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PHAL303 > Neuroinflammatiom > Flashcards

Neuroinflammatiom Flashcards

1
Q

Stroke

A

Risk factors - above 50, genetics, high BP, diabetes, COVID, exercise
Thrombus/clot blocks blood in brain, small vessel disease, atherosclerosis, lipid build up

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2
Q

Stroke management

A

1940s/50s - blood thinners
70s/80s - recovery via reperfusion
90s - tissue plasminogen activator (tPA) and mechanical thrombectomy

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3
Q

Targeting clots

A

Alteplase, tenecteplase (tPA analogues) within 4.5 hours
Bind to fibrin and convert plasminogen to plasmin (degrades clot:

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4
Q

Clot in brain

A

Decrease blood flow, oxygen and glucose
Axonic depolarisation -> release of glutamate and calcium
Gliosus triggers inflammatory signalling and Bb dysfunction
Spreading neuronal cell death

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5
Q

Acute immune system response to stroke

A

Adhesion molecule, complement, DAMPs and cytokines -> neutrophils -> ROS, cytokines, NET
Regulatory immune cells -> brain = immuno depression
Adrenal glands activated
Phagocytosis, apoptosis, differentiation = scars
Neurogenesis = functional improvements

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6
Q

Chronic immune response to stroke

A

Antigen presenting cells and CNS antigens
Trigger differentiation and expansion of T and B cells
Autoreaction via choroid plexus causes chronic inflammation and stop regeration
Depression, fatigue, dementia

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7
Q

Stroke therapies

A

Non approved
Anti CD-11/18, anti VLA-4
Target early immune adhesion or recruitment
G
Fingolimod, minocycline

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8
Q

Fingolimod

A

Sphingosine-1-phosphate analogue
Agonist of GPCR S1P1 -> receptor internalisation
T cells unresponsive, no infiltration into damaged brain, neuronal survival
Trials = decreased infarct growth by 26%, function by 2.6 fold

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9
Q

Minocycline

A

Antibiotic derivative of tetracycline but more lipophilic
Antagonist of bacterial 30S ribosomal subunit, inhibiting protein synthesis
Antioxidant, regulates enzymes, suppress lymphocyte and microglia signalling and proliferation, reduce pro-apoptosis factors
Trial - improved functional 1.6 times more than standard, oral best

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10
Q

Timing of stroke treatment

A

Limit damage and regeneration
Early immunomodulating could inhibit macrophages
Phase regulation

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11
Q

Multiple sclerosis

A

Chronic neurodegenerative disease
Autoimmune disease that occurs in waves (lose inactive phase -> remission)
Lesions in the brain - intolerance of T cells and macrophages lead to demyelation (neurodegeneration)

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12
Q

MS autoimmune activation

A

Macrophages in meningeal, perivascular and ventricular spaces present antigens + microglia and astrocytes = activation of T-cells = inflammation (stress and demyelation)

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13
Q

Chronic MS

A

Gliosis, prevent remyelation inhibiting regeneration of oligodendrocyte cells
Neuronal damage = mitochondrial injury, accumulation of glutamate, backwards spread of degeneration, apoptosis

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14
Q

MS therapies

A

Ocrelizumab - progressive (approved)
Escalation therapy
Induction therapy
Immune reconstitution therapy

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15
Q

Escalation therapy

A

First line have moderate effects
Second line have more efficacy but less safe and expensive

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16
Q

First line escalation therapy

A

Glatiramer acetate - distracting antigens, balance inflame and regulatory
Interferon beta-1a, 1b, p - reduce antigen presentation and T cell proliferation/trafficking
Teriflunomide - inhibit synthesis/proliferation B and T cells
Dimethyl fumarate - Nrf-2 pathway = inti-inflammatory and cytoprotective

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17
Q

Interferon beta

A

Braod acting, non selective anti-viral, anti-proliferative immunomodulator
Decrease T cell activation, prevent BBB migration, increase anti-inflammatory cytokines, decrease antigen presentation
Clear benefit via trial
Adverse effects - flu like symptoms, injection site reaction, increase liver enzymes, rare liver toxicity

18
Q

Second line escalation therapy

A

Fingolimod - inhibit S1P pathway, prevent lymphocytes -> CNS
Cladribine - inhibit purine synthesis, deplete B/T cells
(Dal)Fampridine - K+ channel blocker, improve conduction in demyelated axons
Ocrelizumab, alemtuzumab, natalizumab - antibodies against CD20, 52, a-4 integrin

19
Q

Cladribine

A

Small molecule prodrug, enzyme found in T and B cells -> necrosis/apoptosis
Inhibit methylation in DNA synthesis = damage to DNA and mt membrane
Adverse effects - lymphopenia, infection, including TB, malignancy, tetratogenic (no adaptive immunity)
Trial - better than interferons and DMF but not fingolimod

20
Q

Natalizumab

A

Adverse effects - dizziness, shivering, nausea, itchy skin, rash, hypersensitivity reactions, herpes
a4 integrin = selectively expressed during inflammation, block lymphocyte binding to VCAM1 on brain endothelium -x> CNS
Trials - long term effectiveness, lower relapse rate, serious adverse events 4.6%

21
Q

Progressive multifocal leukoencephalopathy

A

Latent virus in oligodendrocytes
Immune system surpassed - demyelination of nerve cells in white matter
Clumsy, weak, death 3-4 months

22
Q

Induction therapy

A

More aggressive disease - quick remission
Highly effective first -> deplete lymphocytes
Long term maintenence

23
Q

Immune reconstitution therapy

A

Haematopoietic stem cells, deplete autoreactive lymphocytes, autologous transfer of non-reactive lymphocytes

24
Q

Haematopoietic stem cells

A

From patients bone marrow and expanded
IV injection back in -> differentiation into leukocytes
Trials - uncontrolled, increase PFS 74%, GvHD dropped, 30% no remission after 10 years

25
Q

Alzheimers disease`

A

Progressive, neurodegenerative -> dementia
Familial and sporadic forms
B-amyloid plaques, tauopathy, astrogliosis and microgliosis
Neuronal and synaptic loss
Memory impairment, function, behavourial

26
Q

Familial vs sporadic AD

A

Familial less than 3%, APP, PSEN1&2 genes
Sporadic - ages female, vascular lifestyle, ApoE4, TREM2 genes

27
Q

AD pathology

A

Severe atrophy in hippocampus and cerebral cortex, enlarged ventricles
Tau staining -> NFT, B-amyloid staining -> neuritic and diffuse plaques

28
Q

Amyloid cascase hypothesis

A

Familial forms and genetic
Amyloid precursor cleaved by B and gamma secretases
Oligomerisation of AB peptide -> plaque (naturally cleaved by microglia)
Mutations change peptide size -> plaque

29
Q

Other causes of AD (not amyloid)

A

Disregulate breakdown of AB aggression -> neurofibrillary tangles
Tau protein - stabilises microtubules, phosphorylation destabilises
Tau phosphorylation without microtubules -> tangles
Kill neurons

30
Q

Gliosis

A

Reactive microglia and astrocytes -clean up damage, promote repair
Age - microglia not working, decreasing reactivity and recognition = lose clean up activity
TREM2 - partial loss of function of mcroglia - can’t clear AB peptide
Astrocytes - produce apolipoproteins transport cholesterols and immune signalling
APOEs - microglial survival and phagocytosis (TREM2)
APOEe4 - poor AB clearance

31
Q

PD diagnosis

A

AB positron emission tomography (PET)
- may use cerebrospinal fluid biomarkers (pTau/AB ratio)
30% healthy older people are amyloid positive

32
Q

AD immunotherapies

A

Target AB via vaccines, antibodies
Inflammatory - NSAIDs, mast cell stabilisers (microglia)

33
Q

NSAIDs in AD

A

COX1and2 or COX2
Less PGs - reduce inflammation, cell proliferation, haemostats
May prevent AD, studies not recommended

34
Q

Mast cell stabilisers

A

Prevent degranulation of patrolling mast cells via Ca2+ release from ER
Cromolyn - prevents cytokine and mediator release -> increase microglia activation and phagocytosis of AB42
Trial - safe, decrease CSF amyloid and CRP levels

35
Q

Amyloid-B vaccines

A

Innate immune response to AB
B/T cell epitopes and immune booster
CAD106

36
Q

CAD106

A

Virus -> peptides only (copies of AB1-6 fragment)
Animals - reduce amyloid-B accumulation, no adverse inflammatory reactions
Trials - no change in cognition (but plaques decrease)
Worsening cognitive function APOE4 carriers

37
Q

Amyloid-B antibodies

A

Activate microglia
Mop up excess in systematic system
Aducanumab

38
Q

Aducanumab

A

IgG1 antibody for AB3-7
Higher affinity to AB monomers (as well as aggregates)
Mice - decrease AB plaque
Trial - leaky brains, 53% discontinuation, worse APOE4 carriers, decrease AB brain load and improve cognition at 52 weeks
Trial - no benefit vs placebo, EMERGE increase cognitive benefit, reduce amyloid

39
Q

Vestibular system

A

Eye movement response to movement
Cochlea and 3 semicircular canals
Sacculus - sound sensitive
Vestibular and cochlea nerves
Hair cells - increase sensitivity to gravity?
CaCO2 crystals - drag on hair cells, may come off in whiplash -> vertigo

40
Q

Vestibular loss/vestibulotoxicity

A

Aminoglycoside ototoxicity, gentamicin antibiotic
Doesn’t link up between movement and vision (vestibule-occular reflexes)
Blurred vision, memory loss, get lost
Bilateral atrophy of hippocampus (spatial navigation), unilateral signs, gait ataxia

41
Q

Vestibulotoxicity mechanism

A

Mechanoelectrical transduction channels take up drug
Bind to mt ribosomes, impair mRNA translocation and protein synthesis, decrease ATP, release cytochrome C, ROS and apoptosis

42
Q

Paeony

A

Main bioactive component of Chinese plant
Anti-inflammatory, anti-oxidant, analgesic
Protects from amino glycoside ototoxicity from gentamicin

PHAL303 (8 decks)

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