Cerebral ischemia (stroke), a major cause of human neurological morbidity and mortality, is associated with a poor prognosis. According to the American Heart Association, there are over 700,000 new cases reported annually in the U.S with an estimated 150,000 deaths. Despite numerous clinical trials, with the exception of recombinant tissue plasminogen activator (rt-PA), which is used in less than 5% of all stroke patients, no standard safe and efficacious treatment has been yet identified.1
Ischemic stroke is characterized by the activation of several separate cellular pathways that are initiated by the disruption in blood flow resulting in loss of energy supply. Furthermore, the depletion of neuronal ATP initiates a cascade of events that includes overstimulation of neuronal glutamate receptors (excitotoxicity), ion imbalances, intra-neuronal calcium overload, mitochondrial injury, generation of reactive oxygen species (ROS), inflammation, apoptosis, and ultimately cell death.2 A large and diverse number of neuroprotective agents designed to interfere with these pathological pathways have been investigated in clinical trials. Over the last two decades, approximately one billion dollars have been invested on drug development for the treatment of ischemic stroke.
Despite extensive research and significant advances in our understanding of the underlying mechanisms of ischemic stroke, neuroprotective compounds have failed to demonstrate efficacy in large clinical trials. This lack of translation from pre-clinical research to clinical outcomes was the basis for the formation of a group referred to as the “Stroke Therapy Academic Industry Roundtable” (STAIR). This panel of experts from both academia and industry established a set of recommendations for optimal pre-clinical evaluation of neuroprotective compounds for the treatment of acute stroke. In subsequent discussions, STAIR focused on recommendations for improving the development of drugs for the treatment of stroke from preclinical phases to trial design. Some of these recommendations include longer therapeutic time-window, an adequate dose-response curve, efficacy results from at least two different animal models of stroke, experimental results from at least two different species (both small and large), proof of efficacy in white matter tissues, improved functional recovery, therapeutic time-window in clinical trials supported by pre-clinical data and the appropriate selection of subtype of stroke patients. Their approach has enhanced the current strategy for the development of drugs for the treatment of ischemic stroke. However, despite following these guidelines closely, the failure of NXY-059, a free radical scavenger, in the SAINT trial shows that fine tuning the current approach to the development of monotherapy drug treatment for acute stroke does not necessarily result in a successful therapeutic outcome.3
The lack of success in stroke treatment can likely be attributed to the activation of multiple heterogeneous, complex, and time-dependent biochemical pathways. In recent years it has been suggested that the approach to the treatment of stroke should be with pharmacological agents that possess multiple mechanisms of action (each potentially important in attenuating the ischemic damage) or with a combination of agents to target the multiple pathways involved in tissue damage. Such a treatment approach should be superior to treatments focused on ...