Stroke

• STROKE ON NEURON LEVEL - Ischemic cascade

  • no blood supply —> lack of O2 —> no ATP via aerobic metabolism
  • Switches to anaerobic metabolism
  • but.. doesn’t produce enough energy (15x less) and produces lactic acid (disturbs acid base balance in brain)
  • Na+/K+ pump works less efficiently due to less ATP —> Na+ build up in intracellular fluid
  • H20 in extracellularly fluid moves into ICF to dilute conc
  • neuron swells (=cytotoxic edema)
  • Na+/ Ca2+ pump stops working —> Ca2+ build up in neuron
• WHY HIGH CA2+ IN NEURONS IS BAD:

  • Na+/ Ca2+ pump stops working —> Ca2+ build up in neuron

  1. EXCITOTOXICITY: High Ca2+ causes NTs like glutamate to be released from neuron —> excites other neurons —> causes neurons to increase levels of Ca2+ (cycle)
  2. Activate degradation enzymes —> Ca2+ activate protease (breaks down proteins) and lipases (breaks down neuron cell membrane) —> other chemicals can the enter the neuron
  3. Free radials + reactive oxygen species generation at the cell membrane
• NEURONS CAN DIE AFTER A STROKE BY:

  1. cytotoxic edema (H2O swelling)
  2. calcium causes (excitotoxicity, degradative enzymes and free radicals + reactive oxygen species generation)
  3. Mitochondria may break down and release apoptosis factors —> causing apoptosis
• TREATMENTS TO ISCHAEMIC STROKE

  • lowering the brain temperature by a few degrees can reduce neuronal death (in ischaemic stroke, traumatic brain injury and cardiac arrest)
  • cooling to 32c can be tolerated for >1 day
  • best if hypothermia is induced as soon as possible after ischaemic event
  • cooling creates a low oxygen demand (stroke = reduced oxygen supply)
• MECHANISMS OF HYPOTHERMIA AS A TREATMENT

  • in early stages of a stroke, reducing excitotoxicity and decreasing brain oxygen demands play a major role
  • may also help prevent some of the issues with microcirculation that can occur when an ischaemc area becomes reperfused
  • in later stages of a stroke, hypothermia reduces apoptosis and reduces inflammation
  • may also help reduce the disruption of the blood brain barrier
• LIMITATIONS TO HYPOTHERMIA AS A TREATMENT

  • Difficult to move from animal experiments into clinical use for humans
  • cooling a 70kg human requires more energy and effort than a small animal
  • Ways to cool:

  1. ice packs/ cooling blankets
  2. cooling catheter inserted into the femoral vein and threaded into the vena cava
  3. selectively cool the brain
  4. circumvent the body’s homeostatic mechanisms and prevent shivering
  5. MOST FREQUENT: i to block thermoregulatory responses (can cause pneumonia)
• SYMPTOMS SEEN IN A HAEMORRHAGIC STROKE, BUT NOT UN AN ISCHAEMIC STROKE:

  • Severe headache
  • facial weakness and slurred speech occur in both types of strokes
• HAEMORRHAGIC STROKE is due to the spontaneous rupture of a blood vessel within the brain

  • leads to build up of intracranial pressure, which frequently results in severe headache and vomiting
  • If untreated, raised intracranial pressure can lead to ‘coning’, where the cerebellum at tonsils are forced through the foramen magnum at the base of the skull
  • this event frequently results in severe disability or death
• TRANSIENT ISCHAEMIC ATTACK (mini-stroke)

  • TIAs result from a brain blood vessel becoming blocked for a short period (where the patient will experience stroke like symptoms)
  • when the blockage clears from the blood vessel, the symptoms will resolve
  • TIAs can be regarded as a warning that the patient will eventually have a proper stroke — so treat with aspirin or statins to reduce risk of stroke
• • When blood supply is restores following a ischaemic stroke, a second phase of brain damage can occur called reperfusion injury
  • when blood begins to flow back into an ischaemic tissue (i.e the tissue is reperfused) instead of normal function being restored, an inflammatory response is initiated via mediators such as interleukins
  • oxidative stress can also occur
• FACTORS INCREASING RISK OF STROKE:

  • obesity
  • age
  • atrial fibrillation
  • Asian, Afro-Caribbean ancestory
  • atherosclerosis
  • diabetes (2x)
  • excessive alcohol
  • family history of stroke
  • heart disease
  • high blood pressure and cholesterol
  • smoking
• CAUSES OF STROKE:

  • brain artery blocks
  • brain artery bleeds
  • poor general circulation
  • heart failure
  • drowning
  • low oxygen at birth
• SYMPTOMS OF STROKE:

  • sudden severe headache with no known causes
  • unexplained dizziness, unsteadiness or sudden falls
  • sudden difficulty speaking or understanding speech
  • sudden dimness or loss of vision, particularly in one eye
  • sudden weakness or numbness of the face, arm or leg on one side of the body
• ISCHAEMIC STROKE IS THE MOST COMMON TYPE OF STROKE
• REPERFUSION INJURY

  • restoration of blood flow to an area of the brain previously rendered ischaemic by a thrombotic blockade of a key artery
  • caused by lysis or dislodgement of the clot
  • results in inflammation and oxidative stress
• POST STROKE DISABILITIES:

  • paralysis/ motor control
  • sensory disturbance (pain)
  • language problems
  • memory impairment
  • depression/ anxiety
• CURRENT AVAILABLE TREATMETNS FOR STROKE:

  • thromolysis
  • endovascular thrombectomy
  • <20% patients (none with haemorrhage)
• INFLAMMATION

  • response to immune system to infection
  • characterised by: heat, redness, swelling, pain, loss of function
• INFLAMMATORY MEDIATORS

  • glial cell activation (astrocytes, microglia)
  • oedema
  • systemic acute phase response
  • expression of adhesion molecules
  • invasion of immune cells
  • synthesis of inflammatory mediators (cytokines, free radicals, prostaglandins)
• CYTOKINES

  • produced by damaged cells —> act on the brain —> communicate between cells
  • IN STOKE< produced in the brain (particularly after brain injury)
  • microglial cells are a main source
  • interleukin-1 particularly important
• EFFECTS OF CYTOKINES IN THE BRAIN

  • fever
  • weight loss
  • hormonal changes
  • altered appetite
  • activation of sympathetic nervous system
  • altered immune system
  • sleepiness
  • lethargy
  • fatigue
• INTERLEUKIN-1

  • ‘master cytokine’
  • key inflammatory mediator
  • major disease target
  • produced rapidly in the brain
  • naturally occurring and highly selective antagonist, IL-1Ra
• IL-1 MEDIATES BRAIN INJURY

  • Rapid upregulation of IL-1α, IL-1β, IL-Ra spatial temporary pattern consistent with contribution to injury
  • exogenous or endogenous IL-1 enhances brain injury
  • inhibition of IL-1 markedly inhibits injury
• INHIBITION OF IL-1 REDUCES:

  • focal, global, permanent, reversible ischaemia
  • traumatic injury
  • excitotoxic damage (NMDA, AMPA/KA)
  • Clincal symptoms of EAE
  • Heat stroke damage
  • Epileptic seizures
• CELLULAR TARGETS OF IL-1

  • neurons
  • glia
  • endothelial cells
• HOW DOES INTERLEUKIN-1 CAUSE DAMAGE?

  • systemic inflammation linked to cardiovascular disease
  • IL-1 expression peripherally induces CNA responses
  • Rapid IL-1 production in brain after acute insults
  • Systemic IL-1 exacerbates brain damage
  • activates glia and releases toxins
  • direct effects on neurons
  • cerebrovascular actions
• INCREASED INTERLEUKIN-1 (IL-1) IN THE BRAIN:

  • Stroke —> Alzheimer’s disease |
  • Brain injury —> Parkinson’s
  • epilepsy —> motor neuron disease
  • brain infections—> multiple sclerosis
  • brain tumours —> Down’s syndrome