Stroke

Stroke, the sudden death of some brain cells due to lack of oxygen when the blood flow to the brain is lost by blockage or rupture of an artery to the brain, is also a leading cause of dementia and depression.

Fig.1 Stroke subtypes. (Marsh, 2010)

Risk Factors for Stroke

Risk factors associated with stroke can be classified as either non-modifiable or potentially modifiable.

Cell Death in Stroke

Brain tissue can be severely damaged when the blood flow supply is reduced to less than 20%. The hypoxia leads to ATP depletion within minutes, inducing the failure of the Na⁺/K⁺ pump, neuronal depolarization, and release of glutamate. Because glutamate cannot be taken up by either neurons or astrocytes, levels of glutamate rapidly rise in the extracellular space, leading to activation of glutamate receptors (mainly N-Methyl-D-Aspartat Receptors, NMDAR) that allow the entrance of Ca²⁺. Increased intracellular Ca²⁺ activates calpains and phospholipases, leading to excitotoxic cell death.

Fig.2 Major pathways implicated in ischaemic cell death: excitotoxicity, ionic imbalance, oxidative and nitrosative stresses, and apoptotic-like mechanisms. (Lo, 2003)

Selective Treatments for Multiple Stroke

• Combination therapy

Most ischaemic strokes are caused by thromboembolic occlusions of major arteries that supply the brain. Agents that lyse these clots reperfuse the ischaemic brain and form the basis of thrombolytic therapy. Indeed, thrombolysis using recombinant tPA is currently the only therapy for acute stroke approved by the US Food and Drug Administration.

In animal models, various neuroprotective combinations have been used with some success, including co-administration of an NMDA receptor antagonist with GABA (γ-aminobutyric acid) receptor agonists, free radical scavengers, citicholine, the protein synthesis inhibitor cycloheximide, caspase inhibitors, or growth factors such as basic fibroblast growth factor (bFGF).

• Lessons from preconditioning

Two temporally distinct types of tolerance are induced by preconditioning stimuli: acute - observed within minutes and delayed - developing after hours. Preconditioning might offer insights into the molecular mechanisms responsible for endogenous neuroprotection, and so provide new strategies for making brain cells more resistant to ischaemic injury.

• The microcirculation

Armed with the new knowledge that patients and experimental animals show improved outcomes after the early restoration of blood flow, many strategies have emerged that preserve cerebral blood flow and render the microcirculation more resistant to acute ischaemic injury. Among the most promising methods to enhance nitric oxide synthesis by the vascular endothelium, both increasing vascular endothelial NOS expression or increasing NOS enzymatic activity seems to be effective in experimental models.

Fig.3 Therapeutic targets for microcirculation. (Lo, 2003)

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References

1. Marsh, J.D.; Keyrouz, S.G. Stroke prevention, and treatment. Journal of the American College of Cardiology. 2010, 56(9): 683-691.
2. Lo, E.H.; et al. Mechanisms, challenges and opportunities in stroke. Nature reviews neuroscience. 2003, 4(5): 399-414.