COMBINATION OF A NMDA RECEPTOR CHANNEL BLOCKER AND A PKC ACTIVATOR FOR TREATMENT OF ALZHEIMER'S DISEASE

摘要

Background: Excitotoxicity, which is associated with the excessive activation of NMDA receptors, has been implicated as playing an important role in the progressive neuronal damage in.Alzheimer's disease (AD). Memantine, an open-channel blocker of NMDA receptors, is being used clinically to prevent the excitotoxicity. However, excitotoxicity is not the only process in which NMDA receptors can be dysregulated in AD. Recent studies have demonstrated that Aß targets excitatory synapses, down regulates the surface expression of NMDA receptors, and induces reversible synaptic loss through NMDA receptor dependent pathways. To effectively treat Alzheimer's disease, a new therapeutic approach, which not only reduces the exitotoxicity but also potentiates normal NMDA receptor functions, needs to be explored. Objective: Given the fact that PKC activation potentiates functions of NMDA receptors, we aim to determine effects of the combination of a PKC activator, bryostatin-1, and memantine on the excitotoxicity and synaptic function. Methods: We used a biotinylation method and cell viability assays to determine the surface expression of NMDA receptors and the excitotoxicity of hippocampal neurons with or without the presence of bryostatin-1 and/or memantine. Results: We demonstrated that bryostatin-1 significantly enhanced the surface expression of NMDA receptors in hippocampal neurons. Treatment with the combination of bryostatin-1 together with memantine did not increase the excitotoxicity. On the contrary, it was more effective than either bryostatine-1 or memantine alone in the prevention of neuronal death caused by Aß, regardless of the synaptic or extrasynaptic origin of the excitotoxicity. Conclusion: This study demonstrates that the combination of bryostatin-1 with memantine has potential as a new therapeutic approach for the effective treatment of Alzheimer's disease.