Lecture 28: Stroke Flashcards
What is stroke?
- Group of disorders involving haemorrhage or occlusion of brain blood vessels.
- Worldwide the 3rd leading cause of death. Commoner in older people. Huge worldwide burden.
What are the main types of stroke?
- 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).
Is stroke mostly focal or global?
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).
What are some risk factors to Stroke?
- Diabetes
- Hypertension
- Atherosclerosis (contributes to 50% of ischemic strokes)
- Genetic polymorphisms
Name the regions affected by Stroke
- 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.
Cells in the Penumbra region die by _______
Apoptosis
Cells in the Core/Infarct zone die by ________
Necrosis
What are the causes of necrosis?
Cell lysis (cells burst)
What are the causes of apoptosis
- 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.
What is the excitotoxicity theory?
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.
What is the main excitatory NT in the brain.
Glutamate
What are the 2 types of glutamate receptors?
-
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.”
What are AMPA Receptors (Ligand-Gated Ion Channel)
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).
What are Kainate Receptors?
(Ligand-Gated Ion Channel)- Glutamate Inotropic receptor
What are NMDA receptors?
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)
What do “angle dust” act on?
NMDA, inotropic glutamate receptors
Describe a Metabotropic glutamate receptor
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.
Summarize the involvement of glutamate in stroke
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)
How does Increasd calcium cause nerve cell death?
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.
Describe the process of neuronal apoptosis
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.
