WEEK 11: STROKE - L20

Question 1

What are the 2 types of stroke?

Answer 1

1. Ischaemic
2. Intracerebral Haemorrphagic

Question 2

Explain the process of ISCHAEMIC STROKE = 5

Answer 2

1. Occlusion (blockage) of B.Vessel/s within the BRAIN
2. EMBOLIC STROKE - A CLOT FORMED ‘PERIPHERALLY’ that occludes vasculature in the brain
3. THROMBOTIC STROKE - CHOLESTEROL PLAQUES that NARROW the Vasculature - OFTEN IN THE NECK
4. LEAD TO LOSS OF OXYGEN AND NUTRIENTS
5. CELL DEATH

Question 3

Explain the Process of a INTRACEREBRAL HAEMORRHAGIC STROKE = 5

Answer 3

1. RUPTURING OF VASCULATURE
2. Typically result from TRAUMA (i.e injury) or HYPERTENSION
3. LOSS OF OXYEN AND NUTRIENTS
4. AND OTHER INCREASED INTRACRANIAL PRESSURE
5. CELL DEATH

Question 4

LIST THE PHASES OF STROKE AND EXPLAIN THEM: 4

Answer 4

1. HYPER-ACUTE STROKE
   - minutes to less than 24hours
   - Cell death within hours of injury
   - LARGE INFLAMMATORY RESPONSE
2. ACUTE
   - 1-7 DAYS
   - DELAYED cell death
   - large IMMUNE RESPONSE
   - Physiological changes (eg body temp)
3. SUB-ACUTE
   - 1week to 3 months
   - DELAYED CELL DEATH
   - Large immune response
   - HEIGHTENED NEUROPLASTICITY
   - REHABILITATION TYPICALLY BEGINS
4. CHRONIC
   - greater than 3 months
   - Cognitive and physical IMPAIRMENTS may BECOME MORE EVIDENT

Question 5

Explain what EXCITOTOXICITY =

Answer 5

1. Excess Glutamate –> NMDA receptors
2. T he ability of glutamate or related excitatory amino acids to mediate the death of central neurons under certain conditions
3. Different NMDARs MEDIATE CELL SURVIVAL and CELL DEATH
4. SYNAPTIC and EXTRA-SYNAPTIC ‘NMDARs’ FORM ‘FUNCTIONALLY DISTINCT POPULATIONS’
5. NMDAR ‘ACTIVATION’ ACTIVATE a DIVERSE of BIOLOGICAL PATHWAYS

Question 6

Understanding what NMDAR Subtypes are: 2

Answer 6

1. Different subtypes promote cell death or cell survival.
2. Myelin sheaths are also sensitive to EXCITOTOXICITY

Question 7

Understanding what NMDAR OVERSTIMULATION IS:4

Answer 7

1. EXCESS ‘GLUTAMATE IN THE SYNAPSE CAN ‘OVER-STIMULATE’ NMDAR
2. BINDING TO SYNAPTIC + EXTRA SYNAPTIC RECEPTORS ENHANCES EXCITOTOXICITY
3. ACTIVATION OF SPECIFIC RECEPTOR SUBTYPES (eg. GLUN2B) PROMOTES PATHWAYS OF NEURONAL DEATH
4. Na+ INFLUX via NMDAR causes ‘CELL SWELLING’ = CELL DEATH

Question 8

NMDAR ‘OVERSTIMULATION’ can lead to OXIDATIVE STRESS …EXPLAIN = 4

Answer 8

1 * Increased calcium influx

2 * ACTIVATION of ‘Ca2+ ‘ PATHWAYS THAT GENERATE REACTIVE OXYGEN SPECIES (ROS)

3. LARGE INCREASE IN ROS = OXIDATIVE STRESS
4. NEURONAL DEATH

Question 9

LIST THE ROLE ASTROCYTES = physiological conditions = 4

Answer 9

***physiological conditions

1. ionic balance
2. water transport
3. neurotransmission regulator
4. uptake and synthesis of neurotransmitters

other
- vasomodulator
- neurogenesis inductor
- antioxidant
- metabolic regulator

Question 10

ROLE OF ASTROCYTES FOLLOWING STROKE…3

Answer 10

1. following stroke astrocytes BECOME REACTIVE …leading to REACTIVE ASTROGLIOSIS
2. REACTIVE ASTROCYTES ARE LARGE IN SHAPE AND SPAN LARGER IN ‘DISTANCE’/CONTACT MORE NEURONS
3. FORM A SCAR/ENCAPSULATE THE TISSUE

Question 11

DEFINE REACTIVE ASTROGLIOSIS

Answer 11

‘in response to e.g. trauma, stroke, epilepsy, neurodegenerative diseases - upregulation of GFAP and hypertrophy of cellular processes are among the hallmarks’

REACTIBE ATROGLIOSIS IS
- context/disease dependent
- multistage
- region specific
- diffuse or demarcating the lesion
- graded (from mild astrogliosis to a glial scar)

Question 12

REACTIVE ASTROGLIOIS IS A ‘DEFENSIVE REACTION AIMING’ AT

Answer 12

1. HANDLING ACUTE STRESS
2. LIMITING TISSUE DAMAGE
3. RESTORING HOMEOSTASIS

Question 13

What are the ‘POST-STROKE’ Changes to GABA function? = 2

Answer 13

1. PERI-INFARCT TISSUE = Tissue adjacent to the stroke injured tissue
2. CHANGES TO GABA SIGNALLING TO ‘PYRAMIDAL NEURONS’ IN THE PERI-INFRACT TISSUE’

Question 14

What happens if: after stroke -‘Changes to GABA signalling to pyramidal neurons in the peri-infarct tissue’… 2

Answer 14

1. Application of GABAzine (GABA (A) antagonist) PRIMARILY BLOCKS PHASIC (SYNAPTIC) INHIBITION, ALLOWING TONIC (EXTRA-SYNAPTIC ) INHIBITION TO BE ISOLATED.
2. ELEVATED TONIC INHIBITION OBSERVED POST-STROKE RELATIBE TO CONTROL

Question 15

Post-stroke changes to GABA function

• WHAT DOES BLOCKING GABA TRANSPORTERS MEAN? = 3

Answer 15

1. blocking GABA TRANSPORTERS = increase GABA at SYNAPSE = INCREASE IN TONIC INHIBITION
2. BLOCKING GAT-1 ENHANCED TONIC INHIBITION IN STROKE MICE RELATIVE TO CONTROL
3. BENZODIAZEPINES (L655,L708) WITH SENSITIVITY TO EXTRA -SYNAPTIC ‘GABA’ RECEPTORS REDUCES TONIC INHIBITION POST-STROKE

Question 16

Post-stroke changes to GABA function…

‘Do Benzodiazepines (L655)
impact infarct volume?’ = 3

Answer 16

1. Detrimental if given early POST STROKE = LARGER INFARCTION
2. No CHANGES IF GIVEN LATER IN STROKE c.f. non-treated controls
3. Pharmacological treatments to change GABA signalling post stroke may have potential to ENHANCE RECOVERY (BUT NOT NEUROPROTECTIVE)

Question 17

Explain what INTRAVENOUS THROMBOLYTIC THERAPY IS: 3

Answer 17

1. TISSUE PLASMINOGEN ACTIVATOR ‘FDA’ APPROVED FOR THE TREATMENT OF ‘ISCHAEMIC STROKE’
2. within 4.5 hours
3. CAN INCREASE THE RISK OF INTRACEREBRAL HAEMORRHAGE

Question 18

STROKE: EXPLAIN WHAT SECONDARY DEGENERATION IS = 4

Answer 18

1. Degeneration continues after the primary insult
2. Produces a ‘second wave’ of degeneration
3. common feature of all brain injury
4. can occur in regions ‘ADJACENT TO PRIMARY INSULT AND IN REGIONS REMOTE FROM THE SITE OF INJURY (‘DIASCHISIS’)
5. 24 hours to 3 yrs post stroke possible

Question 19

STROKE - ECPLAIN ANTIOXIDANTS = 7

Answer 19

1. INHIBITS OXIDATION
2. CAN TARGET:
   - 3. ROS PRODUCING ENZYMES
   - 4. FREE RADICALS
   - 5. MITOCHONDRIAL DYSFUNCTION
3. MAYBE INCREASING ‘ENDOGENOUS ANTIOXIDANTS’ MAY ALSO IMPROVE OUTCOMES
   — 7. ‘NEUROGLOBIN’: Neuroprotective?

Question 20

Consequences of ROS IMBALANCE = 5

Answer 20

1. Lipid peroxidation
2. DNA fragmentation
3. protein denaturing
4. inflammation
5. apoptosis