Lecture 28: Stroke

Question 1

What is stroke?

Answer 1

• Group of disorders involving haemorrhage or occlusion of brain blood vessels.
• Worldwide the 3^rd leading cause of death. Commoner in older people. Huge worldwide burden.

Question 2

What are the main types of stroke?

Answer 2

• Ischemic: blockage of blood vessels
• Hemorrhagic: rupture of blood vessels

Stroke is mostly focal (loss of blood supply to a particular area of the brain) but can be global (e.g. caused by cardiac arrest).

Question 3

Is stroke mostly focal or global?

Answer 3

Stroke is mostly focal (loss of blood supply to a particular area of the brain) but can be global (e.g. caused by cardiac arrest).

Question 4

What are some risk factors to Stroke?

Answer 4

• Diabetes
• Hypertension
• Atherosclerosis (contributes to 50% of ischemic strokes)
• Genetic polymorphisms

Question 5

Name the regions affected by Stroke

Answer 5

• Nerve cells in the brain region with the greatest loss of blood flow in focal ischemia (so-called core or infarct zone) die rapidly by a necrotic (cell murder) mechanism.
• Around this infarct is a region called the penumbra where nerve cells die by a slower (24-72hrs delayed cell death) process involving apoptosis (cell suicide).

Necrotic cell death probably occurs too rapidly to be amenable to therapeutic intervention, which is why most _{therapy has focused upon rescuing the nerve cells in the penumbra.}

Question 6

Cells in the Penumbra region die by _______

Answer 6

Apoptosis

Question 7

Cells in the Core/Infarct zone die by ________

Answer 7

Necrosis

Question 8

What are the causes of necrosis?

Answer 8

Cell lysis (cells burst)

Question 9

What are the causes of apoptosis

Answer 9

• Massive release of glutamate (saturation of transporters)
• Influx of i_ntracellular calcium_
• F_ree-radical production_
• Activation of brain macrophages (microglia) releasing neurotoxic chemicals such as NO, superoxide, cytokines
• Activation of intrinsic apoptotic mechanisms
• Etc.

Question 10

What is the excitotoxicity theory?

Answer 10

One theory to explain how neurons die during stroke is the excitotoxicity theory

• Excessive activation of glutamate systems in the brain initiate nerve cell death.
• Saturation of glutamate transporters may be involved here.

Question 11

What is the main excitatory NT in the brain.

Answer 11

Glutamate

Question 12

What are the 2 types of glutamate receptors?

Answer 12

• Ionotropic (ion channels): AMPA/Kainate; NMDA
  
  • Ionotropic receptors are transmembrane molecules that can “open” or “close” a channel that would allow smaller particles to travel in and out of the cell.
• Metabotropic: G-protein linked
  
  • Metabotropic receptors do not have a “channel” that opens or closes. Instead, they are linked to another small chemical called a “G-protein.”

Question 13

What are AMPA Receptors (Ligand-Gated Ion Channel)

Answer 13

AMPA receptor is a type of glutamate inotropic receptor.

Receptor composed of multiple subunits GluR1-4.

• Receptors with GluR2 subunit pass sodium but not calcium.
• Receptors without GluR2 but with GluR3 can carry calcium ions.

Ischaemic brain injury causes a down-regulation of GluR2 subunit (and up-regulation of GluR3), which might promote brain damage by increasing calcium fluxes (see later).

Question 14

What are Kainate Receptors?

Answer 14

(Ligand-Gated Ion Channel)- Glutamate Inotropic receptor

Question 15

What are NMDA receptors?

Answer 15

Glutamate inotropic receptors

NMDA is both ligand and voltage gated.

When polarized, Mg2+ occupy and block channel. Depolarisation leads to Mg2+ efflux (hence voltage-dependent).

PCP (phencyclidine, ‘angel dust’) binds inside channel and blocks ion flow (non-competitive antagonists)

• NMDA antagonists are generally neuroprotective but complex (human model for schizophrenia)

Question 16

What do “angle dust” act on?

Answer 16

NMDA, inotropic glutamate receptors

Question 17

Describe a Metabotropic glutamate receptor

Answer 17

Metabotropic (G-Protein-Linked Receptors)

• Group 1 (mGluR1&5)
• Activate phospholipase C and depolarize neurons.
• Group I antagonists are neuroprotective in some model systems
• Group II (mGluR2&3)
• Gi-linked and inhibit adenylate cyclase and cause i_nhibition of neurotransmitter_ release.
• Group II agonists at these receptors are neuroprotective in some model systems.

Question 18

Summarize the involvement of glutamate in stroke

Answer 18

Pathological activation of AMPA, NMDA, and mGluR1/5 receptors cause

1) Increased calcium influx (NMDA), which reslts in delayed nerve cell death ( penumbra)
2) Increased sodium influx, chloride flux and water influx (AMPA) results in rapid nerve cell death (core/infarct zone)

Question 19

How does Increasd calcium cause nerve cell death?

Answer 19

Biochemical pathways intrinsic to the neuron (calcium-sensitive enzymes) are activated by increased calcium, causing cell death by suicide. E.g. cleaved caspase 3.

These intracellular nerve cell death pathways are beginning to be dissected out and novel targets to treat neurodegeneration are being described and drugs developed. Nerve cell survival pathways are also being discovered.

Question 20

Describe the process of neuronal apoptosis

Answer 20

A number of studies suggest that ischemic neuronal cell death requires n_ew gene expression_ which activates caspase enzyme_s that c_leave substrates leading to cell death.

• Caspases (1,2,3,8,9,12) are activated themselves by cleavage and then target substrates leading to _neuronal apoptosis/suicid_e, and caspase 3 is particularly important in neuronal apoptosis.
• Therefore, we want to inactivate caspases to treat stroke.

Question 21

What are some treatment options for stroke patients?

Answer 21

• TPA (tissue plasminogen activator) for thrombolysis, but must be given within a few hours of stroke for benefit.

(the below haven’t really worked)

• Glutamate antagonists have so far not worked due to complex role of glutamate receptors, for example:
  
  • Activation of synaptic NMDA receptors by glutamate elicits neuronal survival;
  • But activation of extrasynaptic NMDA receptors elicits neuronal death in the same population of cultured neurons.
• Hypothermia.
• Free-radical scavengers.
• Anti-inflammatory medications.
• Blockers of caspases?

Question 22

What are some extra-neural cells that are involved in strokes?

How are they involved in strokes?

Answer 22

• Astrocytes are very important cells in the brain. One of their functions is to link neuronal activity to blood flow. They also promote n_euronal survival._
• Astrocytes may be an important target for drugs to treat stroke – the concept of astroprotection (cf. neuroprotection) is now developing – keeping them alive and functioning means that the neurovascular unit is maintained.
• Also maintaining the integrity of pericytes and endothelial cells that make up capillaries after stroke may also be a therapeutic strategy. Also, ways of promoting new vessel formation.