J. Neurochem. (2011) 119, 805–814. Abstract The principal active constituent of the botanical drug candidate PBI‐05204, a supercritical CO2 extract of Nerium oleander, is the cardiac glycoside oleandrin. PBI‐05204 shows potent anticancer activity and is currently in phase I clinical trial as a treatment for patients with solid tumors. We have previously shown that neriifolin, which is structurally related to oleandrin, provides robust neuroprotection in brain slice and whole animal models of ischemic injury. However, neriifolin itself is not a suitable drug development candidate and the FDA‐approved cardiac glycoside digoxin does not cross the blood–brain barrier. We report here that both oleandrin as well as the full PBI‐05204 extract can also provide significant neuroprotection to neural tissues damaged by oxygen and glucose deprivation as occurs in ischemic stroke. Critically, we show that the neuroprotective activity of PBI‐05204 is maintained for several hours of delay of administration after oxygen and glucose deprivation treatment. We provide evidence that the neuroprotective activity of PBI‐05204 is mediated through oleandrin and/or other cardiac glycoside constituents, but that additional, non‐cardiac glycoside components of PBI‐05204 may also contribute to the observed neuroprotective activity. Finally, we show directly that both oleandrin and the protective activity of PBI‐05204 are blood brain barrier penetrant in a novel model for in vivo neuroprotection. Together, these findings suggest clinical potential for PBI‐05204 in the treatment of ischemic stroke and prevention of associated neuronal death.

The c-Jun N-terminal kinase (JNK) pathway potentially links together the three major pathological hallmarks of Alzheimer’s disease (AD): development of amyloid plaques, neurofibrillary tangles, and brain atrophy. As activation of the JNK pathway has been observed in amyloid models of AD in association with peri-plaque regions and neuritic dystrophy, as we confirm here for Tg2576/PSM146L transgenic mice, we directly tested whether JNK inhibition could provide neuroprotection in a novel brain slice model for amyloid precursor protein (APP)-induced neurodegeneration. We found that APP/amyloid β (Aβ)-induced neurodegeneration is blocked by both small molecule and peptide inhibitors of JNK, and provide evidence that this neuroprotection occurs downstream of APP/Aβ production and processing. Our findings demonstrate that Aβ can induce neurodegeneration, at least in part, through the JNK pathway and suggest that inhibition of JNK may be of therapeutic utility in the treatment of AD.