Clozapine as the most efficacious antipsychotic for activating ERK 1/2 kinases: Role of 5-HT 2A receptor agonism

Aringhieri, Stefano; Kolachalam, Shivakumar; Gerace, Claudio; Carli, Marco De; Verdesca, Valeria; Brunacci, Maria Giulia; Rossi, Chiara; Ippolito, Chiara; Solini, Anna; Corsini, Giovanni; Scarselli, Marco

doi:10.1016/j.euroneuro.2017.02.005

Cited by 41 publications

(31 citation statements)

References 55 publications

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“…Several series of biased D 2 agonists have been reported [ 7 , 162 , 163 ] as underlying ligand and receptor structural features necessary for biased signaling. Moreover, as has already been mentioned, serotonin 5-HT 2A receptor functional selectivity can be important for the activity of antipsychotics as it was reported for clozapine [ 112 , 164 ].…”

Section: Targeting Novel Gpcr Signaling Mechanisms In Schizophrenimentioning

confidence: 92%

Current Concepts and Treatments of Schizophrenia

2018

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Schizophrenia is a debilitating mental illness which involves three groups of symptoms, i.e., positive, negative and cognitive, and has major public health implications. According to various sources, it affects up to 1% of the population. The pathomechanism of schizophrenia is not fully understood and current antipsychotics are characterized by severe limitations. Firstly, these treatments are efficient for about half of patients only. Secondly, they ameliorate mainly positive symptoms (e.g., hallucinations and thought disorders which are the core of the disease) but negative (e.g., flat affect and social withdrawal) and cognitive (e.g., learning and attention disorders) symptoms remain untreated. Thirdly, they involve severe neurological and metabolic side effects and may lead to sexual dysfunction or agranulocytosis (clozapine). It is generally agreed that the interactions of antipsychotics with various neurotransmitter receptors are responsible for their effects to treat schizophrenia symptoms. In particular, several G protein-coupled receptors (GPCRs), mainly dopamine, serotonin and adrenaline receptors, are traditional molecular targets for antipsychotics. Comprehensive research on GPCRs resulted in the exploration of novel important signaling mechanisms of GPCRs which are crucial for drug discovery: intentionally non-selective multi-target compounds, allosteric modulators, functionally selective compounds and receptor oligomerization. In this review, we cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling.

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Section: Targeting Novel Gpcr Signaling Mechanisms In Schizophrenimentioning

confidence: 92%

Current Concepts and Treatments of Schizophrenia

2018

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“…Unfortunately, the mechanism of the stimulatory effects of CLZ on the process of Cx43 expression in the plasma membrane via post-translational modification system remains to be clarified. Among the revealed phosphorylation/ubiquitylation processes of Cx43, the activation of PKB signalling induced by CLZ [ 19 , 124 ] provides a notable molecule underling the mechanisms of Cx43 expression and impaired glucose tolerance [ 125 , 126 ]. CLZ increased the time- and concentration-dependently increased Ser473 phosphorylated-PKB (pPKB) [ 127 , 128 ].…”

Section: Effects Of Clz On Cx43 and Its Associated Signal Transducmentioning

confidence: 99%

“…The majority of psychiatrists are aware of the effectiveness of CLZ [ 16 , 17 ]; however, the reasons for the underutilization of CLZ concern the possible severe/lethal adverse drug reactions and rigorous clinical monitoring required [ 16 , 17 , 18 ]. In other words, many psychiatrists evaluate that the possible adverse effects of CLZ outweigh its benefits [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

Okada

Fukuyama

Shiroyama

et al. 2020

IJMS

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Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization’s (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.

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“…Xu and co-workers also showed that 25C-NBOMe concentration of 50 µM inhibited activities of phosphorylated Akt-kinase (pAkt) and pSer9 (GSK3b Antibody)-Glycogen synthase kinase 3 beta (GSK3β) and enhanced expression of pERK. Thus 25C-NBOMe may produce in vitro neurotoxicity via a PI3-K/Akt pathway inhibition and the activation of the extracellular signal-regulated kinase (ERK) signaling pathway cascade by agonist action on 5-HT 2A ERK [15,16]. Gatch and co-workers have reported in their work that administration of 25C-NBOMe (0.5, 1, 2.5, and 5 mg/kg) resulted in time-and dosedependent locomotor activity depression with depressant effects occurred within 10 min after injection which lasted 30-60 min [17].…”

Section: Pharmacological Characterisationmentioning

confidence: 99%

25C-NBOMe short characterisation

2020

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Purpose N-Methoxybenzyls, a group of toxic phenylethylamine derivatives of the 2C family compounds, are a new class of potent serotonin 5-HT 2A receptor agonist hallucinogens with potential harmful effects. This study summarizes current state of knowledge of one of the most dangerous representative of this group-N-(2-methoxybenzyl)-2,5-dimethoxy-4-chlorophenethylamine (25C-NBOMe). Due to hallucinogenic properties similar to those observe after lysergic acid diethylamide (LSD) usage (altered thoughts, feelings, and awareness of one's surroundings), this compound is very attractive to hallucinogenic substances users. Methods An exhaustive literature search was carried out in PubMed, Google Scholar and other biomedical data bases without limiting period, to identify relevant articles. Results Despite frequent recreational use, knowledge about the 25C-NBOMe action and toxic and fatal consequences is still very limited. Most data on this drug come from clinical reports, from cases of acute fatal and non-fatal intoxications. Some animal and in vitro studies indicated a route of metabolism of the drug in the body. The drug and its metabolites were also detected in human blood and urine using combinations of chromatographic separation and mass spectrometry detection. Conclusions Overall, findings show that 25C-NBOMe is a powerful hallucinogen. Easy online availability, low prize and the lack of knowledge of 25C-NBOMe makes this substance potentially very dangerous to its users. Thus, further investigation on the mechanism of action, chemical, pharmacological and toxicological properties is needed to evaluate 25C-NBOMe potential harmful effects.

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Clozapine as the most efficacious antipsychotic for activating ERK 1/2 kinases: Role of 5-HT 2A receptor agonism

Cited by 41 publications

References 55 publications

Current Concepts and Treatments of Schizophrenia

Current Concepts and Treatments of Schizophrenia

A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

25C-NBOMe short characterisation

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