Stroke is arguably one of the most feared cardiovascular events among healthy subjects as well as those with existing cardiovascular disease. 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 both Phase I and II clinical trials 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 rodent 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 series of publications 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 (OGD).
The microphotograph above depicts healthy neurons depicted with a yellow fluorescent stain and the loss of healthy neurons following oxygen and glucose deprivation (i.e. stroke mediated ischemic injury), The prevention of OGD-mediated damage is depicted in the third photo panel whereby administration (oral) of PBI-05204 to mice resulted in protection of brain ischemic injury.
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. Our research has shown that PBI-05204 induces the production of an important brain growth factor (BDNF) which is necessary for healthy neurons and even neuronal recovery from damaging events such as ischemic injury. In addition, PBI-05204 has been shown to induce the production of Nrf-2 elements which increase the antioxidant activity within brain tissue.
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.
Research conducted at the Univ. Texas at San Antonio has shown that PBI-05204 reduces mRNA expression of pro-inflammatory cytokines and neuroinflammatory reactions within microglial cells. Administration of PBI-05204 to transgenic mice which develop beta-amyloid deposits within brain tissue has shown the ability of PBI-s drug to significantly reduce Abeta plaque formation which may indicate a potential use as a drug capable of treating or maybe even preventing Alzheimer’s disease.