Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson's Disease.

The accumulation of misfolded and aggregated α-synuclein can trigger endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), leading to apoptotic cell death in patients with Parkinson's disease (PD). As the major ER chaperone, glucose-regulated protein 78 (GRP78/BiP/HSPA5) plays a key role in UPR regulation. GRP78 overexpression can modulate the UPR, block apoptosis, and promote the survival of nigral dopamine neurons in a rat model of α-synuclein pathology. Here, we explore the therapeutic potential of intranasal exogenous GRP78 for preventing or slowing PD-like neurodegeneration in a lactacystin-induced rat model. We show that intranasally-administered GRP78 rapidly enters the substantia nigra pars compacta (SNpc) and other afflicted brain regions. It is then internalized by neurons and microglia, preventing the development of the neurodegenerative process in the nigrostriatal system. Lactacystin-induced disturbances, such as the abnormal accumulation of phosphorylated pS129-α-synuclein and activation of the pro-apoptotic GRP78/PERK/eIF2α/CHOP/caspase-3,9 signaling pathway of the UPR, are substantially reversed upon GRP78 administration. Moreover, exogenous GRP78 inhibits both microglia activation and the production of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in model animals. The neuroprotective and anti-inflammatory potential of exogenous GRP78 may inform the development of effective therapeutic agents for PD and other synucleinopathies.

Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort.

BACKGROUND AND OBJECTIVES: Inverse associations between caffeine intake and Parkinson disease (PD) have been frequently implicated in human studies. However, no studies have quantified biomarkers of caffeine intake years before PD onset and investigated whether and which caffeine metabolites are related to PD. METHODS: Associations between self-reported total coffee consumption and future PD risk were examined in the EPIC4PD study, a prospective population-based cohort including 6 European countries. Cases with PD were identified through medical records and reviewed by expert neurologists. Hazard ratios (HRs) and 95% CIs for coffee consumption and PD incidence were estimated using Cox proportional hazards models. A case-control study nested within the EPIC4PD was conducted, recruiting cases with incident PD and matching each case with a control by age, sex, study center, and fasting status at blood collection. Caffeine metabolites were quantified by high-resolution mass spectrometry in baseline collected plasma samples. Using conditional logistic regression models, odds ratios (ORs) and 95% CIs were estimated for caffeine metabolites and PD risk. RESULTS: In the EPIC4PD cohort (comprising 184,024 individuals), the multivariable-adjusted HR comparing the highest coffee intake with nonconsumers was 0.63 (95% CI 0.46-0.88, p = 0.006). In the nested case-control study, which included 351 cases with incident PD and 351 matched controls, prediagnostic caffeine and its primary metabolites, paraxanthine and theophylline, were inversely associated with PD risk. The ORs were 0.80 (95% CI 0.67-0.95, p = 0.009), 0.82 (95% CI 0.69-0.96, p = 0.015), and 0.78 (95% CI 0.65-0.93, p = 0.005), respectively. Adjusting for smoking and alcohol consumption did not substantially change these results. DISCUSSION: This study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine and its metabolites years before diagnosis.

Parkinson's Disease in Sub-Saharan Africa: Pesticides as a Double-Edged Sword.

Long-term exposure to pesticides used in agriculture is increasingly being identified as a risk factor for developing Parkinson's disease. How chronic pesticide exposure might contribute to the growth of Parkinson's disease in the mainly agricultural communities of Sub-Saharan Africa has thus far received limited attention. There are specific concerns in this area of the world: aging of the population, in combination with chronic exposure to widely used pesticides, including those that have been restricted elsewhere in the world because of neurotoxicity and other health risks. Of interest, the prevalence of Parkinson's disease among specific (semi)nomadic populations in Tanzania seems very low, possibly due to their lack of exposure to agricultural chemicals. But at the same time, pesticides have also brought important benefits to this part of the world. Specifically, in Sub-Saharan Africa, pesticides have been directly helpful in preventing and controlling famine and in containing major human infectious diseases. This creates a complex risk-benefit ratio to the use of pesticides within a global perspective, and urgently calls for the development and implementation of affordable alternatives for areas such as Sub-Saharan Africa, including non-neurotoxic compounds and non-chemical alternatives for the use of pesticides.

Association of bilateral oophorectomy with incidence of Parkinson's disease: A systematic review and meta-analysis.

INTRODUCTION: Current evidence in the literature is inconclusive due to conflicting results with regards to an association between B/L (B/L) oophorectomy and Parkinson's disease (PD). We included large, powered studies to assess the association of PD in women who have undergone B/L oophorectomy. METHODS: We conducted a comprehensive search across three databases from inception to October 2022 for observational studies including pre-menopausal or post-menopausal women undergoing B/L oophorectomy. Primary outcome of interest was incidence of PD or parkinsonism. The results for these associations were presented as Risk Ratios (RR) with 95% confidence intervals (CI), which were pooled using a generic invariance weighted random effects model using Review Manager (RevMan). RESULTS: Data was included from a total of 4 studies. No significant association was found between B/L oophorectomy and PD (RR: 1.38; 95% CI: 0.76 to 2.49; I2:89 %) in contrast significant association was found with parkinsonism (RR: 1.80; 95% CI: 1.29 to 2.52). Age at surgery didn't significantly affect Parkinsonism incidence (RR: 0.88; 95% CI: 0.59 to 1.3). No significant association was found between ovarian indication and Parkinsonism (RR: 1.08; 95% CI: 0.69 to 1.68). B/L oophorectomy with hysterectomy was associated with higher Parkinson's risk compared to without hysterectomy (RR: 1.4; 95% CI: 1.13 to 1.74). Lastly, there was no significant association between Post Menopausal Hormonal (PMH) use and Parkinson's disease (RR: 1.07; 95% CI: 0.92 to 1.26). CONCLUSION: Our findings suggest that B/L oophorectomy is significantly associated with the incidence of Parkinsonism. Further research is needed to understand the potential relationship between oophorectomy and Parkinson's disease.

Exploring the therapeutic potential of Rab11: A comprehensive study on its effectiveness in alleviating rotenone-induced molecular pathogenesis of Parkinson's disease in SH-SY5Y cells and its synergistic application with L-DOPA in Drosophila models.

Dysfunctional mitophagy contributes to Parkinson's disease (PD) by affecting dopamine-producing neurons. Mutations in parkin and pink1 genes, linked to familial PD, impede the removal of damaged mitochondria. Previous studies suggested Rab11's involvement in mitophagy alongside Parkin and Pink1. Additionally, mitochondria-endoplasmic reticulum contact sites (MERCS) regulate cellular functions, including mitochondrial quality control and calcium regulation. Our study explored whether activating mitophagy triggers the unfolded protein response and ER stress pathway in SH-SY5Y human cells. We induced a PD-like state by exposing undifferentiated SH-SY5Y cells to rotenone, an established PD-inducing agent. This led to reduced Rab11 and PERK- expression while increasing ATP5a, a mitochondrial marker, when Rab11 was overexpressed. Our findings suggest that enhancing endosomal trafficking can mitigate ER stress by regulating mitochondria, rescuing cells from apoptosis. Furthermore, we assessed the therapeutic potential of Rab11, both alone and in combination with L-Dopa, in a Drosophila PD model. In summary, our research underscores the role of mitophagy dysfunction in PD pathogenesis, highlighting Rab11's importance in alleviating ER stress and preserving mitochondrial function. It also provides insights into potential PD management strategies, including the synergistic use of Rab11 and L-Dopa.

Dry-Cleaning Chemicals and a Cluster of Parkinson's Disease and Cancer: A Retrospective Investigation.

BACKGROUND: Environmental exposure to trichloroethylene (TCE), a carcinogenic dry-cleaning chemical, may be linked to Parkinson's disease (PD). OBJECTIVE: The objective of this study was to determine whether PD and cancer were elevated among attorneys who worked near a contaminated site. METHODS: We surveyed and evaluated attorneys with possible exposure and assessed a comparison group. RESULTS: Seventy-nine of 82 attorneys (96.3%; mean [SD] age: 69.5 [11.4] years; 89.9% men) completed at least one phase of the study. For comparison, 75 lawyers (64.9 [10.2] years; 65.3% men) underwent clinical evaluations. Four (5.1%) of them who worked near the polluted site reported PD, more than expected based on age and sex (1.7%; P = 0.01) but not significantly higher than the comparison group (n = 1 [1.3%]; P = 0.37). Fifteen (19.0%), compared to four in the comparison group (5.3%; P = 0.049), had a TCE-related cancer. CONCLUSIONS: In a retrospective study, diagnoses of PD and TCE-related cancers appeared to be elevated among attorneys who worked next to a contaminated dry-cleaning site. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Minimizing pneumocephalus during deep brain stimulation surgery.

BACKGROUND: Deep brain stimulation (DBS) surgery is an effective treatment for movement disorders. Introduction of intracranial air following dura opening in DBS surgery can result in targeting inaccuracy and suboptimal outcomes. We develop and evaluate a simple method to minimize pneumocephalus during DBS surgery. METHODS: A retrospective analysis of prospectively collected data was performed on patients undergoing DBS surgery at our institution from 2014 to 2022. A total of 172 leads placed in 89 patients undergoing awake or asleep DBS surgery were analyzed. Pneumocephalus volume was compared between leads placed with PMT and leads placed with standard dural opening. (112 PMT vs. 60 OPEN). Immediate post-operative high-resolution CT scans were obtained for all leads placed, from which pneumocephalus volume was determined through a semi-automated protocol with ITK-SNAP software. Awake surgery was conducted with the head positioned at 15-30°, asleep surgery was conducted at 0°. RESULTS: PMT reduced pneumocephalus from 11.2 cm3±9.2 to 0.8 cm3±1.8 (P<0.0001) in the first hemisphere and from 7.6 cm3 ± 8.4 to 0.43 cm3 ± 0.9 (P<0.0001) in the second hemisphere. No differences in adverse events were noted between PMT and control cases. Lower rates of post-operative headache were observed in PMT group. CONCLUSION: We present and validate a simple yet efficacious technique to reduce pneumocephalus during DBS surgery.

The epidemiology of Parkinson's disease.

The epidemiology of Parkinson's disease shows marked variations in time, geography, ethnicity, age, and sex. Internationally, prevalence has increased over and above demographic changes. There are several potential reasons for this increase, including the decline in other competing causes of death. Whether incidence is increasing, especially in women or in many low-income and middle-income countries where there is a shortage of high-quality data, is less certain. Parkinson's disease is more common in older people and men, and a variety of environmental factors have been suggested to explain why, including exposure to neurotoxic agents. Within countries, there appear to be ethnic differences in disease risk, although these differences might reflect differential access to health care. The cause of Parkinson's disease is multifactorial, and involves genetic and environmental factors. Both risk factors (eg, pesticides) and protective factors (eg, physical activity and tendency to smoke) have been postulated to have a role in Parkinson's disease, although elucidating causality is complicated by the long prodromal period. Following the establishment of public health strategies to prevent cardiovascular diseases and some cancers, chronic neurodegenerative diseases such as Parkinson's disease and dementia are gaining a deserved higher priority. Multipronged prevention strategies are required that tackle population-based primary prevention, high-risk targeted secondary prevention, and Parkinson's disease-modifying therapies for tertiary prevention. Future international collaborations will be required to triangulate evidence from basic, applied, and epidemiological research, thereby enhancing the understanding and prevention of Parkinson's disease at a global level.

Gastrointestinal Surgery and Risk of Parkinson's Disease: A Meta-Analysis.

Several studies have explored gastrointestinal surgery and the risk of Parkinson's disease (PD), but the results of these studies are still controversial. This meta-analysis aimed to evaluate undergoing gastrointestinal surgery and the risk of PD in patients. PubMed, EMbase, the Cochrane Library, CNKI, and WanFang Data databases were electronically searched to collect studies from inception to 1 March 2023. Stata15.1 software was used to perform meta-analysis of the data. Of 260 references screened, 8 studies involving 9,596,121 people were included eventually. Gastrointestinal surgery had no significant effect on the risk of PD (OR = 1.059, 95% CI: 0.915-1.224, I2 = 90.4%, p = 0.443). Several subgroup analyses showed that the patients with different regions, different surgical locations and different sample sizes after gastrointestinal surgery were not associated with the risk of PD. Furthermore, sensitivity analysis confirmed that the patients after gastrointestinal surgery were not associated with the risk of PD. There was no significant effect of gastrointestinal surgery on the risk of PD, but more studies should be included to confirm this observation. Key Words: Gastrointestinal surgery, Risk factor, Parkinson's disease, Meta-analysis.

Subthalamic Nucleus Deep Brain Stimulation Restores Motor and Sensorimotor Cortical Neuronal Oscillatory Activity in the Free-Moving 6-Hydroxydopamine Lesion Rat Parkinson Model.

OBJECTIVES: Enhanced beta oscillations in cortical-basal ganglia (BG) thalamic circuitries have been linked to clinical symptoms of Parkinson's disease. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces beta band activity in BG regions, whereas little is known about activity in cortical regions. In this study, we investigated the effect of STN DBS on the spectral power of oscillatory activity in the motor cortex (MCtx) and sensorimotor cortex (SMCtx) by recording via an electrocorticogram (ECoG) array in free-moving 6-hydroxydopamine (6-OHDA) lesioned rats and sham-lesioned controls. MATERIALS AND METHODS: Male Sprague-Dawley rats (250-350 g) were injected either with 6-OHDA or with saline in the right medial forebrain bundle, under general anesthesia. A stimulation electrode was then implanted in the ipsilateral STN, and an ECoG array was placed subdurally above the MCtx and SMCtx areas. Six days after the second surgery, the free-moving rats were individually recorded in three conditions: 1) basal activity, 2) during STN DBS, and 3) directly after STN DBS. RESULTS: In 6-OHDA-lesioned rats (N = 8), the relative power of theta band activity was reduced, whereas activity of broad-range beta band (12-30 Hz) along with two different subbeta bands, that is, low (12-30 Hz) and high (20-30 Hz) beta band and gamma band, was higher in MCtx and SMCtx than in sham-lesioned controls (N = 7). This was, to some extent, reverted toward control level by STN DBS during and after stimulation. No major differences were found between contacts of the electrode grid or between MCtx and SMCtx. CONCLUSION: Loss of nigrostriatal dopamine leads to abnormal oscillatory activity in both MCtx and SMCtx, which is compensated by STN stimulation, suggesting that parkinsonism-related oscillations in the cortex and BG are linked through their anatomic connections.

Gene-Environment Interactions for Parkinson's Disease.

OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained. The aim of this study was to test for statistical interactions between PD-related genetic and environmental exposures in the 23andMe, Inc. research dataset. METHODS: Using a validated PD polygenic risk score and common PD-associated variants in the GBA gene, we explored interactions between genetic susceptibility factors and 7 lifestyle and environmental factors: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA). RESULTS: We observed that T2D, as well as higher BMI, caffeine consumption, and tobacco use, were associated with lower odds of PD, whereas head injury, pesticide exposure, GBA carrier status, and PD polygenic risk score were associated with higher odds. No significant association was observed between PA and PD. In interaction analyses, we found statistical evidence for an interaction between polygenic risk of PD and the following environmental/lifestyle factors: T2D (p = 6.502 × 10-8), PA (p = 8.745 × 10-5), BMI (p = 4.314 × 10-4), and tobacco use (p = 2.236 × 10-3). Although BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D, as well as PD and PA, varied depending on polygenic risk score. INTERPRETATION: We provide preliminary evidence that associations between some environmental and lifestyle factors and PD may be modified by genotype. ANN NEUROL 2024;95:677-687.

Association Between Menopausal Hormone Therapy and Risk for Parkinson's Disease.

BACKGROUND: The relationship between menopausal hormone therapy (MHT) and risk of Parkinson's disease (PD) remains controversial. OBJECTIVE: This nationwide population-based cohort study investigated the association between MHT and PD development. METHODS: Data from the National Health Insurance System of South Korea from 2007 to 2020 were used. The MHT group included women who underwent MHT for the first time between 2011-2014, while the non-MHT group included women who visited a healthcare provider for menopause during the same period but never received hormonal therapy. We used propensity score matching (1 : 1) to adjust for potential confounders, and Cox regression models to assess the association between MHT and PD. RESULTS: We selected 303,260 female participants (n = 151,630 per MHT and non-MHT groups). The median age of the participants was 50 (48-54) years, and the follow-up period lasted 7.9 (6.9-8.9) years. Cox regression analysis revealed an increased risk of PD with MHT (hazard ratio [HR] 1.377, 95% confidence interval [CI] 1.184-1.602), particularly with tibolone (HR 1.554, 95% CI 1.297-1.861) and estrogen alone (HR 1.465, 95% CI 1.054-2.036). Tibolone and estrogen alone were linked to PD within three years; however, no association was observed after three years. In contrast, the use of combined estrogen-progesterone was linked to a higher risk of PD, which increased with the duration of MHT (HR 1.885, 95% CI 1.218-2.918 for over five years). CONCLUSIONS: This study demonstrated that the MHT is closely associated with the risk of PD in a regimen- and duration-specific manner.

Neferine exerts anti­inflammatory activity in BV­2 microglial cells and protects mice with MPTP­induced Parkinson's disease by inhibiting NF­κB activation.

Abnormal activation of microglia and the production of proinflammatory cytokines can lead to chronic neuroinflammation, which is an important pathological characteristic of Parkinson's disease (PD). Neferine is a chemical compound extracted from lotus seed which has previously been reported to exert protective effects on the development of several types of cancer, myocardial injury and hypoxic­ischemic encephalopathy. However, its effect on microglial functions in neuroinflammation remains to be clarified. The present study used network pharmacology and screening in a lipopolysaccharide (LPS) model to demonstrate that neferine suppresses the production of inducible nitric oxide synthase, interleukin­6 and tumor necrosis factor α in LPS­treated BV­2 cells. The working concentration of neferine did not exert cytotoxic effects on BV­2 cells. Mechanistically, neferine attenuated inflammation by inhibiting the phosphorylation and nuclear translocation of the NF­κB p65 subunit. In vivo, neferine protected mice from the inflammatory response in the substantia nigra and inhibited the development of nervous disorders in the 1­methyl­4­phenyl­1,2,3,6­tetrahydropyridine­induced PD model. The present study demonstrated that neferine inhibited LPS­mediated activation of microglia by inhibiting NF­κB signaling. These findings may provide a new reference for the prevention and future treatment of PD.

Pesticides and the Microbiome-Gut-Brain Axis: Convergent Pathways in the Pathogenesis of Parkinson's Disease.

The increasing global burden of Parkinson's disease (PD), termed the PD pandemic, is exceeding expectations related purely to population aging and is likely driven in part by lifestyle changes and environmental factors. Pesticides are well recognized risk factors for PD, supported by both epidemiological and experimental evidence, with multiple detrimental effects beyond dopaminergic neuron damage alone. The microbiome-gut-brain axis has gained much attention in recent years and is considered to be a significant contributor and driver of PD pathogenesis. In this narrative review, we first focus on how both pesticides and the microbiome may influence PD initiation and progression independently, describing pesticide-related central and peripheral neurotoxicity and microbiome-related local and systemic effects due to dysbiosis and microbial metabolites. We then depict the bidirectional interplay between pesticides and the microbiome in the context of PD, synthesizing current knowledge about pesticide-induced dysbiosis, microbiome-mediated alterations in pesticide availability, metabolism and toxicity, and complex systemic pesticide-microbiome-host interactions related to inflammatory and metabolic pathways, insulin resistance and other mechanisms. An overview of the unknowns follows, and the role of pesticide-microbiome interactions in the proposed body-/brain-first phenotypes of PD, the complexity of environmental exposures and gene-environment interactions is discussed. The final part deals with possible further steps for translation, consisting of recommendations on future pesticide use and research as well as an outline of promising preventive/therapeutic approaches targeted on strengthening or restoring a healthy gut microbiome, closing with a summary of current gaps and future perspectives in the field.

Uridine as a Regulator of Functional and Ultrastructural Changes in the Brain of Rats in a Model of 6-OHDA-Induced Parkinson's Disease.

Using a model of Parkinson's disease (PD) induced by the bilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA) into rat brain substantia nigra (SN), we showed uridine to exert a protective effect associated with activation of the mitochondrial ATP-dependent potassium (mitoK-ATP) channel. Injection of 4 µg neurotoxin evoked a 70% decrease in the time the experimental animal spent on the rod in the RotaRod test, an increase in the amount of lipid peroxides in blood serum and cerebral-cortex mitochondria and the rate of reactive oxygen species formation, and a decrease in Ca2+ retention in mitochondria. Herewith, lymphocytes featured an increase in the activity of lactate dehydrogenase, a cytosolic enzyme of glycolysis, without changes in succinate-dehydrogenase activity. Structural changes occurring in the SN and striatum manifested themselves in the destruction of mitochondria, degeneration of neurons and synapses, and stratification of myelin sheaths in them. Subcutaneous injections of 30 µg/kg uridine for 22 days restored the neurotoxin-induced changes in these parameters to levels close to the control. 5-Hydroxydecanoate (5 mg/kg), a specific mitoK-ATP channel inhibitor, eliminated the beneficial effect of uridine for almost all characteristics tested, indicating the involvement of the mitoK-ATP channel in the protective effect of uridine. The mechanism of the protective effect of uridine and its therapeutic applications for the prevention and treatment of PD are discussed.

Prediagnostic Blood Metal Levels and the Risk of Parkinson's Disease: A Large European Prospective Cohort.

BACKGROUND: Metals have been postulated as environmental concerns in the etiology of Parkinson's disease (PD), but metal levels are typically measured after diagnosis, which might be subject to reverse causality. OBJECTIVE: The aim of this study was to investigate the association between prediagnostic blood metal levels and PD risk. METHODS: A case-control study was nested in a prospective European cohort, using erythrocyte samples collected before PD diagnosis. RESULTS: Most assessed metals were not associated with PD risk. Cadmium has a suggestive negative association with PD (odds ratio [95% confidence interval] for the highest quartile, 0.70 [0.42-1.17]), which diminished among never smokers. Among current smokers only, lead was associated with decreased PD risk (0.06 [0.01-0.35]), whereas arsenic showed associations toward an increased PD risk (1.85 [0.45-7.93]). CONCLUSIONS: We observe no strong evidence to support a role of metals in the development of PD. In particular, smoking may confound the association with tobacco-derived metals. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson's Disease.

The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson's disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson's disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson's disease treatment.

Association between Low Blood Pressure and Subsequent Risk of Parkinson's Disease in Older Adults Aged ≥75 Years.

INTRODUCTION: The association between blood pressure (BP) and incidence of Parkinson's disease (PD) in older adults remains uncertain. Therefore, this study aimed to investigate the association between BP (high or low) and PD incidence in adults aged ≥75 years. METHODS: In this nationwide population-based cohort study, we enrolled participants aged ≥75 years without a prior PD diagnosis who had undergone health examination provided by the Korean National Health Insurance Service at least once from January 1, 2009, to December 31, 2012. The participants were followed up until December 31, 2019, or the date of their death. The Cox proportional hazards model was used to assess the risk of PD depending on systolic BP (SBP), diastolic BP (DBP), and pulse pressure. RESULTS: Overall, 963,525 participants were enrolled in the analysis and followed up until December 31, 2019, or the date of death (40.7% male, mean age 78.5 ± 3.6 years). The mean SBP and DBP were 131.4 ± 16.7 and 77.9 ± 10.3 mm Hg, respectively. During the 10-year follow-up period, 16,414 (1.7%) newly diagnosed cases of PD were reported. A significant inverse dose-response association was found between SBP and PD incidence. In the subgroup analysis, this association was maintained for most variables, including sex, use of antihypertensive medication, comorbidities, alcohol consumption, physical activity, and body mass index, except for smoking status. CONCLUSION: Lower SBP and DBP were associated with a higher PD incidence in older adults. These results may have substantial implications for determining the optimal BP control target in adults aged ≥75 years.

A Role of ß2-Adrenoreceptor Agonists Related to the Development of Parkinson's Disease.

Background: Several studies have suggested the potential protective role of ß2-adrenoreceptor agonist (ß2AR-agonist) on the development of Parkinson's disease (PD). However, those could not reflect a different epidemiologic background in eastern countries. We explored ß2AR-agonist's effect on PD development by controlling for smoking. Materials and Methods: We used the Korean national sample cohort data (from 2002 to 2013) containing 1,025,340 participants (2.2% of the whole population). The subjects over 60 years were included. PD was defined based on the ICD-10 code, which should be diagnosed by neurologists. Atypical Parkinsonisms or ataxic disorders were excluded. We made Set 1 (from 2003 to 2007) and Set 2 (from 2003 to 2008) based on the exposure period for the sensitivity analysis. We observed whether PD had developed during the follow-up periods in each subset. Results: The PD (Set 1, n = 742; Set 2, n = 699) and non-PD group (Set 1, n = 57,645; Set 2, n = 66,586) were collected. Old age, Medicaid, and asthma were risk factors, whereas smoking was a significant protective factor for PD development. The proportion of ß2AR-agonist use was significantly higher in the PD group than in the non-PD group (Set 1, 3.6% vs. 2.4%; Set 2, 4.1% vs. 2.6%). ß2AR-agonist use still was a risk factor in developing PD from the multiple logistic regression analysis. Conclusions: ß2-AR-agonist looked like a risk factor rather than a protective factor for PD development. Well-controlled studies reflecting various epidemiologic backgrounds are required to confirm the role of ß2AR-agonist.

Use of gastrointestinal prokinetics and the risk of parkinsonism: A population-based case-crossover study.

BACKGROUND: The disease burden of parkinsonism is extremely costly in the United States. Unlike Parkinson's disease, drug-induced parkinsonism (DIP) is acute and reversible; exploring the causative drug is important to prevent DIP in patients at high-risk of parkinsonism. OBJECTIVE: To examine whether the use of gastrointestinal (GI) prokinetics is associated with an increased risk of parkinsonism. METHODS: We conducted a case-crossover study using nationally representative data. We included patients who were newly diagnosed with parkinsonism (ICD-10 G20, G21.1, G25.1) between January 1, 2007 and December 1, 2015. The first prescription date of G20, G21.1, or G25.1 diagnoses was defined as the index date (0 day). Patients with prior extrapyramidal and movement disorders or brain tumors were excluded. We assessed the exposure within the risk (0-29 days) and control periods (60-89 days), before or on the index date. Conditional logistic regression estimated the adjusted odds ratio (aOR) for parkinsonism. RESULTS: Overall, 2268 and 1674 patients were exposed to GI prokinetics during the risk and control periods, respectively. The use of GI prokinetics significantly increased the occurrence of parkinsonism (aOR = 2.31; 95% Confidence Interval [CI], 2.06-2.59). The use of GI prokinetics was associated with a higher occurrence of parkinsonism in elderly patients (≥65 years old; aOR = 2.69; 95% CI, 2.30-3.14) than in younger patients (aOR = 1.90; 95% CI, 1.59-2.27). CONCLUSIONS: The use of GI prokinetics was significantly associated with higher occurrences of parkinsonism, necessitating close consideration when using GI prokinetics.