Quetiapine Attenuates Schizophrenia-Like Behaviors and Demyelination in a MK-801–Induced Mouse Model of Schizophrenia

Abstract

Brain demyelination is possibly one of the main pathological factors involved in schizophrenia, and targeting on myelination may be a useful strategy for schizophrenia treatment. Quetiapine, a widely used atypical antipsychotic drug for schizophrenia treatment, has been reported to have neuroprotective effects on cerebral myelination in a demyelination animal model. The objective of the present study was to evaluate the effect and underlying neuroprotective mechanism of quetiapine on the schizophrenia-like behaviors and possible cerebral demyelination induced by MK-801, an N-methyl-Daspartate glutamate receptor antagonist. Mice were treated with chronic quetiapine (10 mg/kg/day, intraperitoneally) for 28 days. From day 22 to 28, 1 h after the administration of quetiapine, the mice were administered MK-801 (2 mg/kg/day, subcutaneously). The positive symptom of schizophrenia was measured in a locomotor activity test on day 29, the memory was evaluated by a Y-maze test on day 30, and the sensorimotor gating deficit in mice was measured by prepulse inhibition test on day 31. After the behavioral tests, the protein expression of myelin basic protein (MBP) was measured by Western Blot, and the protein expression of brain-derived neurotrophic factor (BDNF) was measured by ELISA in the frontal cortex of mice. Our results showed quetiapine attenuated schizophrenia-like behaviors including hyperactivity, memory impairment, and sensorimotor gating deficit in the MK-801 mice. In the same time, quetiapine attenuated demyelination, concurrent with attenuated BDNF decrease in the brain of MK-801-injected mice. These results suggest that the beneficial effects of quetiapine on schizophrenia might be partly related to its neuroprotective effect on brain myelin basic protein and its upregulating neuroprotective proteins such as BDNF, and indicate that modulation of cerebral demyelination could be a novel treatment target of schizophrenia.

Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats

“…The most important finding of our multicohort study is the observation that quetiapine was able to normalise the PPI disturbances in adult male offspring in the MIA model. As presented in the literature, this atypical antipsychotic has shown efficacy in treating positive and negative symptoms as well as cognitive impairment in schizophrenia patients [ 88 ]. Moreover, consistent with our data, quetiapine attenuated schizophrenia-like behaviours, including not only sensorimotor gating deficits but also hyperactivity and memory impairment, in the MK-801-treated mouse model [ 88 ].…”

“…As presented in the literature, this atypical antipsychotic has shown efficacy in treating positive and negative symptoms as well as cognitive impairment in schizophrenia patients [ 88 ]. Moreover, consistent with our data, quetiapine attenuated schizophrenia-like behaviours, including not only sensorimotor gating deficits but also hyperactivity and memory impairment, in the MK-801-treated mouse model [ 88 ]. Therefore, the present research reaffirmed the face and construct validity of the use of MIA in modelling schizophrenia-like symptoms and the predictive validity of quetiapine administration.…”

Dorsal hippocampal CA1 NMDA receptors mediate the interactive effects of quetiapine and lithium on memory retention in male rats

“…Quetiapine was found to improve the decrease in BDNF-positive cells in the basolateral amygdala and hippocampus of transgenic models of mice with Alzheimer's disease (Tempier et al, 2013) through its modulating effects on neuroprotective factors such as reducing demyelination and increasing BDNF (He et al, 2020).…”

“…The stimulatory effects of quetiapine on monoamines such as norepinephrine, dopamine, and serotonin have been reported to be mediated by NMDA/glutamate receptors (Yamamura et al, 2009). Moreover, quetiapine has been shown to reduce schizophrenia-like behaviors, including memory loss, and attenuate BDNF reduction in mice treated with MK-801 (Fumagalli et al, 2004, He et al, 2020. Hence, it can be said that quetiapine affects NMDA receptor activity and modulates the effect of lithium on these receptors.…”

Activation of A2Badenosine receptor protects against demyelination in a mouse model of schizophrenia

“…Therefore, a better understanding of OLs may aid in the development of SCZ treatment strategies (4,5). Postmortem studies demonstrated a strong association between aberrant OL development and function, as well as demyelination and the pathogenesis of SCZ (6,7). Moreover, histological examinations of the brain revealed a decrease in the number of hippocampal OLs and neurons in patients with SCZ, and the interaction between OLs and neurons was abnormal (8,9).…”