Ebselen: prospective therapy for cerebral ischaemia

Stroke occurs due to haemorrhage or occlusive injury and results in ischaem ia and reperfusion injury. A variety of destructive mechanisms are involved including oxygen radical generation, calcium overload, cytotoxicity and ap optosis as well as the generation of inflammatory mediators. Ebselen, 2-phe nyl-1,2-benzisoselenazol-3(2H)-one (PZ 51, DR3305), is a mimic of GSH perox idase which also reacts with peroxynitrite and can inhibit enzymes such as lipoxygenases, NO synthases, NADPH oxidase, protein kinase C and H+/K+-ATPa se. Ebselen is in a late stage of develop ment for the treatment of stroke. The molecular actions of ebselen contribute to its anti-inflammatory and a nti-oxidant properties, which have been demonstrated in a variety of in viv o models. Numerous in vitro experiments using isolated LDL, liposomes, micr osomes, isolated cells and organs have established that ebselen protects ag ainst oxidative challenge. Unlike many inorganic and aliphatic selenium com pounds, ebselen has low toxicity as metabolism of the compound does not lib erate the selenium moiety, which remains within the ring structure. Subsequ ent metabolism involves methylation, glucuronidation and hydroxylation. Exp erimental studies in rats and dogs have revealed that ebselen is able to in hibit both vasospasm and tissue damage in stroke models, which correlates w ith its inhibitory effects on oxidative processes. Results from randomised, placebo-controlled double-blind clinical studies on the neurological conse quences of acute ischaemic stroke, subarachnoid haemorrhage and acute middl e cerebral artery occlusion, have revealed that ebselen significantly enhan ces outcome in patients who have experienced occlusive cerebral ischaemia o f limited duration. The benefit achieved-with ebselen is closely related to the rapidity with which the-treatment is initiated, following the onset of the stroke attack. Safety and tolerability are good and no adverse effects have become apparent. Ebselen is, currently at the pre-registration stage for subarachnoid haemorrhage and stroke in Japan.