Dataset Information

SLC6A3, HTR2C and HTR6 Gene Polymorphisms and the Risk of Haloperidol-Induced Parkinsonism.

ABSTRACT: Antipsychotic-induced parkinsonism (AIP) is the most common type of extrapyramidal side effect (EPS), caused by the blockage of dopamine receptors. Since dopamine availability might influence the AIP risk, the dopamine transporter (DAT) and serotonin receptors (5-HTRs), which modulate the dopamine release, may be also involved in the AIP development. As some of the individual differences in the susceptibility to AIP might be due to the genetic background, this study aimed to examine the associations of SLC6A3, HTR2C and HTR6 gene polymorphisms with AIP in haloperidol-treated schizophrenia patients. The Extrapyramidal Symptom Rating Scale (ESRS) was used to evaluate AIP as a separate entity. Genotyping was performed using a PCR, following the extraction of blood DNA. The results revealed significant associations between HTR6 rs1805054 polymorphism and haloperidol-induced tremor and rigidity. Additionally, the findings indicated a combined effect of HTR6 T and SLC6A3 9R alleles on AIP, with their combination associated with significantly lower scores of ESRS subscale II for parkinsonism, ESRS-based tremor or hyperkinesia and ESRS subscales VI and VIII. These genetic predictors of AIP could be helpful in better understanding its pathophysiology, recognizing the individuals at risk of developing AIP and offering personalized therapeutic strategies for the patients suffering from this EPS.

SUBMITTER: Nedic Erjavec G

PROVIDER: S-EPMC9776373 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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SLC6A3, HTR2C and HTR6 Gene Polymorphisms and the Risk of Haloperidol-Induced Parkinsonism.

Nedic Erjavec Gordana G Grubor Mirko M Zivkovic Maja M Bozina Nada N Sagud Marina M Nikolac Perkovic Matea M Mihaljevic-Peles Alma A Pivac Nela N Svob Strac Dubravka D

Biomedicines 20221213 12

Antipsychotic-induced parkinsonism (AIP) is the most common type of extrapyramidal side effect (EPS), caused by the blockage of dopamine receptors. Since dopamine availability might influence the AIP risk, the dopamine transporter (DAT) and serotonin receptors (5-HTRs), which modulate the dopamine release, may be also involved in the AIP development. As some of the individual differences in the susceptibility to AIP might be due to the genetic background, this study aimed to examine the associat ...[more]

PMID: 36551993

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Project description:Parkinson's disease (PD) is a complex, age-related neurodegenerative disease that causes neuronal loss and dysfunction over time. An imbalance of redox potential of oxidative stress in the cell causes neurodegenerative diseases and dysfunction of neurons. Plants are a rich source of bioactive substances that attenuate oxidative stress in a variety of neurological disorders. The aim of the present study was to evaluate the Prunus armeniaca L. methanolic extract (PAME) for anti-Parkinson activity in rats. PD was induced with haloperidol (1 mg/kg, IP). The PAME was administered orally at 100, 300, and 800 mg/kg dose levels for 21 days. Behavioral studies (catalepsy test, hang test, open-field test, narrow beam walk, and hole-board test), oxidative stress biomarkers (SOD, CAT, GSH, and MDA) levels, neurotransmitters (dopamine, serotonin, and noradrenaline) levels, and acetylcholinesterase activity were quantified in the brain homogenate. Liver function tests (LFTs), renal function tests (RFTs), complete blood count (CBC), and lipid profiles were measured in the blood/serum samples to note the side effects of PAME at the selected doses. Histopathological analysis was performed on the brain (anti-PD study), liver, heart, and kidney (to check the toxicity of PAME on these vital organs). Motor functions were improved in the behavioral studies. Dopamine, serotonin, and noradrenaline levels were significantly increased (P < 0.001), whereas the level of acetylcholinesterase was decreased significantly (P < 0.001). The levels of superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) were increased, while malondialdehyde (MDA) and nitrite levels were decreased in the PAME-treated groups significantly compared with the disease control group, hence reducing oxidative stress. The incidence of toxicity was determined by biochemical analysis of LFT and RFT biomarkers testing. The histopathological analysis indicated that neurofibrillary tangles and plaques decreased in a dose-dependent manner in the PAME-treated groups. Based on the data, it is concluded that PAME possessed good anti-Parkinson activity, rationalizing the plant's traditional use as a neuroprotective agent.

Project description:ObjectiveTo determine whether genetic polymorphisms related to pharmacodynamics with metabolic adverse effects, namely leptin promoter (LEP) rs7799039, leptin receptor rs1137101, dopamine D2 rs4436578, serotonin 5-HT2A rs6313, and serotonin 5-HT2C rs518147 and rs12836771, are associated with hyperglycemia induced by risperidone or clozapine in adult Thai patients with psychosis.MethodsA total of 180 patients treated with risperidone-based (n=130) or clozapine-based (n=50) regimens were included in this study. Blood samples were analyzed for genotyping of the candidate genes and biochemical testing. Genotyping was performed by conducting a TaqMan real-time polymerase chain reaction-based analysis.ResultsThe prevalence of hyperglycemia was higher in patients receiving clozapine (64.0%) than in those receiving risperidone (30.8%). Among the candidate genes, only the LEP rs7799039 polymorphism demonstrated a significant association with hyperglycemia (χ2=9.879, P=0.008) in patients treated with risperidone; patients with the AA genotype had the highest risk (41.1%), followed by those with AG (20.8%) and GG (0%) genotypes. Using the recessive genetic model (AA vs AG + GG), the odds ratio and 95% CI were 3.28 and 1.44 -7.50, respectively. None of the genes were associated with hyperglycemia in patients treated with clozapine. A binary logistic regression revealed that the LEP rs7799039 polymorphism demonstrated a significant association with hyperglycemia, independent of body-mass index (BMI) in patients receiving risperidone; the odds ratio (95% CI) was 3.188 (1.399-7.262), P=0.006. By contrast, none of the pharmacodynamic genetic factors, except for BMI, were significantly associated with hyperglycemia in patients receiving clozapine.ConclusionThe risk of type 2 diabetes mellitus is associated with the LEP rs7799039 polymorphism in Thai adults receiving risperidone but not in those receiving clozapine. Clarifying underlying mechanisms and risk of hyperglycemia provides an opportunity to prevent impaired glucose metabolism in patients receiving risperidone or clozapine.

Dataset Information

SLC6A3, HTR2C and HTR6 Gene Polymorphisms and the Risk of Haloperidol-Induced Parkinsonism.

Publications

<i>SLC6A3</i>, <i>HTR2C</i> and <i>HTR6</i> Gene Polymorphisms and the Risk of Haloperidol-Induced Parkinsonism.

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