Central Nervous System Flashcards
What is Brain Injury?
- Multiple disabilities due to damage of the brain after birth.
- Results in cognitive, behavioral or independent functioning.
- Can be due to accidents, strokes, Alzheimer’s etc.
Explain the autoregulation of Cerebral Blood Flow and its importance. ⭐️
- Diameter of blood vessels constrict or dilate due to physiological changes.
Systemic BP –> if raised, arterioles constricts to reduce blood flow and vice-versa.
Blood gases –> increased CO2, arterioles dilate to increase blood flow.
- This meets changing demands for O2 and glucose AND protects the brain by increasing O2 delivery and removing acidic metabolites during hypoxia or ischemia.
What is Hypoxia?
- Deprivation of oxygen supply
What is Ischemia?
- Restriction of blood supply; leading to immediate neurologic dysfunction as neurons cannot generate ATP for energy-requiring processes.
What is a stroke and what are the 2 main types?
- Rapidly developing loss of neurological function due to altered blood supply to the brain.
- Ischemic stroke accounts for 80-86%
- Hemorrhagic stroke accounts for 15- 20% of all cases.
What are the risk factors for stroke?
Non-modifiable: Age/ Hereditary/ Sex/ Cardiac Arrest
Modifiable: High BP/ Smoking/ Diabetes Mellitus/ Sedentary lifestyle/ Poor diet
What are the 3 main causes for Ischemic Stroke?
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Thrombus: a blood clot that blocks an artery supplying the brain.
Embolism: Lodging of blood borne particle in blood vessel (like cholesterol or fat)
Systemic Hypoperfusion: Low blood flow due to circulatory failure induced by heart failing to pump blood to blood. E.g. cardiac arrest.
What is the Ischemic Penumbra?
- Rim of tissue outside the ischemic core.
- Viable for therapeutic intervention so it’s reversible though there’s risk for infarction.
FYI: Ischemic core is the graveyard for dead cells AKA irreversible
Describe the 7 mechanisms for Ischemic Brain Cell Death. ❗️
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- Cellular Energy Failure
- Excitotoxicity
- Oxidative Stress
- Inflammation
- Reperfusion Injury
- Apoptosis
- Peri-infarct Depolarisation
Describe Cellular Energy Failure. ⭐️
- Neuronal tissue requires a lot of ATP and have limited anaerobic metabolism so it’s highly sensitive to O2 deprivation.
1. Decreased O2 = Low ATP, which leads to low Na+ pump function (even they need ATP to work) thus ion gradients are disrupted (influx of Ca2+, H2O and Na+, efflux of K+) ; results in blebs and ER swelling.
2. Anaerobic Glycolysis –> increased lactic acid –> cellular acidosis = nuclear chromatin clumping
3. Detachment of Ribosomes –> decrease protein synthesis = lipid deposition
More depletion of ATP results in necrotic cell death.ya
Describe Excitotoxicity and its role in cell death. ⭐️
- Excessive stimulation of receptors for L-Glutamate leads to cell death. Reuptake mechanisms (lacks ATP) so fails to remove glutamate.
Disruption of ion homeostasis → sustained depolarization → sustained L-Glutamate neurotransmitter release and action = excitotoxicity
What are Glutamate Receptors and identify the 3 types.
- Allows for Na+ and Ca2+ in; K+ out
The 3 receptors are NMDA / AMPA/ Kainate
How does disrupted sodium/ potassium gradient influence Excitotoxicity?
- Glutamate transporters reverses glutamate transport.
- Further depolarization increase downstream synaptic release of glutamate.
- Decrease in cystine –> decrease in Glutathione antioxidant = increase in ROS (reactive oxygen species)
How does high influx of calcium affect Excitotoxicity?
- Influx of high Ca2+ and Na+, accompanied by H2O = swelling.
- Cascade of cell degradation initiates –> proteases disrupts membrane proteins; phospholipases degrades lipids; ATPase reduces ATP; nitric oxide synthase damage cell structures = membrane and nuclear damage, reduction in ATP.
- Ca2+ sequestered by mitochondria → opening of mitochondrial permeability transition pore = decrease in ATP; production of ROS; Apoptosis signalled by cytokine C.
- Activate nitric oxide synthase = produce nitric oxide
Describe Oxidative stress in ischemic brain cell death. ⭐️
- Mitochondrial dysfunction leads to Ca2+ (calcium ion) overload –> inflammation and reperfusion injury –> balance of oxidants vs antioxidants disrupted –> increase in ROS
First outcome: Membrane breakdown (lipids) –> increase in proteolysis (proteins) –>Damage to DNA = apoptosis
Second outcome: Feedback loop, damaging mitochondria and mito DNA = produce more ROS
Name the oxygen and nitrogen radicals as well as anti-radical enzymes.
Oxygen radicals: superoxide, hydroxyl
Nitrogen radicals: nitric oxide, peroxynitrite, nitrosyl
Enzymes that counteract radicals: superoxide dismutase, catalase, glutathione peroxidase
How does inflammation cause Ischemic Brain cell death? ⭐️
- Rapid activation of microglia —> produces pro-inflammatory cytokines and chemokines
- induces ICAM-1
- infiltration of leukocytes
- Production of ROS and protein matrix is broken down
- Finally disrupts BBB and cell death
Explain Reperfusion Injury. ⭐️
- Restoration of blood flow after blockage can result in secondary injury called reperfusion injury.
- When O2 re-enters cells, erratic transfer of electrons to oxygen produce ROS
- Cell membranes undergo lipid peroxidation
- Excess Intracellular Ca2+ also activates various lipases which break down glycerophospholipids to release arachidonic acid
- This initiates cascade which leads to more free radicals → ultimately increasing BBB permeability.
Describe apoptosis as a mechanism in Ischemic Brain Cell Death. ⭐️
Apoptotic pathways require ATP, hence it is associated with damage in the penumbra.
- Ca2+ overload & disruption of mitochondria leads to intrinsic pathway AKA (Mitochondrial INTRINSIC pathway cell injury)
- Ischemia leads to upregulation of death receptors AKA (Death Receptor EXTRINSIC pathway receptor ligand interactions)
Explain Peri-infarct depolarization. ⭐️
- Decrease in ATP and release of K+ and Glutamate → Neurons and glia depolarize.
Ischemic core: Cells undergo ischemic depolarization and never repolarize
Penumbra: Cell repolarize and depolarize again due to increase in release of K+ and Glutamate → repetitive depolarization leads to peri-infarct depolarizations
What is a traumatic brain injury and what is the difference between primary and secondary TBI?
- Head injury that disrupts normal function of the brain; leads swelling and bleeding of brain tissue.
- Primary brain injury —> tissue distortion and destruction of brain tissue.
- Secondary brain injury —>cellular changes after initial injury. This changes cell function and degeneration of glia and axons = depolarization; excitotoxicity etc.
What are the classifications of TBI?
- Clinical Severity - Glasgow coma scale
2. Injury type - focal vs diffusion
What are focal injuries?
- Cerebral contusions - usually on surface on brain at frontal and temporal lobes.
- Lacerations - tearing injury which leads to bleeding which leads to oedema and hematomas.
- Skull Fractures
What is Alzheimer’s Disease and its symptoms? ⭐️
- Affects Amyloid beta and tau proteins
- Affects women more than men
- Caused by loss of dopamine neurons in substantia nigra.
Early symptoms: short-term memory loss; mood swings
Late symptoms: long-term memory loss; loss or reduction of speech
Define Parkinson’s Disease and its symptoms
- Affects alpha-synuclein; substantia nigra midbrain.
- Tremors, slowed movement, muscle stiffness
Describe Huntington’s Disease and its symptoms.
- inherited autosomal dominant; affects huntingtin gene, cerebral cortex.
- caused by loss of med. sized spiny internucial neurons in striatum.
Early symptoms: Fidgetiness
Late symptoms: cognitive impairment, depression, behavioural disturbances
Explain what is Motor neuron disease or Amyotrophic lateral sclerosis and their symptoms. ⭐️
- Affects Superoxide Dismutase (SOD1); affects brainstem.
- caused by death of upper and lower motor neurons.
- Genes involved familial ALS is SOD-1, TDP-43, FUS-TLS.
- Muscle weakness in hands, arms, legs; progressive paralysis, voluntary movement is eventually lost
Describe the pathway common to all neurodegenerative diseases. ❗️
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- Held by molecular chaperones
- Degraded through ubiquitin-proteosome system.
- Degraded by fusion of autophagosomes and lysomes - autolysomes
- Chaperone-mediated autophagy - selectively degraded misfolded proteins with KFERQ motif
- Formation of oligomers —> arranged to fibrils, forming intracellular inclusions or extracellular aggregates.
- Mitophagy initiated by damaged mitochondria - PINK-1 Parkinson’s pathway
- Ultimately if protein aggregates cannot be degraded through UPS or autophagy is over saturated = unfolded protein commits to apoptosis.
How do protein aggregates cause disease? ⭐️
- Loss of function - PINK1 mutation causes mitochondrial damage results in Parkinson’s
- Gain of toxic function —> mutation that confers new activity. (Alpha-synuclein mutation has high likelihood to aggregate which renders hsp70 inactive)
Explain the 4 mechanisms of Neuronal Death.
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- ER stress and the unfolded protein response (UPR)
- Ubiquitin-Proteosome System (UPS)
- Autophagy
- Apoptosis
Describe the process of Unfolded Protein Response. ⭐️
- Misfolded proteins leads to ER stress to trigger UPR.
- Initial response is pro-survival aimed at relieving stress and restoring homeostasis.
- BiP chaperon binds PERK, IRE1 and ATF6.
- ER stress recruits BiP to bind to misfolded proteins instead of having them go through PERK, IRE1 and ATF6 pathway.
- If ER stress is severe, apoptotic cell death occurs.
FYI:
PERK pathway - stops protein translation by interfering with 80S ribosome. Activates ATF4 to trigger cell death if ER stress is chronic.
IRE1 pathway - triggers ER Associated Proteins to degrade misfolded proteins by splicing Xbp1 which activates its binding to ERSE and UPRE.
ATF6 pathway - increase BiP expression which is key to protein folding by translocating to golgi to be cleaved by proteases.
What is the Ubiquitin- Proteosome System? ⭐️
- Ubiquitin chains are added to lysine resides by Ub ligase and chaperoned to proteosome to be degraded.
In neurodegenerative disorders, misfolded proteins:
- Cannot be ubiquinated; inaccessible to lysine residues because it’s misfolded(duh)
- Cannot enter pore of proteosome —> inhibits proteosome activity
- This leads to large aggregates accumulating in the cytosol
- reduced UPS directly impinges on Autophagy
What is Autophagy?⭐️
- Disassembly of dysfunctional cellular components or proteins with long half life.
- Defective mitochondria (produces a lot of ROS) is degraded by Autophagy.
- Fusion of Lysosome + Autophagosome = autolysosome
E.g. in Parkinson’s, alpha-synuclein sequesters hsp70 and binds irreversibly to LAMP-2A, blocking lysosome action
What is Apoptosis in the context of neuronal cell death? ⭐️
- Cell deaths in neurodegenerative conditions are mediated by apoptosis.
- Via intrinsic mitochondrial pathway:
- mitochondrial damage leads to outer membrane permeability.
- release of cytokine C
- apoptosis - Via extrinsic (death receptor) pathway:
- death receptor activates
- assembly of Death Inducing Signalling Complex
- activates caspase 8
- triggers cytokine c release from mitochondria
- apoptosis
In neurodegenerative diseases, mitochondria can trigger intrinsic apoptotic pathway when they are dysfunctional in Alzheimer’s/ Huntington/ Parkinson’s etc.
- this is catastrophic for neurons as they need ATP to survive. Decreased activity in Complex I and IV reduces ATP production.
- dysfunctional calcium ion signaling
