Neuroprotection in stroke: past, present, and future

Abstract

Stroke is a devastating medical condition, killing millions of people each year and causing serious injury to many more. Despite advances in treatment, there is still little that can be done to prevent stroke-related brain damage. The concept of neuroprotection is a source of considerable interest in the search for novel therapies that have the potential to preserve brain tissue and improve overall outcome. Key points of intervention have been identified in many of the processes that are the source of damage to the brain after stroke, and numerous treatment strategies designed to exploit them have been developed. In this review, potential targets of neuroprotection in stroke are discussed, as well as the various treatments that have been targeted against them. In addition, a summary of recent progress in clinical trials of neuroprotective agents in stroke is provided.

Figure 1

Damaging inflammatory mechanisms in stroke. Proinflammatory cytokines and reactive oxygen species released by damaged neurons lead to the activation of microglia and the expression of cellular adhesion molecules on endothelial cells and migrating inflammatory cells. Infiltrating inflammatory cells and activated microglia secrete additional cytokines and oxygen species, resulting in further tissue damage, oxidative stress, and activation of matrix metalloproteinases leading to disruption of the blood-brain barrier and edema.

Figure 2

Mechanisms of induction of apoptosis. In the classical pathway, mitochondria release cytochrome C in response to cell stress and damage, leading to activation of caspase 9 and subsequent activation of caspase 3 and other effectors of apoptosis. Alternatively, mitochondria may also release apoptosis-inducing factor (AIF), which leads to apoptosis by a caspase independent mechanism. The death receptor pathway involves the activation of FADD by various cell signal receptors, followed by activation of caspase 8 and the subsequent caspase cascade leading to apoptosis.

Figure 3

The process of autophagy and its regulation. Induction of autophagy is inhibited by mTOR, the activity of which is controlled by numerous upstream signaling pathways that respond to metabolic activity, energy status, and tissue damage. Progression of autophagy requires several members of the ATG protein family, leading to the production of a membranous structure that engulfs damaged cellular components to form the autophagosome. Subsequent fusion of the autophagosome with a lysosome results in degradation of the damaged components. Proteins involved in the regulation of autophagy are shown in shaded boxes. Positive interactions are denoted by arrows and negative interactions by lines with flat ends.