1MeTIQ Provides Protection Against Aβ-Induced Reduction of Surface Expression of Synaptic Proteins and Inhibits H2O2-Induced Oxidative Stress in Primary Hippocampal Neurons

Abstract

Alzheimer’s disease (AD) is associated with increased brain levels of β-amyloid (Aβ) peptides, which readily self-aggregate into fibrils and oligomers that have particularly deleterious properties towards synapses of excitatory glutamatergic neurons. Here, we examined the neuroprotective effects of 1-methyl-1,2,3,4,-tetrahydroisoquinoline (1MeTIQ) against Aβ-induced loss of synaptic proteins in cultured primary hippocampal neurons. Exposure of mature primary hippocampal neurons to 10 μM synthetic Aβ1-40 over 72 h resulted in approximately 60% reduction in the surface expression of NR1 subunit of the NMDA receptor (NMDAR), PSD-95, and synaptophysin, without causing neuronal death. Concomitant treatment with 500 μM of 1MeTIQ, a low affinity NMDAR antagonist significantly ameliorated the loss of synaptic protein markers. The neuroprotective properties of 1MeTIQ were compared with those of MK-801, which at 0.5 μM concentration also prevented Aβ1-40-induced loss of synaptic proteins in primary neuronal cultures. Furthermore, we provide novel evidence demonstrating effectiveness of 1MeTIQ in reducing the level of reactive oxygen species (ROS) in primary neuronal culture system. As oxidative stress contributes importantly to neurodegeneration in AD, 1MeTIQ may provide a dual neuroproctective effect in AD both as a NMDARs antagonist and ROS formation inhibitor. 1MeTIQ occurs endogenously at low concentrations in the brain and its synthetic form readily penetrates the blood-brain-barrier after the systemic administration. Our results highlight a possibility of the application of 1MeTIQ as a neuroprotective agent in AD related neurodegeneration.

The Impact of the Combined Administration of 1MeTIQ and MK-801 on Cell Viability, Oxidative Stress Markers, and Glutamate Release in the Rat Hippocampus

“…In addition, 1MeTIQ reduced H 2 O 2 -induced ROS production in immature hippocampal neuronal cultures. All in vitro results support the hypothesis that 1MeTIQ is an NMDAR antagonist with strong antiradical activity (Kuszczyk et al 2014). Moreover, it was demonstrated that 1MeTIQ inhibited the binding of radioactive [ 3 H]MK-801 to isolated brain membranes (Antkiewicz-Michaluk et al 2006).…”

“…Second, there is evidence that 1MeTIQ protects the activity of NADH-ubiquinone oxidoreductase enzyme, suppresses the inhibition by MPP + of mitochondrial respiratory complex I and thus prevents the ROS-mediated neurotoxic effect of MPP + (Parrado et al 2000). Third, 1MeTIQ is an NMDAR antagonist and may indirectly inhibit excitotoxicity-evoked ROS production (Kuszczyk et al 2014).…”

Inhibition of NADPH oxidase by apocynin prevents learning and memory deficits in a mouse Parkinson's disease model

“…Although the exact mechanisms of how oxidative stress and neuroinflammation impair learning and memory capacity remain unclear, disruption or loss of synapse might be one of the reasons. It's reported that H 2 O 2 induced by Aβ, the main component of plaque in AD, is capable of inducing reduction of synaptic proteins and loss of synapse, which is implicated in Aβ-induced cognitive deficits [64], [65]. Furthermore, in mouse AD models, inhibition of oxidative stress and neuroinflammation attenuates synaptic loss and cognitive dysfunction [66].…”

Extracellular vesicle-Serpine-1 affects neural progenitor cell mitochondrial functions and synaptic density: modulation by amyloid beta and HIV-1

“…Quantitative analysis of synaptic protein expression was performed similarly to a previously published method, with modi cations [39]. After immuno uorescence staining for PSD95 and synaptophysin, elds were selected randomly using the guidance of DAPI nuclear staining (three images/treatment group, total 9 images from three independent experiments), then confocal images were taken.…”