Extended neuroleptic administration modulates NMDA-R subunit immunoexpression in the rat neocortex and diencephalon

Krzystanek, Marek; Bogus, Katarzyna; Pałasz, Artur; Wiaderkiewicz, Anna; Filipczyk, Łukasz; Rojczyk, Ewa; Worthington, John J.; Wiaderkiewicz, Ryszard

doi:10.1016/j.pharep.2016.05.009

Cited by 7 publications

(9 citation statements)

References 44 publications

(39 reference statements)

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“…Results of expression of NMDAR subunits in the hypothalamus, as shown in Figure 5, turn out to be surprising [67]. It is only the rat brain structure where we observed an increase of NR1 expression after a long-term administration of olanzapine or haloperidol.…”

Section: Expression Of Nmda Receptor Subunits In the Rat Brain Aftmentioning

confidence: 90%

“…In the present work, we compared and concluded results from a series of our own studies, aimed at analyzing the influence of antipsychotics on the expression of NMDAR subunits in the rat brain. We performed immunohistochemical studies of the influence of four-week intraperitoneal administration of olanzapine, clozapine, or haloperidol on the expression of NMDAR subunits: NR1, NR2A, and NR2B in CA1, CA2, and CA3 hippocampal regions, gyrus dentatus, neocortex, thalamus, and in subthalamus [66,67]. Obtained results show that the expression of NMDAR subunits has different modality, depending on the brain area and the used antipsychotic.…”

Section: Glutamatergic Signaling and Cognitive Deficits In Schizopmentioning

confidence: 99%

“…Targeted microinjection of NMDA inhibitors into the rat thalamus causes cognitive deficits [102], that may support this hypothesis. Olanzapine, clozapine, and haloperidol decrease NMDAR expression in the rat thalamus [67], as shown in Figure 5, suggesting that long-term treatment with antipsychotic drugs can reduce the glutamate transmission in this structure, as shown in Figure 6. There could be two consequences of that finding.…”

Section: Expression Of Nmda Receptor Subunits In the Rat Brain Aftmentioning

confidence: 99%

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NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality

Krzystanek¹,

Pałasz²

2019

IJMS

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Schizophrenia is a chronic mental disease, affecting around 1% of the general population. Schizophrenia is characterized by productive, negative, affective, and disorganization symptoms, and cognitive deficits. Cognitive deficits prevail in most of the schizophrenia patients and are one of the most disabling symptoms. They usually occur before the acute episode of the disease and tend to become chronic with no satisfactory treatment from antipsychotic drugs. Because of their early manifestation in patients’ lives, cognitive deficits are suggested to be the primary symptom of schizophrenia. The pathogenesis of cognitive deficits in schizophrenia is not fully understood. They are linked with hypofrontality, which is a decrease in blood flow and glucose metabolism in the prefrontal lobe of schizophrenia-suffering patients. Hypofrontality is linked with disturbances of the corticolimbothalamic circuit, important for cognition and memory in humans. The circuit consists of a group of neuroanatomic structures and hypothetically any disturbance in them may result in cognitive deficits. We present a translational preclinical model of understanding how antipsychotic medication may decrease the N-methyl-D-aspartic acid (NMDA) receptors’ activity and produce dysfunctions in the corticolimbothalamic circuit and hypofrontality. From several pharmacological experiments on rats, including mainly our own recent findings, we collected data that suggest that antipsychotic medication may maintain and escalate hypofrontality in schizophrenia, decreasing NMDA receptor activity in the corticolimbothalamic circuit in the human brain. We discuss our findings within the literature of the subject.

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Section: Expression Of Nmda Receptor Subunits In the Rat Brain Aftmentioning

confidence: 90%

Section: Glutamatergic Signaling and Cognitive Deficits In Schizopmentioning

confidence: 99%

Section: Expression Of Nmda Receptor Subunits In the Rat Brain Aftmentioning

confidence: 99%

See 1 more Smart Citation

NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality

Krzystanek¹,

Pałasz²

2019

IJMS

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“…Dietary methionine is also a component of 1-carbon metabolism; readily converted to SAM by methionine adenosyltransferase driving epigenetic modification (Krzystanek et al 2011). SAM has a number of roles in human biochemistry, not only as a major methyl donor, but also as a precursor for cysteine-a rate limiting amino acid for endogenous production of glutathione (James 2013).…”

Section: One-carbon Metabolismmentioning

confidence: 99%

Epigenetics and Nutritional Environmental Signals

Mazzio¹,

Soliman²

2014

Integrative and Comparative Biology

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All terrestrial life is influenced by multi-directional flows of information about its environment, enabling malleable phenotypic change through signals, chemical processes, or various forms of energy that facilitate acclimatization. Billions of biological co-inhabitants of the earth, including all plants and animals, collectively make up a genetic/epigenetic ecosystem by which adaptation/survival (inputs and outputs) are highly interdependent on one another. As an ecosystem, the solar system, rotation of the planets, changes in sunlight, and gravitational pull influence cyclic epigenetic transitions and chromatin remodeling that constitute biological circadian rhythms controlling senescence. In humans, adverse environmental conditions such as poverty, stress, alcohol, malnutrition, exposure to pollutants generated from industrialization, man-made chemicals, and use of synthetic drugs can lead to maladaptive epigenetic-related illnesses with disease-specific genes being atypically activated or silenced. Nutrition and dietary practices are one of the largest facets in epigenetic-related metabolism, where specific "epi-nutrients" can stabilize the genome, given established roles in DNA methylation, histone modification, and chromatin remodeling. Moreover, food-based "epi-bioactive" constituents may reverse maladaptive epigenetic patterns, not only prior to conception and during fetal/early postnatal development but also through adulthood. In summary, in contrast to a static genomic DNA structure, epigenetic changes are potentially reversible, raising the hope for therapeutic and/or dietary interventions that can reverse deleterious epigenetic programing as a means to prevent or treat major illnesses.

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“…In line, atypical antipsychotics were shown to be neuroprotective by inhibiting inflammation-induced microglia activation and reactive oxygen species production in cortical neuron-glia cultures (Hu et al 2012 ) and by decreasing the level of proinflammatory cytokines in the serum of lipopolysaccharide-treated mice (Sugino et al 2009 ). Antagonism towards NMDA receptor of some antipsychotics in rat brain neurons (Barygin et al 2017 ) as well as downregulation of NMDA receptor subunit expression in rat thalamus were reported, what may stimulate negative symptoms, and limit these drugs clinical efficacy (Krzystanek et al 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Influence of Cyclooxygenase-2 Inhibitors on Kynurenic Acid Production in Rat Brain in Vitro

et al. 2018

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Significant body of evidence suggests that abnormal kynurenic acid (KYNA) level is involved in the pathophysiology of central nervous system disorders. In the brain, KYNA is synthesized from kynurenine (KYN) by kynurenine aminotransferases (KATs), predominantly by KAT II isoenzyme. Blockage of ionotropic glutamate (GLU) receptors is a main cellular effect of KYNA. High KYNA levels have been linked with psychotic symptoms and cognitive dysfunction in animals and humans. As immunological imbalance and impaired glutamatergic neurotransmission are one of the crucial processes in neurological pathologies, we aimed to analyze the effect of anti-inflammatory agents, inhibitors of cyclooxygenase-2 (COX-2): celecoxib, niflumic acid, and parecoxib, on KYNA synthesis and KAT II activity in rat brain in vitro. The influence of COX-2 inhibitors was examined in rat brain cortical slices and on isolated KAT II enzyme. Niflumic acid and parecoxib decreased in a dose-dependent manner KYNA production and KAT II activity in rat brain cortex in vitro, whereas celecoxib was ineffective. Molecular docking results suggested that niflumic acid and parecoxib interact with an active site of KAT II. In conclusion, niflumic acid and parecoxib are dual COX-2 and KAT II inhibitors.

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Extended neuroleptic administration modulates NMDA-R subunit immunoexpression in the rat neocortex and diencephalon

Cited by 7 publications

References 44 publications

NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality

NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality

Epigenetics and Nutritional Environmental Signals

Influence of Cyclooxygenase-2 Inhibitors on Kynurenic Acid Production in Rat Brain in Vitro

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