P4–311: PAN–811 protects primary neurons from Aβ neurotoxicity: A potential drug for Alzheimer's disease

PAN–811 is a small lipophilic compound with a molecular mass of 195 Dalton, belonging to the (N)–heterocyclic carboxaldehyde thiosemicarbazone class of molecules originally developed for cancer therapy. Our previous result has demonstrated highly effective function in protecting ischemic neurotoxicity through a dual mechanism of divalent metal chelation and free radical scavenging. It has proved to be non–toxic in human clinical trials and crosses brain / blood barrier. We have evidence that oxidative stress is the most likely mediator of Aβ neurotoxicity and our objective is to demonstrate that PAN–811 could be an effective neuroprotector. To prove this hypothesis, first we established that Aβ has neurotoxicity in primary neurons in culture. Using Aβ1–42 or Aβ25–35, the rate and intensity of neurotoxicity was increased by age in culture and oxidative stress. For 2–week old neurons, the neurotoxicity was observed in 12 to 16 days after the insult and required 0% antioxidant level (high oxidative stress) whereas neurotoxicity occurred after 1 day for 3–week old neurons under 90% antioxidant level(mild oxidative stress). There was no neurotoxicity in young neurons low oxidative stress when treated with less than 80μm Aβ. The neuronal cell death was by apoptotic process. Neurotoxicty of Aβ1–42 and Aβ25–35 is specific since a reversed sequence peptide Aβ35–25 was unable to induce any toxicity. We have clearly demonstrated that PAN–811 inhibits Aβ–induced neurotoxity. PAN–811 at doses as low as 2μM and as late as 3–hours post insult (Aβ1–42 or Aβ25–35 treatment) effectively protects neurons. We conclude that PAN–811 protects primary neurons from Aβ neurotoxicity and should be pursued as a viable candidate for therapeutic drug development for Alzheimer's disease.