The concept of combination therapy in acute ischemic stroke

Acute ischemic stroke is usually caused by thromboembolic occlusion of an intracranial artery.¹ The arterial occlusion and the consequent lowering of CBF result in a complex series of events that transform ischemic tissue into infarction.^2,3 The survival time of tissue after ischemia depends mainly on the residual CBF through collaterals and on selective neuronal vulnerability to ischemia.³ The time window from ischemia to neuronal death therefore varies widely. It may be a few minutes, e.g., in brain tissue with a residual CBF below 10 ml/100 g/min (the so-called threshold for energy failure), or several hours, e.g., in tissue with CBF values between 10 and 20 ml/100 mg/min (the ischemic penumbra). In the context of penumbra tissue, the electrical neuronal function is abolished but the neurons themselves are viable⁴ until the amount of ATP produced falls below 50% of normal values and the breakdown of energy-producing metabolites causes lactoacidosis, ion pump failure, and eventually irreversible membrane damage⁵ (figure 1). As a consequence, tissue that at a certain point in time is alive or can be saved from ischemia may be irreversibly damaged soon after. In other words, there is a "point of no return" in the ischemic cascade, a factor that is crucial for both the so called therapeutic window⁶ and for acute stroke treatments.

Ischemia may be reversed by reperfusion.⁷ However, on return of blood flow, together with the resumption of the principal neuronal functions (e.g., oxygen delivery, provision of substrates for metabolism), interactions between blood and the already damaged tissue can be responsible for further tissue …