Abstract
Haloperidol is a commonly used antipsychotic drug for treating schizophrenia. Clinical imaging studies have found that haloperidol can cause volume loss of human brain tissue, which is supported by animal studies showing that haloperidol reduces the number of synaptic spines. The mechanism remains unknown. Gut microbiota metabolites, short chain fatty acids including propionate, are reported to have neuroprotective effect and influence gene expression. This study aims to investigate the effect and mechanism of propionate in the protection of neurite lesion induced by haloperidol. This study showed that 10 μM haloperidol (clinical relevant dose) impaired neurite length in human blastoma SH-SY5Y cells, which were confirmed by using primary mouse striatal spiny neurons. We found that haloperidol impaired neurite length were accompanied by a decreased neuropeptide Y (NPY) expression, but no effect on GSK3β signaling. Importantly, this project research found that propionate was capable of protecting against haloperidol-induced neurite lesions and preventing NPY reduction. To confirm this finding, we used specific siRNAs targeting NPY which blocked the protective effect of propionate on haloperidol-induced neurite lesions. Furthermore, since NPY is regulated by the nuclear transcription factor CREB, we measured pCREB that was decreased by haloperidol and was normalized by propionate. Therefore, propionate has a protective effect against pCREB-NPY mediated haloperidol-induced neurite lesions.
Highlights
Antipsychotic drugs are the primary therapeutic agents used to treat schizophrenia and its allied mental disorders (Huang and Song, 2018)
In order to investigate the effects of haloperidol on neurite morphology, RA-induced differentiated SH-SY5Y cells were incubated with various concentrations of haloperidol (0, 1, 10, 50 μM) for 24 h
The results suggested that neuropeptide Y (NPY) was associated with neurite reduction induced by haloperidol
Summary
Antipsychotic drugs are the primary therapeutic agents used to treat schizophrenia and its allied mental disorders (Huang and Song, 2018). Propionate Protects Haloperidol-Induced Neurite Lesions hallucinations, delusions, and aggressiveness (Jafari et al, 2012; Dold et al, 2015). It can cause various side effects including extrapyramidal syndrome, tardive dyskinesia, and cerebrovascular events (Hufner et al, 2015). Another study shows that chronic administration of haloperidol at ∼0.35 mg/kg at 2-week intervals for 1 year significantly reduces neuronal cytoskeleton and spine-associated proteins in the cortices of rhesus monkey, where are rich in dopamine innervation and are implicated in the psychopathology of schizophrenia (Lidow et al, 2001). There is an urgent need to search for a way to protect antipsychotic drug-induced neurite lesion
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