinguish real from perceived threats
- e.g. delivering a speech may produce an inflammatory response, and increased blood pressure, heart rate and cortisol levels
- > response due to subject’s self-esteem
What is the potential benefit of depressive symptoms?
- Inflammation response enhances host survival and reproduction
- Evolution favoured organisms with activated inflammatory systems in response to threats
