NOX, NOS and sGC as new therapeutic targets in stroke

Ischemic stroke is the second leading cause of death worldwide and the leading cause of disability. Despite this high medical need only a single drug is available but due to its limited time window and risk of bleeding 85% of all patients are excluded from treatment. Here we address three different new targets in stroke highly related to oxidative stress. NADPH oxidase is one of the most important sources of reactive oxygen species, which has been recently considered as a promising target in ischemic stroke. Neuronal nitric oxide synthase (NOS1) has been also suggested as a possible target so that its partial inhibition can lead to neuroprotective effects. Similarly, NOX possibly acts by scavenging or toxifying NO to nitrating species and oxidising the NO receptor, soluble guanylate cyclase (sGC). This then diminishes physiological NO-cGMP signalling, a process that could be reversed in mice by so-called sGC activator compounds. Pharmacological targeting of apo-sGC in vitro under oxygen and glucose deprivation conveyed strong neuroprotection via PKG/ERK/CREB signalling pathway. In vivo, post-stroke apo-sGC activation by two distinct members of this compound class augmented cerebral blood-flow whilst leaving systemic blood pressure unaffected, reduced infarct size and increased survival. Thus, both inhibiting NOX/NOS-dependent oxidative stress and augmenting cGMP signalling are neuroprotective in stroke. Current and future experiments are aimed at validating these finding in a second rodent species for further preclinical and clinical development as first-in-class neuroprotective drugs.