Abstract
MK-801, as an N-methyl-D-aspartate (NMDA) receptor inhibitor, causes elevation in glutamate release, which may lead to an increase in excitotoxicity, oxidative stress and, consequently, cell death. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) shows antioxidant activity. The aim of the present study was to evaluate the effect of combined treatment with 1MeTIQ and MK-801 on cell viability, antioxidant enzyme activity, and glutamate release in the rat hippocampus. Cytotoxicity was measured using lactate dehydrogenase leakage assay (LDH) and the methyl tetrazolium (MTT) assay; antioxidant enzyme activity (glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT)) were measured by ELISA kits. The release of glutamate in the rat hippocampus was measured using in vivo microdialysis methodology. An in vitro study showed that MK-801 induced cell death in a concentration-dependent manner and that 1MeTIQ partially reduced this adverse effect of MK-801. An ex vivo study indicated that MK-801 produced an increase in antioxidant enzyme activity (GPx, GR, and SOD), whereas coadministration of MK-801 and 1MeTIQ restored the activity of these enzymes to the control level. An in vivo microdialysis study demonstrated that combined treatment with both drugs decreased the release of glutamate in the rat hippocampus. The above results revealed that 1MeTIQ shows limited neuroprotective activity under conditions of glutamate-induced neurotoxicity.
Highlights
NMDA receptors are associated with memory, learning, cognition and synaptic plasticity (Dore et al 2017; Fouad et al 2018)
The cell damaging effect of 200 μM MK-801 was accompanied by induction of cytotoxicity, as shown by lactate dehydrogenase (LDH) release assay, where this agent evoked a significant increase in LDH release after 24 and 48 h of treatment (Fig. 2B)
The results obtained in the present study indicated that MK-801 exhibits dose-dependent neurotoxic properties
Summary
NMDA receptors are associated with memory, learning, cognition and synaptic plasticity (Dore et al 2017; Fouad et al 2018). Excessive activation of the NMDA receptor causes powerful release of calcium ions, inducing excitotoxicity and, cell death (Ju and Cui 2016). Another cause of neuronal death is oxidative stress, which is observed in schizophrenia patients (Mahadik and Mukherjee 1996). Some authors have indicated that MK-801 induces apoptosis (Zhang et al 1996; Bueno et al 2003), and the effect is related to the dosage of MK-801, brain regions, and rodent sex Biochemical assays such as the lactate dehydrogenase leakage (LDH) and the methyl tetrazolium (MTT) reduction assays are widely used in in vitro toxicology studies to estimate cell toxicity and viability, respectively. Increased antioxidant enzyme activity may reflect a preceding cellular oxidative stress or serve as a compensatory mechanism
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