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

Michael J Van Kanegan,Daniel D Mccoy,Dong Ning He,Jiangnan Peng,Linda S Kaltenbach,Peiying Yang,Donald C Lo,Robert A Newman,Lin Du,Bijal Shah,Li Shen,Robert H Cichewicz,Denise E Dunn

doi:10.1038/srep25626

Abstract

We previously reported neuroprotective activity 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 neuroprotective activity is mediated through its principal cardiac glycoside constituent, 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 oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents 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 neuroprotection in 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.

Highlights

We previously reported neuroprotective activity 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 subsequently demonstrated that the neuroprotective activity of the oleandrin component of PBI-05204 is mediated by induction of neural expression of the potent CNS neurotrophic factor brain-derived neurotrophic factor (BDNF)[8]
We previously reported robust neuroprotection in the brain slice oxygen-glucose deprivation (OGD) model provided by the full PBI-05204 supercritical CO2 extract of Nerium oleander across a broad range of concentrations, whereas the concentration-response relation for its principal cardiac glycoside component, oleandrin, was much narrower and thereby could likely account quantitatively for only a portion of the neuroprotective activity of the full botanical extract

Summary

Introduction

We previously reported neuroprotective activity 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 neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). Roles for neurotransmitters and neurotrophic factors in tumor progression and reprogramming of the stromal microenvironment are increasingly appreciated[4,5] In this context, we previously reported the neuroprotective activity of the anti-cancer botanical drug candidate PBI-052046 in brain tissue and in vivo models for ischemic stroke[7]. We subsequently demonstrated that the neuroprotective activity of the oleandrin component of PBI-05204 is mediated by induction of neural expression of the potent CNS neurotrophic factor brain-derived neurotrophic factor (BDNF)[8]. We demonstrate the programmatic induction of nuclear factor erythroid 2 related factor 2 (Nrf2)-dependent antioxidant genes as a potential mechanism underlying the neuroprotective activity of PBI-04711 and its triterpenoid components

Methods

Results

Conclusion