| Neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and ischemic stroke, are characterized by the progressive loss of neurons in the brain and amongst the most common causes of death in the world. Although their exact causes and mechanisms remain unclear, and no effective therapy is yet available, the coupling of prolonged activation of N-methyl-D-aspartate (NMDA) receptors to excitotoxicity is thought to be the final common pathway in the pathogenesis of these disorders. Thus, neuroprotection targeting the NMDA receptor has been considered essential for the treatment of these diseases. Many NMDA receptor antagonists, however, have failed in clinical trials because they interfere with the normal functions of NMDA receptors. Therefore, drugs interacting with NMDA receptors only during states of pathological activations but not of physiological functions, also designated as pathologically activated therapeutic (PAT) drugs, are actively pursued.;Our laboratory has developed several series of dimeric acetylcholinesterase (AChE) inhibitors that are expected to elevate the level of acetylcholine in the brain. Bis(7)-tacrine, one of such dimers, has previously proved to prevent glutamate-induced neuronal apoptosis by acting on multiple targets including NMDA receptors. My thesis study is aimed to characterize the effects of some of these dimers on NMDA receptors and their underlying mechanisms in order to search for the most promising candidate for preventing and treating neurodegenerative disorders.;In this study, bis(7)-tacrine is demonstrated to prevent glutamate-induced excitotoxicity in cultured rat cortical neurons and to block intracellular Ca2+ elevation. Electrophysiological data reveal that it selectively inhibits NMDA-activated current in a concentration-dependent manner by reducing channel open probability. The inhibition depends on extracellular pH, however, it is non-competitive and independent of the voltage. Furthermore, a series of tacrine homodimers, bis(n)-tacrines, exhibit the tether-length differential potency and voltage-dependency in inhibiting NMDA-activated current. Among them, bis(3)-tacrine is found to inhibit NMDA-activated current uncompetitively with the strongest voltage-dependency and fast off-rate, and to possess superior neuroprotective activities both in vitro and in vivo .;In conclusion, through my thesis study, I have specially characterized a serial of novel dimers targeting pathologically activated NMDA receptors, which might provide potentially safer and more effective therapy for the prevention and treatment of Alzheimer's disease, ischemic stroke and other relevant neurodegenerative disorders. |
