Pathologically Activated Neuroprotection via Uncompetitive Blockade of N-Methyl-d-aspartate Receptors with Fast Off-rate by Novel Multifunctional Dimer Bis(propyl)-cognitin

Abstract

Uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and ␥-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis-(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [ 3 H]MK-801 with a K i value of 0.27 M, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced longterm potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.Neurodegenerative disorders are among the leading cause of death in the elderly, and this medical problem is expected to become more serious as the population continues to age. N-Methyl-D-aspartate (NMDA)3 receptor overactivation-induced excitotoxicity is clearly implicated in a variety of acute and chronic neurodegenerative disorders (1-4). Thus, the NMDA receptor has been considered an attractive therapeutic target for the development of neuroprotectants. However, the NMDA receptor, as the major excitatory neurotransmitter receptor in the central nervous system, mediates many important physiological processes, such as excitatory neurotransmission, synaptic plasticity, learning and memory, and cell survival (5-8). The therapeutic potential of many NMDA receptor antagonists, therefore, was limited, and they failed in clinical trials because of their psychotropic side effects and memoryimpairing effects resulting from the blockade of NMDA receptor-mediated physiological activities (9, 10). Clinically well tolerated and effective NMDA receptor antagonists for the therapy of neurodegenerative disorders have been pursued over the past several decades.The strategies applie...

Activation of Transcription Factor MEF2D by Bis(3)-cognitin Protects Dopaminergic Neurons and Ameliorates Parkinsonian Motor Defects

“…4D), suggesting that the protective effect of B3C is mainly via MEF2D. The neuroprotective effect against MPP ϩ -induced toxicity is specific to B3C because B7C and tacrine, two structurally related molecules (21), offered SN4741 cells no protection (Fig. 4E).…”

“…Enhances the MEF2 Activity-B3C has been shown to regulate NMDA receptors and protect neurons from strokeinduced death (20,21). Because transcription factor MEF2 promotes neuronal survival in several experimental paradigms, we tested the possibility that B3C may regulate MEF2 activity.…”

“…However, B7C still possesses a high toxicity (20,21). Interestingly, bis(3)-cognitin (B3C), an analog of B7C, was shown to be neuroprotective in middle cerebral artery occlusion-induced brain damage with low toxicity (21).…”

Bis(propyl)-cognitin Prevents β-amyloid-induced Memory Deficits as Well as Synaptic Formation and Plasticity Impairments via the Activation of PI3-K Pathway

“…B3C, a novel multifunctional dimer, has attracted increasing interest as a possible player in various associated neurodegenerative disorders; it prevented glutamate-induced excitotoxicity 10 times more potently than that of memantine [12,13] and provided substantial neuroprotection against K + deprivation-induced apoptosis in primary cerebellar granule neurons [21]. In the present study, we provide novel sights into the possible potential of B3C in the treatment of AD.…”

“…Over the past several years, B3C has drawn great attention as a potential drug to treat neurodegenerative disorders. It is not only a novel acetylcholinesterase (AChE) inhibitor with dual binding sites within the catalytic cavity of AChE [11] but also an uncompetitive NMDA receptor antagonist moderately blocking NMDA receptors at the MK801 binding sites in a moderate potency and strong voltage dependence way, a mechanism similar to the action of memantine (an FAD-proved AD drug) [12]. B3C has been reported to prevent neuronal death from glutamate-induced excitotoxicity in cultured neural cells and scopolamine-induced memory deficits in mice [13,14].…”