Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke

We previously reported neuroprotectiveactivity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotectiveactivity is mediated through its principal cardiac glycosideconstituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor(BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrinas a single agent. We thus surmised that PBI-05204 contains an additional neuroprotectivecomponent(s), distinct from oleandrin. We report here that neuroprotectiveactivity is also provided by the triterpenoidconstituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0–4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0–4 provides broad neuroprotectionin organotypic brain slice models for neurodegeneration driven by amyloid precursor protein(APP) and tau implicated in Alzheimer’s disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD.