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Questions and Answers

Which mechanism facilitates communication between cytokines and the brain, according to the passage?

  • Direct injection of cytokines into the cerebrospinal fluid.
  • Active transport of all cytokines across an intact blood-brain barrier.
  • Passive diffusion in areas of blood-brain barrier deficiency. (correct)
  • Exclusive binding of cytokines to opioid receptors in the brain.

How does inflammation affect glucocorticoid receptor (GR) sensitivity, according to the passage?

  • Inflammation enhances GR sensitivity by promoting receptor upregulation.
  • Inflammation increases GR sensitivity by preventing receptor degradation.
  • Inflammation has no direct effect on GR sensitivity.
  • Inflammation reduces GR sensitivity through cytokine signaling pathway interaction. (correct)

What is the consequence of excessive cytokine production in animal models exposed to stress?

  • Decreased production of nitric oxide.
  • Diminished neurotropic support and reduced neurogenesis. (correct)
  • Improved oxidative status in the central nervous system.
  • Enhanced neurotropic support and increased neurogenesis.

How does neuroinflammatory activation contribute to the neuropathophysiology of depression, according to the passage?

<p>By enhancing oxidative status and stimulating nitric oxide production. (C)</p> Signup and view all the answers

According to the passage, how does inflammation modulate the serotonergic system to induce depressive symptoms?

<p>By upregulating the kynurenine pathway of tryptophan metabolism. (C)</p> Signup and view all the answers

What is the role of the enzyme IDO in the context of inflammation and depression, as described in the passage?

<p>IDO converts tryptophan into kynurenine, potentially reducing serotonin synthesis. (A)</p> Signup and view all the answers

If kynurenic acid is an NMDA receptor antagonist, what effect does it have in the context of the pathophysiology of depression, according to the passage?

<p>It is neuroprotective. (D)</p> Signup and view all the answers

How does the passage suggest that inflammation and glucocorticoid receptor (GR) sensitivity are related?

<p>Inflammation can lead to decreased GR sensitivity, and reduced GR sensitivity can lead to elevated levels of inflammation. (B)</p> Signup and view all the answers

Elevated levels of C-reactive protein (CRP) are associated with an increased risk of which of the following conditions?

<p>Increased risk of angina (D)</p> Signup and view all the answers

According to the World Health Organization, what is the projected status of chronic heart disease and depression by the year 2020?

<p>They will be the first and second leading causes of disability worldwide. (C)</p> Signup and view all the answers

What is the nature of the association between cardiovascular disease and depression, according to research findings?

<p>There is a bi-directional association between the two disorders. (A)</p> Signup and view all the answers

How does depression affect glucocorticoid responsiveness in CHD patients, as indicated by recent studies?

<p>It leads to attenuated glucocorticoid responsiveness. (A)</p> Signup and view all the answers

What is the current understanding of the brain's protection from peripheral inflammatory activation?

<p>The concept of complete protection has been challenged by neuroimmunology research. (C)</p> Signup and view all the answers

In the context of heart disease and depression, what characterizes CHD patients with depression compared to those without depression?

<p>Higher levels of inflammation and alterations in HPA axis function (A)</p> Signup and view all the answers

What is the role of glucocorticoid signalling in depressed CHD patients?

<p>Insufficient signalling leads to the elevation of inflammation. (C)</p> Signup and view all the answers

What is the impact of depression as a risk factor for cardiovascular health?

<p>Recognised as an independent risk factor, increasing the risk of heart-related morbidity and mortality. (A)</p> Signup and view all the answers

In individuals with major depression, the coexistence of elevated cortisol and increased inflammation is paradoxical because:

<p>Cortisol and inflammation usually have a direct inverse relationship; one should decrease when the other increases. (B)</p> Signup and view all the answers

Glucocorticoid resistance in individuals with major depression directly impairs the:

<p>Capacity of cortisol to inhibit the production of CRH and ACTH, disrupting the HPA axis feedback loop. (B)</p> Signup and view all the answers

How does glucocorticoid resistance contribute to elevated inflammation in individuals with major depression?

<p>By preventing cortisol from effectively suppressing the release of pro-inflammatory cytokines by the immune system. (B)</p> Signup and view all the answers

In a healthy individual, cortisol is released in response to stress and subsequently regulates its own production through negative feedback. In individuals with major depression and glucocorticoid resistance, this process is impaired because:

<p>The receptors are less sensitive to cortisol, diminishing its ability to inhibit CRH and ACTH production. (D)</p> Signup and view all the answers

Which of the following best describes the impact of glucocorticoid resistance on the inflammatory response in individuals with major depression?

<p>An unregulated and prolonged inflammatory response due to diminished sensitivity of immune cells to cortisol. (C)</p> Signup and view all the answers

If a researcher aims to study the effectiveness of a novel drug designed to restore glucocorticoid receptor sensitivity in depressed patients, which biological marker would be most useful to monitor?

<p>Levels of pro-inflammatory cytokines in the blood. (B)</p> Signup and view all the answers

What percentage of patients with major depression are estimated to exhibit glucocorticoid resistance, based on the information provided?

<p>80% (B)</p> Signup and view all the answers

Consider a clinical trial assessing a new therapy for depression. If the therapy successfully mitigates glucocorticoid resistance, what changes would be expected in HPA axis activity and inflammatory markers?

<p>Normalized HPA axis activity and decreased inflammatory markers. (A)</p> Signup and view all the answers

In the context of inflammation and the kynurenine pathway, what enzymatic action contributes to a shift towards a potentially neurotoxic profile?

<p>Increased activity of IDO and KMO enzymes, diverting kynurenine towards the production of 3-hydroxykynurenine. (B)</p> Signup and view all the answers

Why might a subset of individuals with depression not respond to conventional antidepressant treatments?

<p>The complexity of depression involves neuroendocrine abnormalities and immune activation, which are not adequately addressed by conventional treatments. (D)</p> Signup and view all the answers

What is the primary objective in targeting inflammation-induced depression?

<p>To identify inflammatory biomarkers, prevent depression development, and develop new anti-depressants. (B)</p> Signup and view all the answers

How does the amygdala respond to perceived threats, and what physiological responses are triggered as a result?

<p>It fails to distinguish between real and perceived threats, activating the fight and flight response. (B)</p> Signup and view all the answers

When individuals are subjected to stress, such as delivering a speech to a judgmental panel, what key physiological and inflammatory pathways are activated?

<p>Increased heart rate, blood pressure, cortisol, catecholamines, and activation of inflammatory pathways. (C)</p> Signup and view all the answers

What role do pre-inflammatory cytokines play in the context of inflammation and the kynurenine pathway?

<p>They enhance the activity of IDO and KMO enzymes, diverting the kynurenine pathway towards neurotoxic metabolites. (D)</p> Signup and view all the answers

Which of the following best describes the relationship between chronic stress, inflammation, and depression?

<p>Chronic stress and inflammatory exposure represent challenges that patients with depression often face, requiring neural, endocrine, and immune system adaptation. (D)</p> Signup and view all the answers

In the context of the fight and flight response, why is it considered not always accurate?

<p>It is often triggered by perceived threats that are not actually threats to survival. (B)</p> Signup and view all the answers

Flashcards

Cortisol and Inflammation in Depression

Depressed patients often show elevated cortisol and increased inflammation simultaneously.

Glucocorticoid Resistance (GR)

Glucocorticoid resistance (GR) is when the body doesn't respond properly to cortisol.

GR Resistance Prevalence

GR resistance is observed in about 80% of patients with major depression.

HPA Axis and GR Resistance

In depression, the HPA axis becomes hyperactive, producing more cortisol, but GR resistance impairs cortisol's negative feedback effect.

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Impact of GR Resistance on CRH/ACTH

GR resistance causes receptors to be less sensitive, failing to effectively inhibit CRH and ACTH production.

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Inflammation and GR Resistance

Elevated inflammation in depression occurs because GR resistance prevents glucocorticoid hormones from terminating the inflammatory response.

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Immune Cells and GR Resistance

GR resistance diminishes the sensitivity of immune cells to glucocorticoid hormones.

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Impaired Anti-inflammatory Response

GR resistance prevents the immune system from inducing an appropriate anti-inflammatory response.

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Inflammation in Depression

Depressed individuals often exhibit elevated levels of pre-inflammatory cytokines and clinical inflammatory biomarkers.

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CRP and Cardiac Risk

Elevated C-reactive protein increases the risk of heart attack, angina, and other cardiac events.

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Depression & Heart Disease

There's a proven link showing that depression is associated with CHD, or coronary heart disease.

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Leading causes of disability

Heart disease and depression are major causes of disability in developed countries.

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Bi-directional Relationship

Cardiovascular issues and neuroendocrine dysfunction can significantly raise depression risk; depression itself is a risk factor for cardiovascular disease.

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CHD & Depression Effects

CHD patients with depression show higher inflammation, HPA axis issues, and GR resistance compared to those without depression.

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Glucocorticoid Response

Reduced glucocorticoid responsiveness in depressed CHD patients leads to insufficient signaling and increased inflammation.

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Brain Inflammation

Despite prior beliefs, research shows inflammatory responses can occur within the central nervous system.

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Blood-Brain Barrier Hypothesis

The hypothesis that a compromised blood-brain barrier allows inflammatory molecules to enter the brain, potentially contributing to psychiatric conditions like depression.

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Cytokine Penetration

Inflammatory molecules that can cross the blood-brain barrier through specific transport mechanisms or where the barrier is deficient.

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Glucocorticoid Resistance

Reduced sensitivity to glucocorticoids (like cortisol) due to chronic stress and prolonged exposure to inflammatory cytokines.

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Inflammation & GR Interaction

Inflammation reduces GR sensitivity via cytokine signaling pathways, disrupting receptor function, which can then elevate inflammation, creating a feedback loop.

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Stress, Cytokines, & Neurogenesis

Excessive cytokine production due to stress which can reduce neurogenesis (new neuron growth).

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Inflammation & Serotonin

Inflammation can modulate the serotonergic system via the kynurenine pathway. Reduced tryptophan which affects serotonin production.

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IDO (Indoleamine 2,3-dioxygenase)

An enzyme that converts tryptophan into kynurenine and kynurenic acid, affecting serotonin production.

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IDO Activation Effects

Following IDO activation, reduced tryptophan availability leads to reduced serotonin synthesis and production of neurotoxic tryptophan metabolites.

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Neurotoxic Metabolites in Depression

3-hydroxykynurenine and quinolinic acid stimulate NMDA receptors, potentially harming neurons and contributing to depression.

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Inflammation's Effect on Kynurenine Pathway

Inflammation boosts IDO and KMO enzymes, shifting the kynurenine pathway towards neurotoxic 3-hydroxykynurenine production.

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Stress, Inflammation, and Depression

Chronic stress and inflammation are common challenges in depression, requiring neural, endocrine, and immune system involvement.

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Treatment-Resistant Depression Causes

Some patients don't respond to antidepressants due to neuroendocrine abnormalities and immune activation.

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Goals for Targeting Inflammation-Induced Depression

Key goals include identifying inflammatory markers, preventing depression, monitoring vulnerability changes, and targeting inflammation with new drugs.

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Amygdala and Threat Perception

Amygdala initiates fight/flight automatically but can't distinguish between real and perceived threats.

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Stress-Induced Inflammation

Stress activates inflammatory pathways, increasing inflammatory cytokine levels.

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Physiological Response to Stress

Delivering speech to a judgmental group induces fight or flight, raising heart rate, blood pressure, cortisol, catecholamines, and inflammatory cytokines.

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Study Notes

  • Depressed patients exhibit elevated cortisol levels alongside increased inflammation.

Glucocorticoid Resistance

  • Glucocorticoid resistance helps explain how high cortisol and inflammation can coexist.
  • In about 80% of patients with major depression, glucocorticoid resistance is observed.
  • In depression, the HPA axis is hyperactive, leading to increased cortisol production, which impairs glucocorticoid hormones, exerting their physiological effects via negative feedback.
  • GR (glucocorticoid) resistance reduces the sensitivity of receptors, impairing their ability to effectively inhibit the production of CRH and ACTH.

Inflammation and GR Sensitivity

  • Elevated inflammation is found in patients with major depression due to impaired glucocorticoid receptor sensitivity.
  • GR resistance prevents glucocorticoid hormones from terminating the inflammatory response, thus reducing the sensitivity of immune cells.
  • The immune system cannot induce an appropriate anti-inflammatory response, resulting in excessive release of pre-inflammatory cytokines.
  • Depressed individuals show high circulating pre-inflammatory cytokines, such as interleukins and clinical inflammatory biomarkers like C-reactive proteins (CRP).
  • Inflammatory genes are associated with depression.

Health Consequences of Inflammation

  • Elevated C-reactive protein increases the risk of heart attack, angina, and other cardiac events.
  • Depression is linked to coronary heart disease (CHD), and often the two coexist.
  • By 2020, the World Health Organization approximated CHD and depression would be the first and second leading causes of disability worldwide.
  • Cardiovascular disease, marked by changes in homeostatic and neuroendocrine function, is a significant risk factor for depression.
  • Depression is an independent risk factor for cardiovascular disease and increases the risk of heart-related morbidity and mortality.
  • CHD patients with depression exhibit even higher levels of inflammation with HPA axis alteration and GR resistance, with attenuated glucocorticoid responsiveness, and insufficient glucocorticoid signalling, leading to increased inflammation

Blood Brain Barrier

  • The belief that the blood-brain barrier protects the brain from peripheral inflammatory activation has been challenged.
  • Research indicates that inflammatory responses occur within the central nervous system.
  • The blood-brain barrier hypothesis suggests that its breakdown and abnormal communication allow inflammatory molecules to penetrate the brain.
  • Cytokines can penetrate the brain via specific mechanisms, including transport mechanisms, passive diffusion where the barrier is deficient, and binding to transport molecules.
  • Glucocorticoid resistance may also arise from chronic stress and prolonged exposure to inflammatory cytokines.
  • Inflammation directly reduces GR sensitivity through interaction of cytokine signalling pathways, disrupting the functional properties of the receptors.
  • Inflammation can affect GR, and reduced GR sensitivity leads to increased inflammation.
  • Cytokines cause diminished neurotropic support and neurogenesis in animal models under acute or chronic stress.
  • Neuroinflammatory activation enhances oxidative status in the central nervous system, stimulating nitric oxide production.

Depressive Symptoms

  • Increased inflammation induces depressive symptoms by affecting the brain and modulating the serotonergic system via the kynurenine pathway.
  • Tryptophan is converted into kynurenine or kynurenic acid by the enzyme IDO.
  • IDO activation reduces tryptophan availability, leading to reduced serotonin synthesis, and the production of neurotoxic tryptophan metabolites.
  • Kynurenic acid is neuroprotective as an NMDA receptor antagonist, whereas 3-hydroxykynurenine and quinolinic acid are neurotoxic NMDA receptor agonists.
  • Pre-inflammatory cytokines amplify IDO and KMO enzyme activation, diverting the kynurenine pathway towards neurotoxic pathways.

Immune Response

  • Chronic stress and inflammatory exposure contribute to depression.
  • Adaptation involves neural, endocrine, and immune mechanisms. One-third of patients do not respond to antidepressant therapies.
  • Future treatment approaches: target inflammation-induced depression, identify inflammatory biomarkers, prevent depression development, use biomarkers to monitor vulnerability changes, and target inflammation pharmacologically to develop new antidepressants.

Evolutionary Perspective

  • The fight and flight response is not always accurate and can often be a false alarm.
  • The amygdala initiates the fight and flight response but cannot differentiate between real and perceived threats.
  • Stress activates key inflammatory pathways, increasing inflammatory cytokine levels as an immune response to a perceived threat to self-esteem.
  • Adaptive theories suggest depressive symptoms and inflammation have a potential benefit.
  • Inflammation and depressive symptoms enhance survival and reproduction in stressful environments.
  • Evolution favored organisms with activated inflammatory systems in response to a wide range of threats, including psychological stressors.
  • Inflammation and depression may be linked

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Description

This covers the connection between cytokines, the brain, and inflammation. It details inflammation's effect on glucocorticoid receptor sensitivity, cytokine production under stress, neuroinflammatory activation in depression, inflammation's modulation of the serotonergic system, and the role of IDO. It also touches on the effect of kynurenic acid and the link between inflammation and glucocorticoid receptor sensitivity.

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