Case 1 - cytokine hypothesis of MDD

Question 1

sickness behaviour

Answer 1

• Sickness behavior is a coordinated set of adaptive behavioral changes that occur in physically ill animals and humans during the course of infection. –> acute trigger
• These behaviors include lethargy, depressed mood, reduced social exploration, loss of appetite, sleepiness, hyperalgesia, and, at times, confusion.  might look like MDD

Question 2

bi-directional immune-brain communication

Answer 2

• Cytokines –> (CVOs) brain
• Cytokines –> endothelium of BBB –> cytokines in brain
• Vagus nerve stimulation via cytokines
• Immune cells enter brain

Question 3

sterile inflammation in MDD

Answer 3

• Major Depressive Disorder (MDD) is characterized by chronic, sterile inflammation.
  o The inflammatory response occurs without the presence of pathogens.
• Psychological stressors trigger extracellular release of Damage-Associated Molecular Patterns (DAMPs).
  o PAMPs include molecules like HMGB1, histones, and heat-shock proteins.
  o HMGB1, a key DAMP, binds to Toll-Like Receptor 4 (TLR-4), activating the NF-kB pathway.
  o Activation of NF-kB pathway leads to increased release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α).
• NF-κB pathway activation induces NLRP3 inflammasome activation.
  o NLRP3 inflammasome triggers auto-cleavage of caspase-1, leading to release of mature IL-1β and IL-18.
  o Gasdermin-D (GSDMD) autocleavage results in pore formation in cell membranes, facilitating cytokine release and pyroptotic cell death.
  o Microglia undergo phenotypic change into M1 state upon NLRP3 inflammasome activation.
• Increased BBB permeability allows migration of peripheral immune cells into the brain.

Question 4

inflammatory markers in MDD

Answer 4

1. Observations in Patients:
   * Increased levels of pro-inflammatory cytokines.
   * Decreased levels of anti-inflammatory cytokines.
   * Observed in both Cerebrospinal Fluid (CSF) and blood.
2. Peripheral Inflammatory Markers:
   * Higher levels compared to healthy controls:
   * C-reactive protein (CRP)  low-grade chronic inflammation
   * Interleukin-6 (IL-6)
   * Interleukin-1beta (IL-1b)
   * Interleukin-12 (IL-12).
   * Tumor necrosis factor-alpha (TNF-alpha).
    These are associated with sickness behaviour too
   * TSPO  marker of activated microglia (central marker)

Question 5

IDO-mediated cascade

Answer 5

• Indoleamine 2,3 Dioxygenase (IDO) Activation:
  o IDO is a key enzyme in the tryptophan-kynurenine pathway, responsible for catalyzing the conversion of tryptophan to kynurenine.
  o Activation: IDO is primarily activated by pro-inflammatory cytokines, such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β), in response to inflammatory stimuli.
  o Inflammatory Conditions: Inflammation-induced IDO activation diverts tryptophan metabolism away from serotonin synthesis towards the production of kynurenine and its downstream metabolites.
   It also shift the KA/QA balance towards more QA which is neurotoxic (the balance is, not QA necessarily)
• Key Metabolites and Biological Significance:
  o Kynurenine: The primary metabolite produced by IDO-mediated tryptophan degradation, kynurenine acts as a precursor for several downstream metabolites.
  o Kynurenic Acid (KYNA): KYNA is an endogenous antagonist of glutamate receptors, exerting neuroprotective effects by modulating excitatory neurotransmission.
  o Quinolinic Acid (QUIN): QUIN is a neurotoxic metabolite that stimulates excitatory N-methyl-D-aspartate (NMDA) receptors, leading to excitotoxicity and neuronal damage.
  o 3-Hydroxykynurenine (3-HK) and 3-Hydroxyanthranilic Acid (3-HAA): These metabolites have been implicated in oxidative stress and neurotoxicity, contributing to neuronal dysfunction and apoptosis.