Current mechanisms in stroke

Stroke is one of the leading causes of mortality and adult disability in the world^1,2,3. The occurrence of stroke and stroke-related illness is expected to triple by 2050⁴, due to our vulnerable aging population and ongoing epidemics of diabetes and obesity^1,5. Disabilities associated with stroke survivors have had a significant social and economic impact on societies worldwide². According to the World Health Organization, about 15 million people worldwide suffer a stroke every year. Furthermore, stroke and its related illnesses cost the healthcare system billions of dollars each year, thus becoming significant financial burden and causing economic hardship in the world.

While stroke is a major public health concern, the cellular and molecular mechanisms underlying brain damage following stroke are not yet fully elucidated. A series of pathophysiological events are triggered during stroke, and eventually lead to intracellular ionic imbalance and cell death^6,7. Glutamate mechanisms have dominated in stroke research for the last two to three decades⁸. Although glutamate receptor antagonists are effective in reducing stroke-related neuronal injury in the laboratory setting, clinical trials of anti-excitotoxic therapies have failed to benefit stroke patients⁹. Thus, researchers have started looking beyond glutamate mechanisms in cerebral ischemia and stroke. Recent convincing and promising results, especially from in vivo animal studies, suggest non-glutamate mechanisms are also important in causing ionic imbalance and cell death during cerebral ischemia^8,10. Along with the traditional model of excitotoxicity focused on glutamate-receptor-mediated mechanisms, non-glutamate mechanisms are gaining considerable attention in recent years^8,10. The latter include acid-sensing ion channels^11,12, TRP channels^13,14, K_ATP channels^15,16, hemichannels^17,18, volume-regulated anion channels¹⁹, adenosine receptors, sodium-calcium exchangers, and other ion exchangers and nonselective cation channels.

In this special issue of stroke research, we aim to cover the revised models of neuronal injury involving glutamate mechanisms and several newly identified non-glutamate mechanisms in stroke. We will discuss the current understanding of pathophysiological roles of ion channels and exchangers involved in non-glutamate mechanisms in cerebral ischemia and stroke, as well as the potential for therapeutic intervention. We will describe new studies using recently developed experimental models for stroke research. The primary scope of our reviews is to highlight findings from in vivo studies involving new strategies and drug developments for stroke treatment. The in vivo experimental approaches cover state of the art techniques currently used in the fields including molecular, genomic, proteomic, in vivo functional and behavioural assessments. We intend to highlight novel therapeutic strategies targeting non-glutamate mechanisms to prevent neuronal damage in stroke and to promote neuronal survival, regeneration and functional recovery after stroke, thus providing long-term economic, social, and healthcare benefits worldwide.