Despite much study of the biochemical pathways triggered by ischemic stroke, molecular targets that have been targeted to date in clinical studies have failed to provide effective neuroprotection to injured neurons.  Previously, we implemented a screen of known signaling pathways in a brain slice model for ischemic stroke, and found that several cardiac glycosides could provide direct neuroprotection to brain slices following ischemic injury induced by transient oxygen-glucose deprivation (OGD). Critically, we could show neuroprotective benefit of cardiac glycosides even when applied many hours after OGD, corresponding to the accessible time window for therapy in clinical stroke. The FDA-approved cardiac glycoside drug digoxin is a known substrate of P-glycoprotein, and thus therapeutic drug levels in CNS are not likely to be achievable. We show that the botanical drug candidate PBI-05204 provides dose-dependent neuroprotection in brain slice models of ischemic stroke. In addition we present evidence that such neuroprotection is mediated at least in part through its principal bioactive ingredient, the cardiac glycoside oleandrin.  We further show that oleandrin can pass effectively across the blood-brain barrier, and present preliminary data for neuroprotection of CNS tissues in rodent models following systemic administration of PBI-05204. That PBI-05204 has already successfully completed a Phase I clinical trial in an oncology indication further suggests that this botanical drug candidate merits further evaluation for therapeutic use in ischemic stroke and related forms of CNS injury.  This work supported in part by Phoenix Biotechnology, Inc.

Effectiveness of the botanical drug candidate PBI-05204 derived from Nerium oleander in ex vivo and in vivo models of ischemic stroke

244th National Meeting (2012)

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