title: BDNF mediates neuroprotection against oxygen-glucose deprivation by the cardiac glycoside oleandrin.
abstract: We have previously shown that the botanical drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, provides neuroprotection in both in vitro and in vivo brain slice-based models for focal ischemia (Dunn et al., 2011). Intriguingly, plasma levels of the neurotrophin BDNF were increased in patients treated with PBI-05204 in a phase I clinical trial (Bidyasar et al., 2009). We thus tested the hypothesis that neuroprotection provided by PBI-05204 to rat brain slices damaged by oxygen-glucose deprivation (OGD) is mediated by BDNF. We found, in fact, that exogenous BDNF protein itself is sufficient to protect brain slices against OGD, whereas downstream activation of TrkB receptors for BDNF is necessary for neuroprotection provided by PBI-05204, using three independent methods. Finally, we provide evidence that oleandrin, the principal cardiac glycoside component of PBI-05204, can quantitatively account for regulation of BDNF at both the protein and transcriptional levels. Together, these findings support further investigation of cardiac glycosides in providing neuroprotection in the context of ischemic stroke.
authors.affiliation: Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27704, and Department of Experimental Therapeutics, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Van Kanegan
authors.forename: Dong Ning
authors.initials: DN
authors.lastname: He
authors.forename: Denise E
authors.initials: DE
authors.lastname: Dunn
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Anne E
authors.initials: AE
authors.lastname: West
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002298:Cardenolides / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000172:deficiency*; D008297:Male; D030007:Nerium; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology*; D010936:Plant Extracts / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; D019208:Brain-Derived Neurotrophic Factor; D002298:Cardenolides; D018696:Neuroprotective Agents; D010936:Plant Extracts; C021065:oleandrin; D005947:Glucose; D010100:Oxygen