The role of neuroinflammation in affective disorders

Question 1

What is an inflammation?

Answer 1

Vital immune response

Attempt to:

• heal after injury
• defend against foreign bodies
• repair tissue

Question 2

What is the biochemical inflammatory process?

Answer 2

Macrophages release cytokines (proteins) as “emergency signals”
- bringing immune cells, hormones and nutrients to fix problem

Question 3

What are the steps of the inflammatory response?

Answer 3

Bacteria and other pathogens enter site of injury

1. Blood platelets release proteins
2. Most cell secretes essential factors to mediate vasodilation and vascular constriction
   - > increased delivery of blood plasma and cells
3. Neutrophils secrete factors that kill, degrade and remove pathogens
   = phagocytosis
4. Inflammatory response continues until foreign materials are removed and injury is repaired

Question 4

What are the characteristics of inflammation described by Aulus Cornelius Celsus in the 1st century?

Answer 4

Cardinal signs:

• redness and warmth
• swelling
• pain

Question 5

What is the biological phenomenon underlying the redness and warmth in an inflammation?

Answer 5

• Dilation of small blood vessels

- Increased rate of blood flow

Question 6

What is the biological phenomenon underlying the swelling in an inflammation?

Answer 6

• Vascular permeability

- Accumulation of plasma fluid outside blood vessels

Question 7

What is the biological phenomenon underlying the pain caused by inflammation?

Answer 7

• Distortion of tissue
• Pressure of fluids or swelling through nerve endings
• Induced by chemical mediators (e.g. serotonin)

Question 8

Which sign of inflammation was described in the 19th century by Rudolf Virchow?

Answer 8

Loss of function

Question 9

What is the biological phenomenon underlying the loss of function caused by inflammation?

Answer 9

• Pain inhibits mobility

- Severe swelling preventing movement

Question 10

What constitutes acute inflammation?

Answer 10

1. Immediate response
2. Activation of monocytes and macrophages
3. Quick resolution

Question 11

What constitutes chronic inflammation?

Answer 11

1. Delayed response
2. Activation of monocytes and macrophages
   AND fibroblast, lymphocytes and plasma
3. Can last for weeks, month or years AND damage tissue
   - > may have to terminate inflammatory response

Question 12

What are the two factors regulating inflammation?

Answer 12

1. Hypothalamic pituitary adrenal (HPA) axis

2. Glucocorticoid receptors (GR)

Question 13

What is the hypothalamic pituitary adrenal (HPA) axis?

Answer 13

• Major neuroendocrine system
• Control of stress response
• Responds to physical and psychological stressors
• Control of inflammation

Question 14

What is the role of glucocorticoid receptors?

Answer 14

• Negative feedback regulation of HPA axis

- Immunosuppressive and anti-inflammatory effect

Question 15

What activates the hypothalamic pituitary adrenal (HPA) axis?

Answer 15

Synthesis and secretion of corticotropin releasing hormone (CRF) and vasopressin from paraventricular nucleus of hypothalamus

Question 16

What are glucocorticoids?

Answer 16

• Final product of HPA axis
• Made of steroid hormones
• Synthesised from cholesterol

Question 17

What is the role of glucocorticoids?

Answer 17

• Restore and maintain bodily stress-related homeostasis
• Modulate neuroendocrine and immune responses
• Regulate energy metabolism and inflammatory reactions
• Influence cardiovascular function

Question 18

What is the process of glucocorticoid receptors activation?

Answer 18

1. When activated, GRs go from cytoplasm to nucleus
2. 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

Question 19

What determines GR sensitivity to glucocorticoids?

Answer 19

Number, affinity and function of glucocorticoid receptors (GRs)
- binding from cytoplasm to nucleus and other signalling pathways

Question 20

What is the transactivation of glucocorticoid receptors (GRs)?

Answer 20

When activation of gene expression by GR stimulates the transcription rate of a respective target gene

Question 21

What is the transrepression of glucocorticoids receptors (GRs)?

Answer 21

When negative alteration of gene expression by GR suppresses other transcription factors activity

Question 22

What mediates the crucial immunosuppressive and anti0inflammatory role of glucocorticoids?

Answer 22

Mediated by GR dependent transrepression

- targets genes associated with inflammatory cytokines (including interleukins)

Question 23

What are the disturbances in the activity of the hypothalamic pituitary adrenal (HPA) axis associated to?

Answer 23

Stress related disorders

- hyperactivation or hypoactivation

Question 24

To which disorders is the hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and hypercorticolism associated to?

Answer 24

• Major depression
• Schizophrenia
• Alzheimer’s disease

Question 25

To which disorders is the hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and hypocorticolism associated to?

Answer 25

- PTSD - Chronic fatigue syndrome and fibromyalgia - Atypical depression

Question 26

What is fibromyalgia?

Answer 26

Disorder characterised by - widespread musculoskeletal pain - accompanied by fatigue, sleep, memory and mood problems

Question 27

What characterises the disturbance of the hypothalamic pituitary adrenal (HPA) axis in major depression?

Answer 27

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

Question 28

Why is there no established biological mechanism established underlying the causality and pathogenesis of major depression?

Answer 28

Depression has is complex and heterogeneous

Question 29

What does the genetic approach to the aetiology of depression propose?

Answer 29

- Heritability of depression is moderate - Specific associated genes - Family history - Environment and major life stressors interact with genetic vulnerability

Question 30

What does the monoamine-deficiency hypothesis of depression (Schildkraut, 1965) propose?

Answer 30

Depletion of monoamine neurotransmistters | - 5-HT, norepinephrine

Question 31

What does the macrophage theory of depression (Smith, 1991) propose?

Answer 31

Excessive secretion of macrophage monokines

Question 32

What does the cytokine hypotheses of depression (Schierpers et al., 2005) propose?

Answer 32

- Psychoneuroimmunology findings - Neural-immune interaction - Elevated levels of pro-inflammatory cytokines

Question 33

What does the hypothalamic-pituitary-cortisol hypothesis of depression (Belmaker and Agam, 2008) propose?

Answer 33

Alteration in cortisol response to stress

Question 34

What does the inflammatory and neurodegenerative hypothesis of depression (Maes et al., 2009) propose?

Answer 34

Inflammatory processes lead to diminished neurogenesis AND increased neurodegeneration

Question 35

What are the two opposite biological events taking place in depression?

Answer 35

Raised cortisol concentration (most potent anti-inflammatory hormone) + Increased inflammation (observed in CSF and periphery)

Question 36

Why does the raised cortisol concentration coexist with the increased inflammation in depression?

Answer 36

Glucocorticoid resistance in 80% of patients with major depression

Question 37

What is the consequence of glucocorticoid receptor resistance in depression?

Answer 37

- 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

Question 38

How is depression associated with cardiovascular disease?

Answer 38

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

Question 39

Does the blood brain barrier protect from peripheral inflammatory activation levels?

Answer 39

Immunology research findings: - breakdown of blood brain barrier and consequent abnormal communication leads to inflammatory molecules in brain - > cytokine can penetrate the brain

Question 40

What does the deficient blood brain barrier hypotheses propose?

Answer 40

- 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

Question 41

What is the current hypothesis on the cause of glucocorticoid resistance?

Answer 41

- Chronic stress - > prolonged exposure to inflammatory cytokines - Inflammation reduces glucocorticoid receptor (GR) sensitivity - Reduced sensitivity leads to inflammation

Question 42

What do animal models show on the effects of inflammation in the brain?

Answer 42

> 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

Question 43

How does increased inflammation induce depressive symptoms?

Answer 43

- Modifying serotoninergic system | - Affecting kynurenine pathway of tryptophan metabolism

Question 44

How is the kynurenine pathway of tryptophan metabolism affected by increased inflammation?

Answer 44

1. Increased pro-inflammatory cytokines enhance IDO activation (indoleamine 2,3-dioxygenase) and KMO enzymes (kynurenine 3-monooxygenase) 2. 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

Question 45

Why should we consider the treatment of neural-endocrine abnormalities and immune activation in depressed patients?

Answer 45

1/3 of depressed patients fail to respond to conventional anti-depressant therapies

Question 46

What are the ultimate clinical goals for neural-endocrine abnormalities and immune activation?

Answer 46

- 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

Question 47

What makes the fight-or-flight response potentially inaccurate?

Answer 47

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

Question 48

What is the potential benefit of depressive symptoms?

Answer 48

- Inflammation response enhances host survival and reproduction - Evolution favoured organisms with activated inflammatory systems in response to threats