Haloperidol and clozapine block formation of autophagolysosomes in rat primary neurons

Park, J.; Chung, Seockhoon; An, Hee-Jung; Kim, J.; Seo, Ji-Yun; Kim, D.H.; Yoon, Seung-Yong

doi:10.1016/j.neuroscience.2012.02.035

Cited by 41 publications

(50 citation statements)

References 44 publications

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“…Wiklund's study also suggested that H1299 cells which lacked p53 protein were more resistant to antipsychotics as compared to A549 cells that harbored the functional tumor suppressor protein p53 [14]. In our study, both yellow and red punctae were detected, which is different from the study of Park et al in which only yellow punctae were observed [33]. Autophagy is a functional influx process.…”

Section: Discussioncontrasting

confidence: 98%

Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

Yin

Lin²,

Chen³

et al. 2015

Cell Physiol Biochem

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Background/Aims: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. Methods: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. Results: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. Conclusions: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

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Section: Discussioncontrasting

confidence: 98%

Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

Yin

Lin²,

Chen³

et al. 2015

Cell Physiol Biochem

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“…Moreover, evidence suggests that HP, chlorpromazine, and thiothixene inhibit complex I in vitro in rat brain mitochondria, as does clozapine, but at a significantly higher concentration . Similar results were also found for cinnarizine and flunarizine . Very interestingly, the study by Meredith et al did not show any differences in typical (eg, HP) versus atypical (eg, eticlopride) neuroleptic‐induced effects in basal ganglia or limbic forebrain regions, thus suggesting that such effects do not reflect a direct consequence of antagonist occupation of dopaminergic receptors …”

Section: The (Possible) Neurotoxic Effects Of Neuroleptics On Dopaminmentioning

confidence: 66%

Parkinsonism following neuroleptic exposure: A double‐hit hypothesis?

2015

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Drug-induced parkinsonism is caused by an offending drug and should resolve after the causative agent has been withdrawn. However, in a number of patients, symptoms persist or may even worsen over time, suggesting the development of concomitant Parkinson's disease. The prevalence estimates of Parkinson's disease after neuroleptic exposure are unexpectedly high, suggesting a causal relationship. We critically review available literature in this regard, and some pathophysiological hypotheses that might explain such a relationship are suggested. Some patients may have an undetermined genetic susceptibility to parkinsonism. We speculate that the possible neurotoxic effect of neuroleptics exerted on a susceptible dopaminergic system would lead over the long-term to a self-fostering, progressive process. Knowledge gaps and future perspectives are discussed.

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“…Chronic clozapine treatment (20 mg/kg/day) reduces Aβ deposition [264]. Although typical and atypical antipsychotics may alleviate diseases featuring aberrant protein misfolding and accumulation, in vivo systematic investigations regarding the efficacy and the molecular mechanisms of these drugs on autophagy have been questioned [265]. This issue is biased by the routine intake of neuroleptics by most schizophrenic patients for long time intervals, sometimes lasting decades.…”

Section: A Step Forward About a Role Of Autophagy In The Pathophysmentioning

confidence: 99%

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Ryskalin

Limanaqi

Frati

et al. 2018

IJMS

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The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations.

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Haloperidol and clozapine block formation of autophagolysosomes in rat primary neurons

Cited by 41 publications

References 44 publications

Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

Parkinsonism following neuroleptic exposure: A double‐hit hypothesis?

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

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