Background: Naltrexone is an opioid receptor antagonist commonly used to treat opioid and alcohol dependence. The use of low dose naltrexone (LDN) was found to have anti-inflammatory properties for ...treatment of diseases such as fibromyalgia, Crohn’s disease, multiple sclerosis and regional pain syndromes. Related to its anti-neuroinflammatory properties, the mechanism of action is possibly mediated via Toll-like receptor 4 antagonism, which is widely expressed on microglial cells. The aim of the present study was to assess the immunometabolic effects of naltrexone on microglia cells in in vitro conditions. Methods: All experiments were performed in the BV-2 microglial cell line. The cells were treated with naltrexone at 100 μM concentrations corresponding to low dose for 24 h. Cell viability was assessed for every drug dose. To induce additional activation, the cells were pretreated with LPS and IFN-γ. Immunofluorescence was used to analyse the classical microglial activation markers iNOS and CD206, while Seahorse was used for real-time cellular metabolic assessments. mTOR activity measured over the expression of a major direct downstream target S6K was assessed using western blot. Results: LDN induced a shift from highly activated pro-inflammatory phenotype (iNOShighCD206low) to quiescent anti-inflammatory M2 phenotype (iNOSlowCD206high) in BV-2 microglia cells. Changes in the inflammatory profile were accompanied by cellular metabolic switching based on the transition from high glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). LDN-treated cells were able to maintain a metabolically suppressive phenotype by supporting OXPHOS with high oxygen consumption, and also maintain a lower energetic state due to lower lactate production. The metabolic shift induced by transition from glycolysis to mitochondrial oxidative metabolism was more prominent in cells pretreated with immunometabolic modulators such as LPS and IFN-γ. In a dose-dependent manner, naltrexone also modulated mTOR/S6K expression, which underlies the cell metabolic phenotype regulating microglia immune properties and adaptation. Conclusion: By modulating the phenotypic features by metabolic switching of activated microglia, naltrexone was found to be an effective and powerful tool for immunometabolic reprogramming and could be a promising novel treatment for various neuroinflammatory conditions.
Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies ...since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson’s disease. Methods: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson’s disease treatment, along with a manual search, and finally included a total of 116 publications in the review. Results: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. Conclusions: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.
In this perspective article, we highlight the possible applicability of genetic testing in Parkinson's disease and dystonia patients treated with deep brain stimulation (DBS). DBS, a neuromodulatory ...technique employing electrical stimulation, has historically targeted motor symptoms in advanced PD and dystonia, yet its precise mechanisms remain elusive. Genetic insights have emerged as potential determinants of DBS efficacy. Known PD genes such as GBA, SNCA, LRRK2, and PRKN are most studied, even though further studies are required to make firm conclusions. Variable outcomes depending on genotype is present in genetic dystonia, as DYT-TOR1A, NBIA/DYTPANK2, DYT-SCGE and X-linked dystonia-parkinsonism have demonstrated promising outcomes following GPi-DBS, while varying outcomes have been documented in DYT-THAP1. We present two clinical vignettes that illustrate the applicability of genetics in clinical practice, with one PD patient with compound GBA mutations and one GNAL dystonia patient. Integrating genetic testing into clinical practice is pivotal, particularly with advancements in next-generation sequencing. However, there is a clear need for further research, especially in rarer monogenic forms. Our perspective is that applying genetics in PD and dystonia is possible today, and despite challenges, it has the potential to refine patient selection and enhance treatment outcomes.
Dystonia is the third most common pediatric movement disorder and is often difficult to treat. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been demonstrated as a safe and ...effective treatment for genetic dystonia in adolescents and adults. The results of DBS in children are limited to individual cases or case series, although it has been proven to be an effective procedure in carefully selected pediatric cohorts. The aim of our study was to present the treatment outcome for 7- to 9-year-old pediatric patients with disabling monogenic isolated generalized DYT-
and DYT-
dystonia after bilateral GPi-DBS.
We present three boys aged <10 years; two siblings with disabling generalized DYT-
dystonia and a boy with monogenic-complex DYT-
. Dystonia onset occurred between the ages of 3 and 6. Significantly disabled children were mostly dependent on their parents. Pharmacotherapy was inefficient and patients underwent bilateral GPi-DBS. Clinical signs of dystonia improved significantly in the first month after the implantation and continued to maintain improved motor functions, which were found to have improved further at follow-up. These patients were ambulant without support and included in everyday activities. All patients had significantly lower Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) values, indicating >25% improvement over the first 15 months. However, there was a decline in speech and upper limb function, manifesting with bradylalia, bradykinesia, and dysphonia, which decreased after treatment with trihexyphenidyl.
Although reports of patients with monogenic dystonia, particularly DYT-
, treated with DBS are still scarce, DBS should be considered as an efficient treatment approach in children with pharmacoresistent dystonia, especially with generalized monogenic dystonia and to prevent severe and disabling symptoms that reduce the quality of life, including emotional and social aspects. Patients require an individual approach and parents should be properly informed about expectations and possible outcomes, including relapses and impairments, in addition to DBS responsiveness and related improvements. Furthermore, early genetic diagnosis and the provision of appropriate treatments, including DBS, are mandatory for preventing severe neurologic impairments.
Peri-lead edema (PLE) is a poorly understood complication of deep brain stimulation (DBS), which has been described in patients presenting occasionally with profound and often delayed symptoms with ...an incidence ranging from 0.4% up to even 100%. Therefore, our study aims to investigate the association of brain and brain compartment volumes on magnetic resonance imaging (MRI) with the occurrence of PLE in Parkinson's disease (PD) patients after DBS implantation in subthalamic nuclei (STN).
This retrospective study included 125 consecutive PD patients who underwent STN DBS at the Department of Neurosurgery, Dubrava University Hospital from 2010 to 2022. Qualitative analysis was done on postoperative MRI T2-weighted sequence by two independent observers, marking PLE on midbrain, thalamus, and subcortical levels as mild, moderate, or severe. Quantitative volumetric analysis of brain and brain compartment volumes was conducted using an automated CIVET processing pipeline on preoperative MRI T1 MPRAGE sequences. In addition, observed PLE on individual hemispheres was delineated manually and measured using Analyze 14.0 software.
In our cohort, PLE was observed in 32.17%, mostly bilaterally. Mild PLE was observed in the majority of patients, regardless of the level observed. Age, sex, diabetes, hypertension, vascular disease, and the use of anticoagulant/antiplatelet therapy showed no significant association with the occurrence of PLE. Total grey matter volume showed a significant association with the PLE occurrence (r = −0.22, p = 0.04), as well as cortex volume (r = −0.32, p = 0.0005). Cortical volumes of hemispheres, overall hemisphere volumes, as well as hemisphere/total intracranial volume ratio showed significant association with the PLE occurrence. Furthermore, the volume of the cortex and total grey volume represent moderate indicators, while hemisphere volumes, cortical volumes of hemispheres, and hemisphere/total intracranial volume ratio represent mild to moderate indicators of possible PLE occurrence.
The results of our study suggest that the morphometric MRI measurements, as a useful tool, can provide relevant information about the structural status of the brain in patients with PD and represent moderate indicators of possible PLE occurrence. Identifying patients with greater brain atrophy, especially regarding grey matter before DBS implantation, will allow us to estimate the possible postoperative symptoms and intervene in a timely manner. Further studies are needed to confirm our findings and to investigate other potential predictors and risk factors of PLE occurrence.
•The first study to investigate the association of brain atrophy with the occurrence of PLE in PD patients after STN DBS.•Total grey matter volume and cortex volume decrease showed a significant association with the PLE occurrence.•Cortical and overall hemisphere volumes, and hemisphere/total intracranial volume ratio showed association with the PLE.•Cortical and total grey volume overall and hemisphere volumes and volume ratio represent moderate indicators of PLE.•The morphometric MRI measurements can provide relevant information about the structural status of the brain in PD patients.
Microglia are resident brain macrophages with key roles in development and brain homeostasis. Cytomegalovirus (CMV) readily infects microglia cells, even as a possible primary target of infection in ...development. Effects of CMV infection on a cellular level in microglia are still unclear; therefore, the aim of this research was to assess the immunometabolic changes of BV-2 microglia cells following the murine cytomegalovirus (MCMV) infection. In light of that aim, we established an in vitro model of ramified BV-2 microglia (BV-2
∅FCS
, inducible nitric oxide synthase (iNOS
low
), arginase-1 (Arg-1
high
), mannose receptor CD206
high
, and hypoxia-inducible factor 1α (HIF-1α
low
)) to better replicate the in vivo
conditions
by removing FCS from the cultivation media, while the cells cultivated in 10% FCS DMEM displayed an ameboid morphology (BV-2
FCS high
, iNOS
high
, Arg-1
low
, CD206
low
, and HIF-1α
high
). Experiments were performed using both ramified and ameboid microglia, and both of them were permissive to productive viral infection. Our results indicate that MCMV significantly alters the immunometabolic phenotypic properties of BV-2 microglia cells through the manipulation of iNOS and Arg-1 expression patterns, along with an induction of a glycolytic shift in the infected cell cultures.
To assess the effect of social isolation due to the coronavirus disease 2019 (COVID-19) pandemic on physical and mental health of Parkinson's disease patients treated at the University Hospital ...Center Rijeka.
This cross-sectional telephone study involved Parkinson's disease patients who had at least one control examination at University Hospital Center Rijeka in 2020 and were Croatian citizens. A questionnaire was used to obtain data on the socio-demographic characteristics and the severity of motor, anxiety, depression, and non-motor symptoms.
The final sample included 87 patients. Most patients reported subjective worsening of motor symptoms. Patients who lived alone had worse motor scores than those not living alone. The majority of patients reported worsening of anxiety symptoms. Significant worsening of anxiety symptoms was found in patients who lived alone, had a longer disease duration, and had avoided check-ups. Fewer patients had depression symptoms than motor and anxiety symptoms. Significantly higher Hamilton Depression Rating Scale scores were observed in patients with a longer disease duration. Significant worsening of non-motor symptoms was identified in patients who lived alone, were less educated, had a longer disease duration, and had a higher Charlson comorbidity index.
Patients who live alone, have longer disease duration, are less educated, avoid check-ups, and have more comorbidities are more vulnerable to the negative effects of social isolation.
Background: Suitable biomarkers that have prognostic values are one of the key points of interest in ischaemic stroke. Increased sympathetic nervous system activity in ischaemic stroke causes ...multiple local and systemic effects that can be detrimental to the outcome. The mechanism of action is increased secretion and activity of catecholamines, whose end metabolic products are vanillylmandelic acid and homovanilic acid. Aim of our study was to determine whether these compounds can be used as potential prognostic biomarkers in ischaemic stroke, as a unique insight into the activity of the sympathetic nervous system.
Methods: Urine samples of 96 patients with ischaemic stroke and transitory ischaemic attacks were analysed. Values of vanillylmandelic and homovanillic acids in urine were tested using liquid chromatography on the first and third day post-stroke. Severity of stroke was determined using the NIHSS scale, while functional outcome was determined using the Modified Rankin Scale.
Results: Values of vanillylmandelic and homovanillic acids positively correlated with functional outcome of ischaemic stroke. Favorable outcomes correlated with decreased values, on contrary to increased values, which were associated with unfavourable outcomes.
Conclusion: Determining the values of these compounds in the urine is an easily available prognostic tool for the ischaemic stroke outcome, while also influencing potential therapeutic changes.
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