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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
Alzheimers disease`
Progressive, neurodegenerative -> dementia Familial and sporadic forms B-amyloid plaques, tauopathy, astrogliosis and microgliosis Neuronal and synaptic loss Memory impairment, function, behavourial
26
Familial vs sporadic AD
Familial less than 3%, APP, PSEN1&2 genes Sporadic - ages female, vascular lifestyle, ApoE4, TREM2 genes
27
AD pathology
Severe atrophy in hippocampus and cerebral cortex, enlarged ventricles Tau staining -> NFT, B-amyloid staining -> neuritic and diffuse plaques
28
Amyloid cascase hypothesis
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
Other causes of AD (not amyloid)
Disregulate breakdown of AB aggression -> neurofibrillary tangles Tau protein - stabilises microtubules, phosphorylation destabilises Tau phosphorylation without microtubules -> tangles Kill neurons
30
Gliosis
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
PD diagnosis
AB positron emission tomography (PET) - may use cerebrospinal fluid biomarkers (pTau/AB ratio) 30% healthy older people are amyloid positive
32
AD immunotherapies
Target AB via vaccines, antibodies Inflammatory - NSAIDs, mast cell stabilisers (microglia)
33
NSAIDs in AD
COX1and2 or COX2 Less PGs - reduce inflammation, cell proliferation, haemostats May prevent AD, studies not recommended
34
Mast cell stabilisers
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
Amyloid-B vaccines
Innate immune response to AB B/T cell epitopes and immune booster CAD106
36
CAD106
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
Amyloid-B antibodies
Activate microglia Mop up excess in systematic system Aducanumab
38
Aducanumab
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
Vestibular system
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
Vestibular loss/vestibulotoxicity
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
Vestibulotoxicity mechanism
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
Paeony
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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