Cerebrovascular Disease Pathophysiology

Ischaemic cascade

A significant fall in ccrebral blood flow produces a cascade of events which, if unchecked, lead to the production and accumulation of toxic compounds and cell death.

Mismatch between cerebral blood flow and metabolic demands (02-glucose) Electrical failure -

Anaerobic metabolism (if sufficient glucose available)

Ionic pump failure ♦

K ' efflux (from neurons)



Membrane phospholipids ♦

(phospholipase A2) t

Arachidonic acid (and other free fatty acids)



Thromboxane A2 (potent vasoconstrictor and platelet aggregant)

Prostaglandin-------(FREE RADICALS) - - Hydroperoxides

Endoperoxides —Prostacyclin \ t

Other prostaglandins

Prostacyclin (potent vasodilator and platelet antiaggregant)

Leukotrienes ♦


Role of neurotransmitters

Recent research has shown that one of the amino acid excitatory neurotransmitters, Glutamate, in excess is a powerful neurotoxin, playing an important role in ischaemic brain damage.

{Adapted from Presynaptic Ischaemia terminal Astrocyte

Rothman & Olney 1986 Annals of Neurology 19:105-111)

Gin = Glutamine Glu = Glutamate


Postsynaptic dendrite

- enhanced glutamate release and/or -

impaired reuptake


Glutamate receptors

- enhanced glutamate release and/or -

impaired reuptake



Glutamate receptors

Depolarisation - Na4 influx

K ' efflux

Ca' ' channel opened U _ ++ . n activates Ca influx .

phospholipid breakdown

- arachidonic acid

(as above)

fNMDA 1 ■! kainatc, / [quisquilate J Therapeutic implications

Identification of harmful neurotransmitters and of the pathways involved in the ischaemic cascade has led to a surge of interest in brain protective agents -

Ca** antagonists: studies of Nimodipine in patients with SAH have shown a significant reduction in ischaemic complications. This drug acts by opening up the collateral circulation and by blocking Ca" influx. There is limited evidence of efficacy in acute infarction

Glutamate antagonists (e.g. NMDA antagonist - 'MK801', CGS 1975S): significantly reduces ischaemia in animal studies. Toxicity may limit clinical trials.

Barbiturates: these reduce cerebral metabolism, thereby reducing neuronal requirements. They also block free radical production. The dosage required to lower metabolism produces significant hypotension and benefits remain unproven.

Free radical scavengers: Early studies suggest that these agents may produce some benefit in reducing ischaemia.

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