Cellular mechanism of neuronal death

Question 1

What are some diseases can causes neuronal loss during development (At birth or during childhood)?

Answer 1

• Leukodystrophy; Loss of specific white matter in the brain

- Cerebral palsy.

Question 2

What are some diseases can causes neuronal loss during Early adulthood? (Reproductive age)

Answer 2

• Multiple sclerosis
• Stroke
• Head trauma
• Motor neurone diseases (MND, ALS)
• Spinal cord injury

Question 3

What are some diseases can causes neuronal loss during Aging? (Neurodegeneration)

Answer 3

• Huntington’s diseases
• Alzheimer’s
• Dementia
• Parkinson’s disease

Question 4

What are the symptoms of neuronal death?

There’s a lot name any 5

Answer 4

- Impaired vision – in one eye or two
• Impaired hearing
• Odd sensations e.g. tingling or numbness
• Weakness in limbs, paralysis
• Cognitive disruption, including speech impairment
• Behavioural changes
• Memory loss
• Loss of dexterity
• Loss of coordination/balance
• Difficulty controlling bowel movements or urination
• Fatigue
• Pain (anywhere)
• Sleep problems
• Depression
• Spasms

Question 5

In a flowchart like manor describe the mechanisms leading to cell death.

Answer 5

Starts with: Normal cell (Homeostasis) —> +Stress = some will adapt which is good. Others won’t adapt and become injured.

Injured–> might be reversible so back to homeostasis but if not then —> Apoptosis or Necrosis both are different types of cell death.

Question 6

What are some of the causes of neuronal loss?

Answer 6

• Traumatic injury
  • Environmental toxins
  • Ischaemia
  • Infectious agents – viruses and bacteria
  • Immunologic reactions
  • Nutritional imbalances
  • Genetic diseases – e.g. defects in proteins and their aggregation

Question 7

How can cell death occur?

Answer 7

• Excitotoxicity
• Apoptosis; Controlled planned.
• Necrosis; Random, irreversible, uncontrollable

Question 8

Describe the process of necrosis.

Answer 8

• Toxicity/ stress induced cell death
• Requires little energy
• Cell swells and may burst
• Usually elicits an acute inflammatory response, neutrophils would be present to mop up.

Results in loss of functional tissue and impaired brain function.

Question 9

Describe the process of Apoptosis?

Answer 9

• Stimulated induced cell death, regulated by a strict programme.
• Controlled by specific genes.
• Requires energy
• Cells shrink, chromatin condenses (pyknosis), and then
  the nucleus fragments in a regular pattern (karyorrhexis).
• The contents of the cell are kept within the membrane or
  blebs and apoptotic bodies form.
• All the debris is phagocytosed by local macrophages and
  microglia.
• No neutrophils present (e.g. no inflammation).

The results are removal of damaged or unneeded cells.

Question 10

What is the main excitatory neurotransmitter in the brain?

Answer 10

Glutamate.

Question 11

What occurs in Excitotoxicity?

Answer 11

• NMDA, AMPA and Kainate receptors are permeable to Ca++ and/or Na+
• Na+ influx will depolarise cells and open voltage gated calcium channels
• (Calcium has normal functions e.g. regulating receptor activity by
  phosphorylation to control synaptic plasticity)
• (Too much calcium is very toxic!)
• (Excitotoxicity arises when glutamate accumulates at synapses).
• Excessive release;
  (can occur in epilepsy), loss of Ca++ homeostasis due to ATP rundown (e.g. after stroke).
• Defective Uptake;
  loss of EAAT(e.g. in MND/ALS) can lead to increased synaptic levels
• Reversal of glutamate transporters due to energy depletion after stroke.
• This results in Ca2+ accumulation at the synapse

- Ca2+ can damage mitochondria and in
addition can activate proteases,
endonucleases, stress activated
kinases, phospholipases and Nitric
Oxide Synthase

Question 12

What can cause Excitotoxicity?

Answer 12

- Head Trauma
▪ Cerebral ischemia (Stroke)
▪ Alzheimer’s, Parkinson’s and Huntington’s
diseases
▪ Motor Neurone Disease (ALS)
▪ Damage following intense seizure activity
(epilepsy) and alcohol withdrawal
▪ Age related cognitive decline

Question 13

What are the 2 types of Stroke, and what is the most common in %?

Answer 13

• Ischaemic stroke (85%)

- Haemorrhagic stroke (15%)

Question 14

What occurs in Ischaemic stroke?

And what can one/ is a risk factor?

Answer 14

• Caused by; a blood
  clot blocking the
  flow of blood in.

Causes/risk factors:
High blood pressure,
smoking, excessive alcohol consumption, diabetes, high
cholesterol.

Question 15

What occurs in Haemorrhagic stroke?

And what can one/ is a risk factor?

Answer 15

• Burst blood vessel and
  bleeding into the brain
• Causes:
  Smoking, excessive alcohol consumption, obesity, lack of
  exercise.

(4x Higher initial morbidity, same
after 3 months)

Question 16

How can ischaemia/ ischaemic stoke lead to cell/ neuronal death?

Answer 16

• Vascular occlusion/ embolism.
• Leads to reduced cerebral blood flow
• Cause apoptosis in some cells.
• Leads to a failure in high energy metabolism (due to lack of blood flow/ O₂).
• Leads to Ion homeostasis = Pump no longer works
• so increase in extracellular Ca, Na and Cl- concentration, so cells depolarise and vesicles are released.
• Leads to glutamate release.
• Glutamate no longer taken up.
• = Glutamate ecotoxicity so results in a rise of intracellular Ca++ concentration.
• Ca++ activates enzymes, which lead to free radical formation, organelle injury and ultimately cell death, then an inflammatory response which spreads the cell death to a greater area.

Question 17

What occurs in Ischaemic stroke in days 1-3 (early)

Answer 17

- Increase in pressure
• Drop in blood flow
• Blood brain barrier
disruption
• Activation of
inflammatory processes
• Excitotoxicity
• Oxidative stress evoked
activation of apoptosis
• Activation of apoptosis
• Headache, neck stiffness.
• Paralysis

Question 18

What occurs in Ischaemic stroke in Delayed cerebral damage

days 4-10

Answer 18

• Activation of proapoptotic pathways
• Disruption of the
blood brain barrier
• Arteriolar constriction
• Thrombosis and
dysfunction of the
microcirculation
• Cortical spreading
ischaemia

Question 19

What occurs in Ischaemic stroke in the greatest recovery (days
7-14)

Answer 19

- Swelling subsides
• Impairments resolve
• Residual impairments
may lead to
permanent disability

Question 20

What is the survival rate in Ischaemic stroke if they get another stroke within a year?

And what % of people do get another stroke within a year and why?

Answer 20

14% of stroke patients
have another within 1
year.

1 year survival
~60%

5 year survival
~31%

• usually the cause of the stroke isn’t treated.

Question 21

What is the treatment of Ischaemic stroke?

Answer 21

• Prognosis is influenced by the time of treatment after the stroke.
• Early rehabilitation is important.
• Thrombolysis (clot-busting) with tPA;
  • Tissue plasminogen activator (tPA) is effective in reducing morbidity rate in strokes by 30%.
• The efficacy of tPA decreases with time (no effect after 3 hours).
• It is used to treat moderate severe strokes that are not improving in the ER.

Also physiotherapy;
Rehab through exercise.

Question 22

What are some preventatives for stroke?

Answer 22

• Stop smoking
  • Eat healthier, lower cholesterol intake
  • Become active
  • Aspirin – antiplatelet – to reduce platelet aggregation
  • Anticoagulants – Warfarin, apixaban etc prevent clotting
  • Antihypertensives – to reduce blood pressure
  • Statins – to reduce cholesterol

Question 23

How would we prevent, block or reverse the effects of cerebral ischaemia (stroke) ?

Answer 23

glutamate receptor blockers, thrombolytic agents.

Question 24

Summarise the main pathophysiological events underlying cell death after cerebral ischaemia
(stroke)

Answer 24

• Energy depletion
• glutamate transporter reversal
• generation of reactive oxygen species
• cell death.