Excitotoxicity and Stroke

Question 1

Define excitotoxicity.

Answer 1

Excitotoxicity is defined as when too much glutamate receptor activity causes neuronal damage and death.

Question 2

How does a sustained calcium overload damage the cell?

Answer 2

Sustained calcium ion overload puts the cell under energetic stress; increasing the energy demand on neurons leading to mitochondrial dysfunction. If calcium increases too much, a cascade of intercellular processes occurs which ultimately leads to cell suicide – apoptosis.

Question 3

Give some examples of exogenous excitotoxins.

Answer 3

Domoic Acid, BOAA, BMAA.

Question 4

Dow does domoic acid act as an exogenous excitotoxin?

Answer 4

Domoic acid structurally resembles kainic acid so acts upon the KAR causing acute neurotoxicity.

Question 5

How does glutamate work in an excitotoxic context?

Answer 5

Excess presynaptic glutamate release causes the expression of too many post synaptic receptors. This results in enhanced postsynaptic receptor sensitivity and impaired deactivation of released glutamine.

Question 6

How does ischemia affect the glutamate transporter?

Answer 6

Ischaemia causes reduced efficiency of the glutamate transporter.

Question 7

Describe the characteristics of a stroke.

Answer 7

Stroke is characterised by rapidly developing symptoms and signs of focal or global loss of cerebral function lasting more than 24 hrs or leading to death.

Question 8

What are the two types of stroke? What is the incidence rate of each one?

Answer 8

Ischaemic (80%), hemorrhagic (20%).

Question 9

What are the risk factors for stroke?

Answer 9

Previous mini-strokes, High BP, Diabetes, Heart Disease, Smoking, Obesity (increased cholesterol).

Question 10

What are the symptoms of a stroke?

Answer 10

Sudden numbness or weakness in the face, arm, or leg especially on one side of the body (FAST campaign), Sudden confusion, trouble speaking or understanding, Sudden problems seeing in one eye or both eyes, Sudden dizziness, loss of balance or coordination, or trouble walking, Sudden severe headache with no known cause.

Question 11

What causes ischaemic stroke?

Answer 11

Thrombosis in cerebrovasculature, Deep Vein Thrombosis, Blood Clots in the heart (atrial fibrillation), Atherosclerosis, Blood infection (bacterial clumps), Injecting illegal drugs.

Question 12

What causes hemorrhagic stroke?

Answer 12

Increased blood pressure, Diseased blood vessels (uncontrolled diabetes, AVM), Tumours (vascular-genesis – weak vessels), Blood clotting deficiencies.

Question 13

What is an ischemic penumbra?

Answer 13

The area around the infarct, feeding the size of the infarct.

Question 14

What is reperfusion injury?

Answer 14

When blood and O2 return, neurones are hyperactive – more excitotoxic injury.

Question 15

How can anoxic long-term potentiation lead to further damage in stroke victims?

Answer 15

It can drive a second wave of excitotoxicity during reperfusion of the ischemic area.

Question 16

Do cells in the core region ever repolarise? Do cells in the penumbra ever repolarise?

Answer 16

No. Yes, but this takes energy and eventually leads to anoxic LTP and eventually, the cells never repolarise.

Question 17

How do the cells in the core region die? How do the cells in the penumbra die?

Answer 17

Necrosis. Apoptosis.

Question 18

Describe apoptosis.

Answer 18

This is a gene activated process where cytochrome C moves from mitochondria to the cytoplasm and forms an ‘apoptosome’ with other proteins. This apoptosome activates caspases. The caspase cascade eventually leads to cell disassembly and death.