ABSTRACT
Levodopa is the most used drug to treat motor symptoms in Parkinson's disease (PD). However, dopaminergic side effects such as nausea and vomiting may occur. Several evidences indicate a major role for dopamine receptors D2 (DRD2) and D3 (DRD3) in emetic activity. The aim of this study was to investigate the relationship of DRD2 rs1799732 and DRD3 rs6280 gene polymorphisms with gastrointestinal (GI) symptoms induced by levodopa in PD patients. Two hundred and seventeen PD patients on levodopa therapy were investigated. DRD2 rs1799732 and DRD3 rs6280 polymorphisms were genotyped by PCR-based methods. Multiple Poisson regression method with robust variance estimators was performed to assess the association between polymorphisms and gastrointestinal symptoms. The analyses showed that DRD2 Ins/Ins (prevalence ratio (PR)=2.374, 95% confidence interval (CI): 1.105-5.100; P=0.027) and DRD3 Ser/Ser genotypes (PR=1.677, 95% CI 1.077-2.611; P=0.022) were independent and predictors of gastrointestinal symptoms associated with levodopa therapy. Despite all the efforts to alleviate GI symptoms, this adverse effect still occurs in PD patients. Pharmacogenetic studies of GI symptoms induced by levodopa therapy have the potential to display new ways to better understand the molecular mechanisms involved in these side effects.
Subject(s)
Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/genetics , Levodopa/adverse effects , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Polymorphism, Genetic/genetics , Receptors, Dopamine D2/genetics , Receptors, Dopamine D3/genetics , Aged , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Parkinson Disease/geneticsABSTRACT
Calcium-binding protein B (S100B), a primary product of astrocytes, is a proposed marker of Parkinson's Disease (PD) pathophysiology, diagnosis and progression. However, it has also been implicated in sleep disruption, which is very common in PD. To explore the relationship between S100B, disease severity, sleep symptoms and polysomnography (PSG) findings, overnight changes in serum S100B levels were investigated for the first time in PD. 17 fully treated, non-demented, moderately advanced PD patients underwent PSG and clinical assessment of sleep symptoms. Serum S100B samples were collected immediately before and after the PSG. Results are shown as median [interquartile range]. Night and morning S100B levels were similar, but uncorrelated (rs=-0.277, p=0.28). Morning S100B levels, as opposed to night levels, positively correlated with the Unified Parkinson's Disease rating scale (UPDRS) subsections I and II (rs=0.547, p=0.023; rs=0.542, p=0.025). Compared to those with overnight S100B reduction, patients with overnight S100B elevation had higher H&Y scores (2.5 [0.87] vs. 2 [0.25], p=0.035) and worse total Pittsburgh Sleep Quality Index (PSQI) and Parkinson's Disease Sleep Scores (10 [3.2] vs. 8 [4.5], p=0.037; 92.9 [39] vs. 131.4 [28], p=0.034). Correlation between morning S100B levels and total UPDRS score was strengthened after controlling for total PSQI score (rs=0.531, p=0.034; partial rs=0.699, p=0.004, respectively). Overnight S100B variation and morning S100B were associated with PD severity and perceived sleep disruption. S100B is proposed as a putative biomarker for sleep-related neuroinflammation in PD. Noradrenergic-astrocytic dysfunction is hypothesized as a possible mechanism underlying these findings.
Subject(s)
Parkinson Disease/metabolism , S100 Calcium Binding Protein beta Subunit/blood , Sleep , Aged , Case-Control Studies , Female , Humans , Inflammation/metabolism , Male , Middle Aged , Parkinson Disease/physiopathology , Polysomnography , Time FactorsABSTRACT
Levodopa is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects.
