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

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.

Evaluación del efecto antioxidante de la olanzapina en combinación con N Acetil Cisteína en un modelo de esquizofrenia inducido por MK-801 en ratón.

“…La hipofunción en estos receptores se asocia con alteraciones en la memoria, cognición y plasticidad neuronal, y con alteraciones en la liberación de glutamato en estructuras neuronales específicas, como el hipocampo y la corteza frontal. 48 Con base en esto, en este estudio se utilizó el modelo de administración aguda de MK-801 en ratones según la metodología reportada por Aquino-Miranda et al, 8 ya que se trata de un modelo estandarizado y reproducible que causa una hipofunción glutamatérgica, estrés oxidativo y muerte celular, tal como se observa en la esquizofrenia. 48 Reportamos un incremento de la lipoperoxidación en el grupo con MK-801 que fue tratado con vehículo, demostrando que el MK-801 incrementa el estrés oxidante y el daño a las membranas celulares.…”

“…48 Con base en esto, en este estudio se utilizó el modelo de administración aguda de MK-801 en ratones según la metodología reportada por Aquino-Miranda et al, 8 ya que se trata de un modelo estandarizado y reproducible que causa una hipofunción glutamatérgica, estrés oxidativo y muerte celular, tal como se observa en la esquizofrenia. 48 Reportamos un incremento de la lipoperoxidación en el grupo con MK-801 que fue tratado con vehículo, demostrando que el MK-801 incrementa el estrés oxidante y el daño a las membranas celulares. Estos hallazgos concuerdan con lo reportado en el estudio de Ozyurt et al, 49 en el cual la administración del MK-801 por vía intraperitoneal en ratas incrementó el estrés oxidante en la corteza frontal, observándose un aumento de la lipoperoxidación.…”

Glutamate and excitotoxicity in central nervous system disorders: ionotropic glutamate receptors as a target for neuroprotection

“…On the contrary, the combined treatment of 1MeTIQ and MK-801 showed promising results in mitigating glutamate-induced neurotoxicity. 74 MK-801, known for its NMDA receptor inhibition, triggered glutamate release and oxidative stress, leading to cell death. However, coadministration of 1MeTIQ effectively attenuated these toxic effects, demonstrating its potential as a neuroprotective agent.…”

Advantages and Limitations of Animal Schizophrenia Models

“…Increased subcortical DA release and related behavior are thought to serve as an experimental model of positive schizophrenia symptoms [ 116 ]. Further studies have shown that injection of MK-801 also leads to an increase in GLU efflux in the hippocampus and medial prefrontal cortex [ 117 , 118 , 119 ]. Regarding the role of the GLUergic system in schizophrenia pathophysiology, excessive GLU efflux in regions such as the prefrontal cortex and hippocampus is believed to produce symptoms of the illness, mainly cognitive symptoms [ 120 ].…”

“…These effects may result in an increased cellular oxidative stress response [ 133 ], which is a widely studied feature of schizophrenia [ 134 , 135 ]. MK-801 has been shown to induce oxidative stress, including elevated MDA levels and altered antioxidant enzyme activity, in several brain regions in rodents, such as the prefrontal cortex, hippocampus, retrosplenial/posterior cingulate cortex [ 119 , 136 , 137 ], and cultured neurons and glial cells [ 138 , 139 ]. Additionally, MK-801 decreases GSH, a main antioxidative compound, leading to a reduced capacity to protect brain cells against oxidative stress [ 140 , 141 ].…”