Stroke is arguably one of the most feared cardiovascular events among healthy subjects as well as those with existing cardiovascular disease. In the United States as elsewhere in the world aging populations suggest that the absolute number of strokes is very likely to increase at least over the next two decades. The types of stroke observed in susceptible populations are changing as well. That is, there is a tendency for less hemorrhagic stroke and an increase in ischemic mediated stroke. Other than the use of various thrombolytic and fibrinolytic therapies that run their own risk for further bleeding in the brain there are few effective strategies for preventing or reducing the untoward and often devastating effects of stroke mediated ischemic brain injury. Thus, there is clearly a need for safer and more effective therapeutic options.
A 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 has recently completed a major phase I clinical trial as a treatment for patients with solid tumors. Research conducted at Duke University has 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 have reported in a recent publication work done in conjunction with Duke University that shows 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 have shown that the neuroprotective activity of PBI-05204 is maintained for several hours of delay of administration after oxygen and glucose deprivation.
This work provides evidence that the neuroprotective activity of PBI-05204 is mediated in part 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 have shown 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.
Figure above depicts an early drawing of Digitalis purpurea from which the well-known cardiac glycoside digitalis is obtained.
Publication: BDNF Mediates Neuroprotection against Oxygen-Glucose Deprivation by the Cardiac Glycoside Oleandrin. Michael J. Van Kanegan, Dong Ning He, Denise E. Dunn, Peiying Yang, Robert A. Newman, Anne E. West and Donald C. Lo. The Journal of Neuroscience, 15 January 2014, 34(3): 963-968; doi: 10.1523/JNEUROSCI.2700-13.2014.
In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models. Dunn DE, He DN, Yang P, Johansen M, Newman RA and Lo DC. J. Neurochem. 2011 Nov;119(4):805-14. PMID: 21950737