title: Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke.
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.
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, US.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Van Kanegan
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, US.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Dunn
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, US.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Kaltenbach
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, US.
authors.forename: Bijal
authors.initials: B
authors.lastname: Shah
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, US.
authors.forename: Dong Ning
authors.initials: DN
authors.lastname: He
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, US.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: McCoy
authors.affiliation: Department of Palliative Care, Rehabilitation and Integrative Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, US.
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina at Wilmington, NC 28403, US.
authors.forename: Jiangnan
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Pharmacy, Medical College of Yangzhou University, Yangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, Natural Products Discovery Group, and Institute for Natural Products Applications and Research Technologies, University of Oklahoma, Norman, Oklahoma 73019, US.
authors.forename: Lin
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, Natural Products Discovery Group, and Institute for Natural Products Applications and Research Technologies, University of Oklahoma, Norman, Oklahoma 73019, US.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Cichewicz
authors.affiliation: Department of Experimental Therapeutics, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, US.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, US.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005591:Chemical Fractionation / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D008297:Male; D030007:Nerium / Q000737:chemistry; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D009828:Oleanolic Acid / Q000737:chemistry / Q000494:pharmacology; D009924:Organ Culture Techniques; D010100:Oxygen / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D018696:Neuroprotective Agents; C000626629:PBI-05204; D010936:Plant Extracts; D009828:Oleanolic Acid; D005947:Glucose; D010100:Oxygen