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Increase in intracellular calcium

Enzyme activation inactivation Mitochondrial damage

Reperfusion of brain

Depolarization (release of glutamate and aspartate)

Activation of non-NMDA receptors

Increase in intracellular sodium

Increase influx of water-cellular swelling

Excitotoxicity -

Increase in

/oxygen radicals *

Inflammation

Changes in gene function and cell death

Apoptosis

Brain infarction

Figure 14.12. Cascade of changes leading to stroke.

termed excitotoxicity and may also be involved in other neurodegenerative processes such as Alzheimer's and Huntington's disease.

In brain ischaemia, the excessive stimulation of glutamate receptors causes a marked increase in intracellular calcium activated enzymes (such as the proteases, kinases, phospholipases and endonucleases) which promote neuronal and glial cell death. In addition, free radicals are produced by the damaged mitochondria and by the reaction of molecular oxygen with iron released from protein binding sites by proteases, acidosis and oxygenases. The cascade of changes which occurs following cerebral ischaemia is illustrated in Figure 14.12.

Because it is necessary for the stroke patient to receive prompt treatment before brain cell death occurs, any useful drug must be effective even when there is considerable time lapse (often several hours) between the occurrence of the stroke and the onset of treatment. The term ''therapeutic window'' refers to the critical time of intervention between the onset of the ischaemia and occurrence of brain infarction. Some of the drugs that have been developed and shown to be effective in the treatment of various animal models of stroke are listed in Table 14.5. It should be emphasized that none of these drugs is currently marketed for the treatment of stroke. All have been developed on animal models and recent positron emission tomography and magnetic resonance imaging studies have shown that the therapeutic window may be much more variable and prolonged in man than in such models. Only extensive double-blind clinical trials (estimated

Table 14.5. Neuroprotective agents of use in the treatment of cerebral ischaemia

1. Calcium channel antagonists - nimodipine, flunarizine

2. Free radical scavengers, antioxidants - ebselen, tirilazad

3. GABA agonists - chlormethiazole

4. Glutamate receptor antagonists - NMDA channel blocker: cerestat, dextromethorphan, dextrophan

- Mg++ site: memantine, remacemide

- polyamine site: eliprodil, ifenprodil

5. Opiate antagonists - naloxone, nalmefene

6. Sodium channel antagonists - fosphenytoin, lubeluzole

Note: Voltage-sensitive sodium and potassium channels are targets affecting depolarization whereas calcium channels control calcium influx which, following ischaemic stroke, enhances glutamate release which leads to cell death. GABA agonists attenuate excitotoxicity and free radical scavenger production, thereby acting as neuroprotectants.

to require 600-2000 patients to demonstrate statistical reliability) will demonstrate which, if any, of these drugs is therapeutically useful.

Pharmacological strategies for the treatment of stroke Drugs blocking glutamate receptors

NMDA receptor antagonists or channel blockers such as phencyclidine or dizocilpine reduce the size of focal ischaemia in many animal models of stroke but are less effective in models of global ischaemia that simulate the conditions following cardiac arrest. Theoretically the NMDA receptor ion channel antagonists may be advantageous in the treatment of acute stroke when the high glutamate concentration in the synapse is more likely to stimulate ion channel openings. Those drugs that modulate the NMDA receptors via an action on the polyamine or glycine sites (for example eliprodil) promote the NMDA ion channel opening and may be useful as neuroprotective agents in those patients liable to suffer from stroke. Some non-NMDA receptor antagonists have also been found to be neuroprotec-tive in animal models of focal and global ischaemia. For example, compounds such as CNQX have been shown to be effective in animal models of global ischaemia.

Free radical scavengers

Oxygen free radicals are highly reactive molecules that damage lipids, nucleic acids, carbohydrates and proteins, thereby contributing to excitotoxic-induced neuronal death. In addition, free radicals can contribute to increased permeability of the blood-brain barrier, to brain oedema and to the movement of macrophages into the ischaemic zone. The gaseous neurotransmitter nitric oxide contributes to cell death by combining with superoxide to form the highly reactive peroxynitrite anion. Two drugs are undergoing clinical trial at present, tiriliazad and pergorgotein, for the treatment of head trauma.

Thrombolysis and anticoagulants

Heparin-like anticoagulants such as nadroparin have been found to be useful in some clinical trials in stroke patients as have streptokinase-like drugs which dissolve the fibrin matrix of blood clots.

Anti-inflammatory agents

White blood cells readily traverse the blood-brain barrier 12-24 hours after ischaemia and contribute to the excessive production of oxygen free radicals. Eventually the infarcted zone becomes infiltrated with lymphocytes, polymorphs and macrophages. The cytokines released from the macrophages contribute to the injury of the vessel walls and to the consequent oedema, haemorrhage and necrosis. Thus the function of the anti-inflammatory agents is to reduce the initial adhesion of the white blood cells and thereby limit the extent of the inflammatory response.

Voltage-dependent channel blockers

The release of neurotransmitters is triggered by the opening of the calcium channels in the neuronal membrane which results from the depolarization of the neuron. The conventional calcium channel blockers (e.g. nimodipine) block the L-channels only and therefore do not affect those calcium channels necessary for neurotransmitter release. Nevertheless, the L-channel blockers may prevent excess calcium influx into the cytoplasmic and mitochrondrial compartments which may assist in preventing stroke in those patients at risk from vasospasm following subarachnoid haemorrhage. In addition to a variety of N-channel blocking compounds which are still largely experimental, drugs such as lamotrigine (an anti-epileptic drug which also modulates NMDA receptors), lubeluzole, rolizole and fosphenytoin have been shown to be effective in reducing ion flux through the sodium channel in the neuron and thereby attenuating neurotransmitter release.

In CONCLUSION, the future drug treatment of stroke will probably depend on a combination of both neuroprotection (e.g. hypothermia, glutamate receptor antagonists, free radical scavengers, etc.) with thrombolysis which attempts to re-establish normal blood flow. Such treatments may help to expand the window between the initial ischaemic episode and brain damage. Whether any of the drugs mentioned here will ultimately be of any value in the prevention and/or treatment of stroke is still a matter of conjecture.

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