Antidiabetic drugs in Parkinson's disease.

This review explores the intricate connections between type 2 diabetes (T2D) and Parkinson's disease (PD), both prevalent chronic conditions that primarily affect the aging population. These diseases share common early biochemical pathways that contribute to tissue damage. This manuscript also systematically compiles potential shared cellular mechanisms between T2D and PD and discusses the literature on the utilization of antidiabetic drugs as potential therapeutic options for PD. This review encompasses studies investigating the experimental and clinical efficacy of antidiabetic drugs in the treatment of Parkinson's disease, along with the proposed mechanisms of action. The exploration of the benefits of antidiabetic drugs in PD presents a promising avenue for the treatment of this neurodegenerative disorder.

Nucleus of the solitary tract neuronal degeneration and impaired hypoxia response in a model of Parkinson's disease.

Parkinson's disease (PD) involves the degeneration of dopaminergic neurons in the substantia nigra (SNpc) and manifests with both classic and non-classic motor symptoms, including respiratory failure. Our study aims to investigate the involvement of the commissural and intermediate nucleus of the solitary tract (cNTS and iNTS) in the attenuated respiratory response to hypoxia in PD. Using a PD rat model induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum of male Wistar rats, we explored potential alterations in the population of Phox2b neurons or hypoxia-activated neurons in the NTS projecting to the retrotrapezoid nucleus (RTN). Additionally, we explored neuronal connectivity between SNpc and cNTS. Projections pathways were assessed using unilateral injection of the retrograde tracer Fluorogold (FG) in the cNTS and RTN. Neuronal activation was evaluated by analyzing fos expression in rats exposed to hypoxia. In the PD model, the ventilatory response, measured through whole-body plethysmography, was impaired at both baseline and in response to hypoxia. A reduction in Phox2b-expressing neurons or hypoxia-activated neurons projecting to the RTN was observed. Additionally, we identified an indirect pathway linking the SNpc and cNTS, which passes through the periaqueductal gray (PAG). In conclusion, our findings suggest impairment in the SNpc-PAG-cNTS pathway in the PD model, explaining the loss of Phox2b-expressing neurons or hypoxia-activated neurons in the cNTS and subsequent respiratory impairment during hypoxic stimulation. We propose that the reduced population of Phox2b-expressing neurons in the NTS may include the same neurons activated by hypoxia and projecting to the RTN.

EFFECTS OF TREADMILL GAIT TRAINING ON BALANCE IN PARKINSON'S PATIENTS AFTER DEEP BRAIN STIMULATION.

Objective: After deep brain stimulation (DBS), patients with Parkinson's disease (PD) typically still present significant gait and postural stability problems, and thus additional interventions are needed. In this way, our purpose was evaluate the comparative effectiveness of treadmill training, with and without body weight support, on balance outcomes among patients with PD after DBS. Methods: Eleven patients with PD that were using bilateral subthalamic nucleus DBS were evaluated using Time Up and Go test (TUG); Berg Balance Scale (BBS) and Static Posturography. In phase 1, all subjects participated in 8-weeks of treadmill training in conjunction with conventional physiotherapy. After six weeks (wash-out), each patient then participated in a subsequent 8-weeks of treadmill training with partial body weight support. Results: After the phase 1, there were improvements on the cognitive TUG performance (Before: 15.7 ± 1,8 sec; After: 13.7 ± 3.1 sec; p < 0.01) and an increase of anteroposterior and medio-lateral body oscillation with eyes closed. After the phase 2, there were improvements in conventional (Before: 12.3 ± 2.0 sec; After: 10.7 ± 1.7 sec; p < 0.01) and cognitive (Before: 14.6 ± 3.5 sec; After: 12.5 ± 1.6 sec; p < 0.05) TUG performances. There were no significant changes in the Berg Balance Scale following either training protocol. Conclusion: Both trainings improved static and dynamic balance and had similar results; however, supported treadmill training seemed to be a potentially superior option, as patients tended to feel safer. Level of Evidence II, therapeutic studies - investigation of treatment outcomes.

Objetivo: Mesmo após a estimulação cerebral profunda (ECP), os pacientes com doença de Parkinson (DP) muitas vezes ainda apresentam problemas significativos de marcha e estabilidade postural, e, portanto, intervenções adicionais são necessárias. Avaliar a eficácia comparativa do treinamento em esteira, com e sem suporte de peso corporal, nos resultados de equilíbrio de pacientes com DP após ECP. Métodos: Onze pacientes com DP em uso de ECP bilateral do núcleo subtalâmico foram avaliados pelos testes Time Up and Go (TUG), escala de equilíbrio de Berg (EEB) e posturografia estática. Na fase 1, todos participaram de oito semanas de treinamento em esteira em conjunto com fisioterapia convencional. Após seis semanas (wash-out), cada paciente participou de oito semanas subsequentes de treinamento em esteira com suporte parcial de peso corporal. Resultados: Depois da fase 1, houve melhora no desempenho cognitivo do TUG (antes: 15,7 ± 1,8 s; depois: 13,7 ± 3,1 s; p < 0,01) e aumento da oscilação anteroposterior e médio-lateral do corpo com os olhos fechados. Após a fase 2, os resultados do TUG convencional (antes: 12,3 ± 2,0 seg; depois: 10,7 ± 1,7 seg; p < 0,01) e cognitivo (antes: 14,6 ± 3,5 s; depois: 12,5 ± 1,6 s; p < 0,05) demonstraram melhora. Os protocolos de treinamento não causaram mudanças significativas na EEB.. Conclusão: Ambos os treinos melhoraram o equilíbrio estático e dinâmico e tiveram resultados semelhantes; no entanto, o treinamento em esteira com suporte é uma opção potencialmente superior, uma vez que os pacientes tendiam a se sentir mais seguros. Nível de Evidência II, estudos terapêuticos - investigação de resultados de tratamento.

Treating activated regulatory T cells with pramipexole protects human dopaminergic neurons from 6-OHDA-induced degeneration.

BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, which promotes a sustained inflammatory environment in the central nervous system. Regulatory T cells (Tregs) play an important role in the control of inflammation and might play a neuroprotective role. Indeed, a decrease in Treg number and function has been reported in PD. In this context, pramipexole, a dopaminergic receptor agonist used to treat PD symptoms, has been shown to increase peripheral levels of Treg cells and improve their suppressive function. The aim of this work was to determine the effect of pramipexole on immunoregulatory Treg cells and its possible neuroprotective effect on human dopaminergic neurons differentiated from human embryonic stem cells. METHODS: Treg cells were sorted from white blood cells of healthy human donors. Assays were performed with CD3/CD28-activated and non-activated Treg cells treated with pramipexole at concentrations of 2 or 200 ng/mL. These regulatory cells were co-cultured with in vitro-differentiated human dopaminergic neurons in a cytotoxicity assay with 6-hydroxydopamine (6-OHDA). The role of interleukin-10 (IL-10) was investigated by co-culturing activated IL-10-producing Treg cells with neurons. To further investigate the effect of treatment on Tregs, gene expression in pramipexole-treated, CD3/CD28-activated Treg cells was determined by Fluidigm analysis. RESULTS: Pramipexole-treated CD3/CD28-activated Treg cells showed significant protective effects on dopaminergic neurons when challenged with 6-OHDA. Pramipexole-treated activated Treg cells showed neuroprotective capacity through mechanisms involving IL-10 release and the activation of genes associated with regulation and neuroprotection. CONCLUSION: Anti-CD3/CD28-activated Treg cells protect dopaminergic neurons against 6-OHDA-induced damage. In addition, activated, IL-10-producing, pramipexole-treated Tregs also induced a neuroprotective effect, and the supernatants of these co-cultures promoted axonal growth. Pramipexole-treated, activated Tregs altered their gene expression in a concentration-dependent manner, and enhanced TGFß-related dopamine receptor regulation and immune-related pathways. These findings open new perspectives for the development of immunomodulatory therapies for the treatment of PD.

Teleassessment using five times sit-to-stand test in older adults with and without Parkinson's disease: Guidelines and barriers.

BACKGROUND AND PURPOSE: Assessing lower limb strength, balance, and fall risk are crucial components of rehabilitation, especially for the older adult population. With the growing interest in telehealth, teleassessment has been investigated as an alternative when in-person assessments are not possible. The Five Times Sit-to-Stand test (5TSTS) provides a quick measure of balance during chair transfers, muscle power, endurance, and the hability to change and maintain body position, and is highly recommended by guidelines. However, the literature is unclear about the viability and safety of teleassessment using the 5TSTS in older adults with and without Parkinson's disease (PD). This study aimed to evaluate the reliability of teleassessment using the 5TSTS and to determine its feasibility and safety for older adults with and without PD. METHODS: This cross-sectional study included older adults with and without PD who were evaluated remotely through a videoconference platform. To ensure effective and comprehensive instructions for the test, we developed a guideline called OMPEPE (an acronym for: Objective; Materials; Position-Start; Execution; Position-End; Environment). We assessed the 5TSTS intra- and inter-rater reliability by comparing scores obtained from the same examiner and from different examiners, respectively. Participants and examiners completed online surveys to provide information about feasibility and safety. RESULTS: Twelve older adults with PD and 17 older adults without PD were included in this study (mean ages 69.0 and 67.6 years, respectively). Based on the participants' perspectives and the absence of adverse effects, teleassessment using the 5TSTS is feasible and safe for older adults with and without PD. Excellent intra- and inter-rater reliability (intraclass correlation coefficient >0.90) was found for all measurements of the 5TSTS. DISCUSSION: This study demonstrated the feasibility, safety, and reliability of teleassessment using the 5TSTS. The guidelines developed may help health professionals minimize barriers and safely conduct an online assessment that includes a physical test such as the 5TSTS in older adults with or without PD. In addition to addressing technological barriers, the OMPEPE guideline might ensure the optimal execution of evaluations. CONCLUSION: Teleassessment using the 5TSTS for older adults with and without PD is feasible and safe. Both synchronous (i.e., live) and asynchronous (i.e., recorded) online 5TSTS tests demonstrate excellent intra- and inter-rate reliability.

NMDA receptor remodeling and nNOS activation in mice after unilateral striatal injury with 6-OHDA.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by selective dopaminergic loss. Non dopaminergic neurotransmitters such as glutamate are also involved in PD progression. NMDA receptor/postsynaptic density protein 95 (PSD-95)/neuronal nitric oxide synthase (nNOS) activation is involved in neuronal excitability in PD. Here, we are focusing on the evaluating these post-synaptic protein levels in the 6-OHDA model of PD. Adult male C57BL/6 mice subjected to unilateral striatal injury with 6-OHDA were assessed at 1-, 2-, or 4-weeks post-lesion. Animals were subjected to an apomorphine-induced rotation test followed by the analysis of protein content, synaptic structure, and NOx production. All biochemical analysis was performed comparing the control versus lesioned sides of the same animal. 6-OHDA mice exhibited contralateral rotation activity, difficulties in coordinating movements, and changes in Iba-1 and glial fibrillary acidic protein (GFAP) expression during the whole period. At one week of survival, the mice showed a shift in NMDA composition, favoring the GluN2A subunit and increased PSD95 and nNOS expression and NOx formation. After two-weeks, a decrease in the total number of synapses was observed in the lesioned side. However, the number of excitatory synapses was increased with a higher content of GluN1 subunit and PSD95. After four weeks, NMDA receptor subunits restored to control levels. Interestingly, NOx formation in the serum increased. This study reveals, for the first time, the temporal course of behavioral deficits and glutamatergic synaptic plasticity through NMDAr subunit shift. Together, these data demonstrate that dopamine depletion leads to a fine adaptive response over time, which can be used for further studies of therapeutic management adjustments with the progression of PD.

A Comprehensive Approach to Parkinson's Disease: Addressing Its Molecular, Clinical, and Therapeutic Aspects.

Parkinson's disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, and epigenetic factors. Clinical symptoms consist of non-motor and motor symptoms, with motor symptoms being the classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, and surgical interventions. Traditional pharmacological treatment consists of administering drugs (MAOIs, DA, and levodopa), while emerging evidence explores the potential of antidiabetic agents for neuroprotection and gene therapy for attenuating parkinsonian symptoms. Non-pharmacological treatments, such as exercise, a calcium-rich diet, and adequate vitamin D supplementation, aim to slow disease progression and prevent complications. For those patients who have medically induced side effects and/or refractory symptoms, surgery is a therapeutic option. Deep brain stimulation is the primary surgical option, associated with motor symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy and a portable infusion pump succeeded in reducing "off" time, where non-motor and motor symptoms occur, and increasing "on" time. This article aims to address the general aspects of PD and to provide a comparative comprehensive review of the conventional and the latest therapeutic advancements and emerging treatments for PD. Nevertheless, further studies are required to optimize treatment and provide suitable alternatives.

Transcranial direct current stimulation and cognitive changes in Parkinson's disease, a systematic review with meta-analysis and meta-regression.

Parkinson's disease is the second most common neurodegenerative disease, but therapeutic options such as neuromodulation continue to show variable effects, making clinical management of the disease difficult. This systematic review with meta-analysis and meta-regression aimed to analyze the isolated effect of cortical modulation with transcranial direct current stimulation (tDCS) compared to sham stimulation on cognitive changes in people with Parkinson's disease. The databases used were: Web of Science, Scopus, PsycINFO, PubMed, and Cochrane. The results showed that tDCS can influence the improvement of cognition in PD (Inverse Variance:0.24 [95% Confidence Interval: 0.09 to -0.40], p < 0.00). The meta-analysis showed that active tDCS can influence cognitive function by improving aspects related to memory (Inverse Variance:0.34 [95% Confidence Interval: 0.07 to 0.61], p < 0.01) and reducing reaction time in cognitive tasks (Inverse Variance:0.42 [95% Confidence Interval: 0.07 to 0.76], p < 0.02). Innovative meta-regression analyses showed that variables such as age (Q = 2.54, df = 1, p < 0.11), education level (Q = 2.62, df = 1, p < 0.10), disease duration (Q = 0.01, df = 1, p < 0.92), and Unified PD Rating Scale stage (Q = 0.01, df = 1, p < 0.92) did not influence the results. Thus, tDCS may be a therapeutic option for cognitive changes in people with PD, and we suggest further studies to identify protocols that can be replicated.

Immunomodulation as a treatment for parkinson's disease in current trials: a systematic review and meta-analysis.

Background: Immunomodulatory drugs and immunotherapies are being evaluated in clinical trials for the treatment of neuroinflammation, as the latter is an essential mechanism for the development and progression of Parkinson's disease. Objective: The objective of the study is to review recent evidence on the evaluation of immunomodulators in randomized controlled clinical trials measuring improvement of motor symptoms. Methods: A meta-analysis of Movement Disorder Society-Unified Parkinson's disease Rating Scale (MDS-UPDRS III) scores extracted from seven articles selected after an online search of PubMed, Cochrane Library, and Clarivate's Web of Science for randomized controlled clinical trials published between 2000 and July 2023 was performed. The selected articles reported clinical trials evaluating the effects of specific immunomodulators or treatments with known effects on the immune system and inflammation. MDS-UPDRS III scores were reported in these studies, and the results of the placebo groups were compared with those of the treatment groups. Results: A total of 590 patients treated with immunomodulators and 622 patients treated with placebo were included. A test for heterogeneity yielded an I2 value > 50%. The mean standard difference for change in MDS-UPDR III score was -0.46 (CI [95%] = -0.90 - -0.02, p < 0.01). No significant differences were found in the change in mean MDS-UPDR III score between the treatment and placebo groups; however, two studies showed a trend toward separation from the mean. Conclusion: The immunomodulatory treatments included in this study showed no efficacy in improving motor symptoms in Parkinson's disease patients. Further clinical trials with larger patient populations are needed.

Levodopa versus levodopa sparing in early parkinson's disease: can we meet halfway?

Monotherapy is the recommended initial treatment for early Parkinson's disease. The pharmacological options for initial treatment include dopaminergic agonists, monoamine oxidase B inhibitors, and levodopa formulations. Several factors should be considered when selecting the optimal treatment, such as disease severity, disease duration, age, activity level, and the risk of developing motor and non-motor complications. Early evidence on the potential role of levodopa formulations in the risk of dyskinesia led to levodopa aversion in the late 1990s and early 2000s, favoring the use of levodopa-sparing options like dopamine agonists. This shift resulted in an increase in behavioral adverse effects, such as impulse control disorders, leading to a subsequent dopamine agonist aversion in the mid-2000s. This review aims to provide a comprehensive evaluation of the existing literature regarding the benefits and drawbacks of levodopa versus levodopa-sparing strategies in drug-naive early-stage Parkinson's disease.

Neuroprotective effects of Tradescantia spathacea tea bioactives in Parkinson's disease: In vivo proof-of-concept.

Background and aim: Tradescantia spathacea (T. spathacea) is a traditional medicinal plant from Central America and its tea, obtained by infusion, has been recognized as a functional food. The aim of this work was to investigate the effects of dry tea containing biocompounds from T. spathacea tea on motor and emotional behavior, as well as tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) expression in 6-hydroxydopamine (6-OHDA)-lesioned rats. Experimental procedure: Bioactives were identified by Ultra Performance Liquid Chromatography (UPLC) and an in vivo study in male Wistar rats was run as proof of concept of neuroprotective effects of DTTS. Results and conclusion: We found 15 biocompounds that had not been previously reported in T. spathacea: the UPLC-QTOF-MS/MS allowed identification five phenolic acids, one coumarin, two flavonoids, one iridoid, one phenylpropanoid glycoside, and six fatty acid derivatives. The dry tea of T. spathacea (DTTS) presented significant antioxidant activity and high contents of phenolic compounds and flavonoids. Doses of 10, 30, and 100 mg/kg of DTTS were protective against dopaminergic neurodegeneration and exhibited modulatory action on the astrocyte-mediated neuroinflammatory response. Behavioral tests showed that 30 mg/kg of DTTS counteracted motor impairment, while 100 mg/kg produced an anxiolytic effect. The DTTS could be, therefore, a promising strategy for the management of Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus under general anesthesia versus local anesthesia in the treatment of Parkinson's disease: a meta-analysis of randomized clinical trials.

Deep brain stimulation (DBS) stands as the preferred treatment for Parkinson's disease (PD) patients manifesting refractory motor symptoms or when medication side effects outweigh the benefits. Though traditionally administered under local anesthesia coupled with sedation (LA + S), recent evidence hints at comparable outcomes under general anesthesia (GA). This systematic review and meta-analysis aimed to scrutinize post-surgical outcomes in randomized PD patients undergoing DBS surgery while GA versus LA + S. We searched PubMed, Cochrane, and Embase databases following PRISMA guidelines. We included randomized studies directly comparing DBS surgery under GA versus LA + S, delineating clinical outcomes. Safety outcomes assessed disparities in infection and hemorrhage risk. Mean differences (MD) and Risk Differences (RD) with 95% Confidence Intervals (CI) were utilized to evaluate outcomes, under a random-effects model. Heterogeneity was evaluated through I² statistics, and in studies exhibiting high heterogeneity, exclusion analysis was performed. Evaluated outcomes encompassed motor improvement, complications, behavioral and mood effects gauged by the Unified Parkinson's Disease Rating Scale (UPDRS), Parkinson's Disease Questionnaire 39 (PDQ39), and daily levodopa equivalent dose (LEDD). A total of 3 studies, encompassing 203 patients, were reviewed. At a 6-month follow-up, in patients undergoing GA during surgery, there was no statistically significant difference compared to the LA + S group in terms of UPDRS III ON (MD 0.19; 95% CI -2.21 to 2.59; p = 0.88; I²=0%), UPDRS III OFF (MD 0.58; 95% CI -4.30 to 5.45; p = 0.21; I²=0%), UPDRS IV ON ( (MD 0.98; 95% CI -0.95 to 2.92; p = 0.32; I²=23%), PDQ39 (MD -1.27; 95% CI -6.31 to 3.77; p = 0.62; I²=0%), and LEDD (MD -1.99; 95% CI -77.88 to 73.90; p = 0.96; I²=32%). There was no statistically significant difference between groups in terms of infection (RD 0.02; 95% CI -0.02 to 0.05; p = 0.377; I²=0%) or hemorrhage (RD 0.04; 95% CI -0.03 to 0.11; p = 0.215; I²=0%). Our findings suggest, based on short-term follow-up, that GA is not inferior to LA + S in terms of benefits for the selected outcomes. However, further studies are needed to determine whether there are significant long-term clinical differences between these groups.

New Perspectives of Deep Brain Stimulation Indications for Parkinson's Disease: A Critical Review.

Deep Brain Stimulation (DBS) is an effective treatment option for patients with dopaminergic complications of Parkinson's disease (PD) and drug-refractory PD tremor. However, DBS and its indications can be challenging, and they are not often debated in the medical community. Through a critical narrative review, the objective of this paper is to improve the comprehension of DBS indications and help to solve the puzzle that this process can be. Proper patient selection is the first step for a good surgical outcome. In this review, then, relevant considerations are discussed, involving PD genes, PD phenotypes, indications of early stages, non-motor symptoms, neuroimaging predictors, comorbidities, and age. Individualized approaches are encouraged, including clinical and radiological factors. Social support during the whole follow-up and expectations alignment are necessary through this process and are also debated.

Parkinson's disease and levodopa-induced dyskinesias: a quantitative analysis through 99mTc-TRODAT-1 SPECT imaging of the brain.

Objective: To compare the dopamine transporter (DAT) density with other risk factors for L-DOPA-induced dyskinesia (LID) in patients with Parkinson's disease (PD), with and without LID. Materials and Methods: We evaluated 67 subjects: 44 patients with idiopathic PD of varying degrees of severity (PD group), and 23 healthy age-matched volunteers (control group). Among the 44 patients in the PD group, 29 were male and the following means were recorded at baseline: age, 59 ± 7 years; disease duration, 10 ± 6 years; Hoehn and Yahr (H&Y) stage, 2.16 ± 0.65; and Unified Parkinson's Disease Rating Scale part III (UPDRS III) score, 29.74 ± 17.79. All subjects underwent 99mTc-TRODAT-1 SPECT. We also calculated specific uptake ratios or binding potentials in the striatum. Results: The DAT density in the ipsilateral and contralateral striata was lower in the PD group. The variables disease duration, L-DOPA dosage, doses per day, L-DOPA effect duration time, H&Y stage, and UPDRS III score explained the occurrence of LID. The DAT density in the ipsilateral striatum, contralateral striatum, and caudate nucleus was lower in the patients with LID than in those without. Conclusion: Our findings suggest that presynaptic dopaminergic denervation is associated with LID in individuals with PD.

Objetivo: Comparar a densidade do transportador de dopamina (DAT) com outros fatores de risco para discinesia induzida pela L-DOPA em pacientes com doença de Parkinson, com e sem discinesias. Materiais e Métodos: Sessenta e sete sujeitos, 23 voluntários saudáveis e 44 pacientes pareados por idade com diferentes graus de gravidade da doença de Parkinson idiopática (29 homens; idade média ± desvio-padrão (DP), 59 ± 7 anos; duração média ± DP dos sintomas, 10 ± 6 anos; H&Y: média ± DP, 2,16 ± 0,65; UPDRS III: média ± DP, 29,74 ± 17,79). Todos os sujeitos realizaram SPECT cerebral com 99mTc-TRODAT-1. Além disso, foram calculadas as taxas de captação específica ou potenciais de ligação no estriado. Resultados: A densidade de DAT do estriado ipsilateral ou contralateral foi menor no grupo doença de Parkinson. As variáveis duração da doença, dosagem de L-DOPA, doses por dia, tempo de duração do efeito da L-DOPA, H&Y e UPDRS III explicaram a ocorrência de discinesia. Adicionalmente, pacientes com discinesia exibiram menor densidade de DAT no estriado ipsilateral ou contralateral e no núcleo caudado do que os pacientes sem discinesia. Conclusão: O presente estudo sugere que a denervação dopaminérgica pré-sináptica na doença de Parkinson está associada ao desenvolvimento de discinesia induzida pela L-DOPA.

Design, Synthesis, and Evaluation of a Novel Conjugate Molecule with Dopaminergic and Neuroprotective Activities for Parkinson's Disease.

The escalating prevalence of Parkinson's disease (PD) underscores the need for innovative therapeutic interventions since current palliative measures, including the standard l-Dopa formulations, face challenges of tolerance and side effects while failing to address the underlying neurodegenerative processes. Here, we introduce DAD9, a novel conjugate molecule that aims to combine symptomatic relief with disease-modifying strategies for PD. Crafted through knowledge-guided chemistry, the molecule combines a nonantibiotic doxycycline derivative with dopamine, preserving neuroprotective attributes while maintaining dopaminergic agonism. This compound exhibited no off-target effects on PD-relevant cell functions and sustained antioxidant and anti-inflammatory properties of the tetracycline precursor. Furthermore, it effectively interfered with the formation and seeding of toxic α-synuclein aggregates without producing detrimental oxidative species. In addition, DAD9 was able to activate dopamine receptors, and docking simulations shed light onto the molecular details of this interaction. These findings position DAD9 as a potential neuroprotective dopaminergic agonist, promising advancements in PD therapeutics.

Exploring circular RNAs as biomarkers for Parkinson's disease and their expression changes after aerobic exercise rehabilitation.

Circular RNAs (circRNAs) are circularized single-stranded ribonucleic acids that interacts with DNA, RNA, and proteins to play critical roles in cell biology. CircRNAs regulate microRNA content, gene expression, and may code for specific peptides. Indeed, circRNAs are differentially expressed in neurodegenerative disorders like Parkinson's disease (PD), playing a potential role in the mechanisms of brain pathology. The RNA molecules with aberrant expression in the brain can cross the blood-brain barrier and reach the bloodstream, which enable their use as non-invasive PD disease biomarker. Promising targets with valuable discriminatory ability in combined circRNA signatures include MAPK9_circ_0001566, SLAIN1_circ_0000497, SLAIN2_circ_0126525, PSEN1_circ_0003848, circ_0004381, and circ_0017204. On the other hand, regular exercises are effective therapy for mitigating PD symptoms, promoting neuroprotective effects with epigenetic modulation. Aerobic exercises slow symptom progression in PD by improving motor control, ameliorating higher functions, and enhancing brain activity and neuropathology. These improvements are accompanied by changes circRNA expression, including hsa_circ_0001535 (circFAM13B) and hsa_circ_0000437 (circCORO1C). The sensitivity of current methods for detecting circulating circRNAs is considered a limitation. While amplification kits already exist for low-abundant microRNAs, similar kits are needed for circRNAs. Alternatively, the use of digital PCR can help overcome this constraint. The current review examines the potential use of circRNAs as non-invasive biomarkers of PD and to assess the effects of rehabilitation. Although circRNAs hold promise as targets for PD diagnosis and therapeutics, further validation is needed before their clinical implementation.

Paradoxical Kinesia Induced by Nightmare: Unique Case Report and Insights regarding the Neural Mechanism Based on Human and Rat Studies.

Introduction: Bradykinesia, characterized by slowed movement, stands out as a primary symptom observed in individuals with Parkinson's disease (PD). Nonetheless, there are instances where PD patients exhibit sudden and effective movements despite the presence of bradykinesia. This phenomenon, referred to as paradoxical kinesia, has remained a subject of interest for neuroscientists, who have struggled to unravel its underlying neural mechanisms for decades. Case Presentation: We describe a patient who is suffering from advanced PD. The patient has severe motor limitations, including difficulty rising from bed and walking, as well as cognitive decline and visual impairment. However, an interesting occurrence took place during a nightmare episode. Surprisingly, the patient was able to get out of bed and quickly run away from the perceived threat within the nightmare, without any assistance. Conclusion: This report presents the first documented case of paradoxical kinesia induced by nightmares in a patient with PD. This phenomenon raises questions about the neurological mechanisms involved, which are still not fully understood. Based on existing research conducted on both animal and human subjects, we propose that after processing the emotion of fear, the brain aversive system activates motor outputs to generate appropriate behavior. Thus, the brain aversive system converts the emotion of fear into action through projections from the inferior colliculus to motor-related areas such as the mesencephalic locomotor region, pontine nuclei, and substantia nigra.

Exposure to Glycolysis-Enhancing Drugs and Risk of Parkinson's Disease: A Meta-Analysis.

Background: Impaired glucose and energy metabolism has been suggested as a pathogenic mechanism underlying Parkinson's disease (PD). In recent cohorts, phosphoglycerate kinase 1 activators (PGK1a) have been associated with a lower incidence of PD when compared with other antiprostatic agents that do not activate PGK1. Objective: We aimed to perform a systematic review and meta-analysis comparing the incidence of PD in patients taking PGK1a versus tamsulosin. Methods: We searched PubMed, Embase, and Cochrane Library for studies comparing PGK1a vs. tamsulosin in adults and elderly. The primary outcome was the incidence of PD. We computed hazard ratios (HR) for binary endpoints, with 95% confidence intervals (CIs). Statistical analysis was performed using Review Manager 5.4 and R (version 4.3.1). Results: A total of 678,433 participants from four cohort studies were included, of whom 287,080 (42.3%) received PGK1a. Mean age ranged from 62 to 74.7 years and nearly all patients were male. Patients taking PGK1a had a lower incidence of PD (PGK1a 1.04% vs. tamsulosin 1.31%; HR 0.80; 95% CI 0.71-0.90; p < 0.01). This result remained consistent in a sensitivity analysis excluding patients of age 60 years old or younger (PGK1a 1.21% vs. tamsulosin 1.42%; HR 0.82; 95% CI 0.71-0.95; p < 0.01). Conclusions: Glycolysis-enhancing drugs are associated with a lower incidence of PD when compared with tamsulosin in adults and elderly individuals with prostatic disease in use of alpha-blockers. Our findings support the notion of glycolysis as a potential neuroprotective mechanism in PD. Future investigations with randomized controlled trials are needed.

It has been suggested that impairment in glucose and energy metabolism is one of the mechanisms underlying the development of Parkinson's disease. In recent studies, medications traditionally prescribed for prostate diseases, called phosphoglycerate kinase 1 activators (PGK1a), have been associated with a lower incidence of Parkinson's disease when compared to other medications for the same purpose that do not activate the same energetic pathway. Therefore, we thoroughly reviewed the literature and combined the results of studies that compared both medications (PGK1a versus another medication  that  does not activate this energetic pathway, called tamsulosin), evaluating the incidence of Parkinson's disease in both groups. We included a total of 678,433 individuals, of whom 42.3% received PGK1a and 57.7% received tamsulosin. In our analysis, patients taking PGK1a had a lower incidence of Parkinson's disease when compared to the other group, even when we excluded patients younger than 60 years of age. As a result, our findings support the notion that the increase of energy metabolism is a potential neuroprotective mechanism in Parkinson's disease and future investigations are needed.

Posterior insula repetitive transcranial magnetic stimulation for chronic pain in patients with Parkinson disease - pain type matters: A double-blinded randomized sham-controlled trial.

OBJECTIVES: Altered somatosensory processing in the posterior insula may play a role in chronic pain development and contribute to Parkinson disease (PD)-related pain. Posterior-superior insula (PSI) repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to have analgesic effects among patients with some chronic pain conditions. This study aimed at assessing the efficacy of PSI-rTMS for treating PD-related pain. METHODS: This was a double-blinded, randomized, sham-controlled, parallel-arm trial (NCT03504748). People with PD (PwP)-related chronic pain underwent five daily PSI-rTMS sessions for a week, followed by once weekly maintenance stimulations for seven weeks. rTMS was delivered at 10 Hz and 80% of the resting motor threshold. The primary outcome was a ≥ 30% pain intensity reduction at 8 weeks compared to baseline. Functionality, mood, cognitive, motor status, and somatosensory thresholds were also assessed. RESULTS: Twenty-five patients were enrolled. Mean age was 55.2 ± 9.5 years-old, and 56% were female. Nociceptive pain accounted for 60%, and neuropathic and nociplastic for 20% each. No significant difference was found for 30% pain reduction response rates between active (42.7%) and sham groups (14.6%, p = 0.26). Secondary clinical outcomes and sensory thresholds also did not differ significantly. In a post hoc analysis, PwP with nociceptive pain sub-type experienced more pain relief after active (85.7%) compared to sham PSI-rTMS (25%, p = 0.032). CONCLUSION: Our preliminary results suggest that different types of PD-related pain may respond differently to treatment, and therefore people with PD may benefit from having PD-related pain well characterized in research trials and in clinical practice.

Motor Control in Parkinson's Disease During the Performance of Multi-Joint Reversal Movements.

We tested if the movement slowness of individuals with Parkinson's disease is related to their decreased ability to generate adequate net torques and linearly coordinate them between joints. This cross-sectional study included ten individuals with Parkinson's disease and ten healthy individuals. They performed planar movements with a reversal over three target distances. We calculated joint kinematics of the elbow and shoulder using spatial orientation. The muscle, interaction, and net torques were integrated into the acceleration/deceleration phases of the fingertip speed. We calculated the linear correlations of those torques between joints. Both groups modulated the elbow and shoulder net torques with target distances. They linearly coupled the production of torques. Both groups did not modulate the interaction torques. The movement slowness in Parkinson's disease was related to the difficulty in generating the appropriate muscle and net torques in the task. The interaction torques do not seem to play any role in movement control.