Focused ultrasound and NXY-059 in experimental cerebral ischemia: A new therapeutic opportunity?

Abstract

troke is the third leading cause of morbidity and mortality worldwide. Many deleterious cellular pathways have been proposed to explain the molecular pathogenesis of this clinically devastating disease [1, 2]. The pathophysiology of stroke is complex and involves not only calcium and glutamate-mediated excitotoxicity but also various inflammatory pathways, disturbance of ionic balance, increased production of free radicals and neuronal cell apoptosis [3-5]. Besides its critical role for ion homeostasis in the central nervous system, disturbance of BBB integrity plays a significant role in stroke pathogenesis [6-8]. In this respect, recent studies have established that loss of BBB integrity and secondary loss of ion regulation may lead to brain edema and subsequent brain damage after cerebral ischemia [7, 9, 10]. This suggests that stabilization of the BBB could be brain protective, although recent studies failed to confirm this [11-13]. Moreover, data show that cerebral ischemia-induced BBB disruption is increased by 24 hours after middle cerebral artery occlusion [14], thus providing only a short window for transport of macromolecular drugs into the infarcted brain [14, 15]. This therapeutic time-frame effectively limits treatment efficacy due to an inability to achieve a sufficiently high dose of drug in the target brain area [15]. Therapeutic agents are often difficult to administer to the brain due to BBB prevention of passage for systemically administered molecules and proteins [16-18]. Because of this pharmacological therapies have made limited progress, and much effort is now being directed to identify compounds that accumulate more efficaciously in the diseased brain.