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Brain Communications 2024The role of brain asymmetries of dopaminergic neurons in motor symptoms of Parkinson's disease is still undefined. Local field recordings from the subthalamic nucleus...
The role of brain asymmetries of dopaminergic neurons in motor symptoms of Parkinson's disease is still undefined. Local field recordings from the subthalamic nucleus revealed some neurophysiological biomarkers of the disease: increased beta activity, increased low-frequency activity and high-frequency oscillations. Phase-amplitude coupling coordinates the timing of neuronal activity and allows determining the mechanism for communication within distinct regions of the brain. In this study, we discuss the use of phase-amplitude coupling to assess the differences between the two hemispheres in a cohort of 24 patients with Parkinson's disease before and after levodopa administration. Subthalamic low- (12-20 Hz) and high-beta (20-30 Hz) oscillations were compared with low- (30-45 Hz), medium- (70-100 Hz) and high-frequency (260-360 Hz) bands. We found a significant beta-phase-amplitude coupling asymmetry between left and right and an opposite-side-dependent effect of the pharmacological treatment, which is associated with the reduction of motor symptoms. In particular, high coupling between high frequencies and high-beta oscillations was found during the OFF condition ( < 0.01) and a low coupling during the ON state ( < 0.0001) when the right subthalamus was assessed; exactly the opposite happened when the left subthalamus was considered in the analysis, showing a lower coupling between high frequencies and high-beta oscillations during the OFF condition ( < 0.01), followed by a higher one during the ON state ( < 0.01). Interestingly, these asymmetries are independent of the motor onset side, either left or right. These findings have important implications for neural signals that may be used to trigger adaptive deep brain stimulation in Parkinson's and could provide more exhaustive insights into subthalamic dynamics.
PubMed: 38894949
DOI: 10.1093/braincomms/fcae201 -
International Journal of Molecular... May 2024This study presents the effects of treating polystyrene (PS) cell culture plastic with oxidoreductase enzyme laccase and the catechol substrates caffeic acid (CA),...
Laccase-Treated Polystyrene Surfaces with Caffeic Acid, Dopamine, and L-3,4-Dihydroxyphenylalanine Substrates Facilitate the Proliferation of Melanocytes and Embryonal Carcinoma Cells NTERA-2.
This study presents the effects of treating polystyrene (PS) cell culture plastic with oxidoreductase enzyme laccase and the catechol substrates caffeic acid (CA), L-DOPA, and dopamine on the culturing of normal human epidermal melanocytes (NHEMs) and human embryonal carcinoma cells (NTERA-2). The laccase-substrate treatment improved PS hydrophilicity and roughness, increasing NHEM and NTERA-2 adherence, proliferation, and NHEM melanogenesis to a level comparable with conventional plasma treatment. Cell adherence dynamics and proliferation were evaluated. The NHEM endpoint function was quantified by measuring melanin content. PS surfaces treated with laccase and its substrates demonstrated the forming of polymer-like structures. The surface texture roughness gradient and the peak curvature were higher on PS treated with a combination of laccase and substrates than laccase alone. The number of adherent NHEM and NTERA-2 was significantly higher than on the untreated surface. The proliferation of NHEM and NTERA-2 correspondingly increased on treated surfaces. NHEM melanin content was enhanced 6-10-fold on treated surfaces. In summary, laccase- and laccase-substrate-modified PS possess improved PS surface chemistry/hydrophilicity and altered roughness compared to untreated and plasma-treated surfaces, facilitating cellular adherence, subsequent proliferation, and exertion of the melanotic phenotype. The presented technology is easy to apply and creates a promising custom-made, substrate-based, cell-type-specific platform for both 2D and 3D cell culture.
Topics: Humans; Laccase; Melanocytes; Cell Proliferation; Polystyrenes; Caffeic Acids; Dopamine; Melanins; Cell Adhesion; Levodopa; Surface Properties; Cell Line, Tumor; Embryonal Carcinoma Stem Cells
PubMed: 38892114
DOI: 10.3390/ijms25115927 -
International Journal of Molecular... May 2024The loss of midbrain dopaminergic (DA) neurons is the fundamental pathological feature of Parkinson's disease (PD). PD causes chronic pain in two-thirds of patients....
The loss of midbrain dopaminergic (DA) neurons is the fundamental pathological feature of Parkinson's disease (PD). PD causes chronic pain in two-thirds of patients. Recent studies showed that the activation of the pedunculopontine tegmental nucleus (PPTg) can effectively relieve inflammatory pain and neuropathic pain. The PPTg is located in the pontomesencephalic tegmentum, a target of deep brain stimulation (DBS) treatment in PD, and is involved in motor control and sensory integration. To test whether the lesion of midbrain DA neurons induced pain hypersensitivity, and whether the chemogenetic activation of the PPTg could modulate the pain, the AAV-hM3Dq receptor was transfected and expressed into the PPTg neurons of 6-hydroxydopamine-lesioned mice. In this study, von Frey, open field, and adhesive tape removal tests were used to assess animals' pain sensitivity, locomotor activity, and sensorimotor function and somatosensory perception, respectively. Here, we found that the lesion of midbrain DA neurons induced a minor deficit in voluntary movement but did not affect sensorimotor function and somatosensory perception in the tape removal test. The results showed that lesion led to pain hypersensitivity, which could be alleviated both by levodopa and by the chemogenetic activation of the PPTg. Activating the PPTg may be a potential therapeutic strategy to relieve pain phenotypes in PD.
Topics: Animals; Pedunculopontine Tegmental Nucleus; Dopaminergic Neurons; Mice; Mesencephalon; Male; Parkinson Disease; Pain; Mice, Inbred C57BL; Deep Brain Stimulation; Disease Models, Animal; Levodopa; Oxidopamine
PubMed: 38891832
DOI: 10.3390/ijms25115636 -
BMC Medical Genomics Jun 2024Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to...
BACKGROUND
Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to produce/use adequate renal dopamine may contribute to the development of hypertension and renal dysfunction. The heterodimeric amino acid transporter LAT2/4F2hc (SLC7A8/SLC3A2 genes) promotes the uptake of L-DOPA, the natural precursor of dopamine. We examined the plausibility that SLC7A8/SLC3A2 gene polymorphisms may contribute to hypertensive CKD by affecting the L-DOPA uptake.
METHODS
421 subjects (203 men and 218 women, mean age of 78.9 ± 9.6 years) were recruited and divided in four groups according to presence/absence of CKD, defined as reduced estimated glomerular filtration rate (eGFR < 60 ml/min/m) calculated using the creatinine-based Berlin Initiative Study-1 (BIS1) equation, and to presence/absence of hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg). Subjects were analysed for selected SNPs spanning the SLC7A8 and SLC3A2 loci by Sequenom MassARRAY iPLEX platform.
RESULTS
The most significant SNP at the SLC3A2 (4F2hc) locus was rs2282477-T/C, with carriers of the C-allele having a lower chance to develop hypertension among CKD affected individuals [OR = 0.33 (CI 0.14-0.82); p = 0.016]. A similar association with hypertensive CKD was found for the SLC7A8 (LAT2) rs3783436-T/C, whose C-allele resulted associated with decreased risk of hypertension among subjects affected by CKD [OR = 0.56 (95% CI 0.35-0.90; p = 0.017]. The two variants were predicted to be potentially functional.
CONCLUSIONS
The association between SLC3A2 and SLC7A8 variants to hypertension development in patients with renal failure could be linked to changes in L-DOPA uptake and consequently dopamine synthesis. Although the associations do not survive correction for Bonferroni multiple testing, and additional research is needed, our study opens new avenues for future basic and translational research in the field of hypertensive CKD.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Fusion Regulatory Protein 1, Heavy Chain; Genetic Predisposition to Disease; Hypertension; Levodopa; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; Risk Factors; Adaptor Proteins, Signal Transducing
PubMed: 38890684
DOI: 10.1186/s12920-024-01935-2 -
Chirality Jun 2024Chirality plays a fundamental role in natural phenomena, yet its manifestation on solid surfaces remains relatively unexplored. In this study, we investigate the...
Chirality plays a fundamental role in natural phenomena, yet its manifestation on solid surfaces remains relatively unexplored. In this study, we investigate the formation of chiroptical melanin-based self-assembled films on quartz substrates, leveraging mussel-inspired surface chemistry. Water-soluble porphyrins serve as molecular synthons, facilitating the spontaneous formation of hetero-aggregates in phosphate-buffered saline containing L- or D-DOPA. Spectroscopic analysis reveals chiral transfer from DOPA enantiomers to porphyrin hetero-aggregates, followed by the disruption of these latter and subsequent generation of chiral melanin structures in solution. Quartz substrates inserted into these solutions spontaneously accumulate homogeneous melanin-like films over days, demonstrating the feasibility of self-assembly. The resulting films exhibit characteristic UV/Vis and CD spectra, with distinct signals indicating successful chiral induction. Interestingly, the AFM characterizations reveal a distinct surface morphology, and in addition, some thermal and mechanical properties have been taken into account. Overall, this study sheds light on the formation, stability, and chiroptical properties of melanin-based films, paving the way for their application in various fields.
PubMed: 38890151
DOI: 10.1002/chir.23695 -
Neuropharmacology Jun 2024Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that...
Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that sub-anesthetic ketamine produces acute anti-parkinsonian, and acute anti-dyskinetic effects in preclinical models of Parkinson's disease (PD). Ketamine is a multifunctional drug and exerts effects through blockade of N-methyl-d-aspartate receptors but also through interaction with the opioid system. In this report, we provide detailed pharmacokinetic rodent data on ketamine and its main metabolites following an intraperitoneal injection, and second, we explore the pharmacodynamic properties of ketamine in a rodent PD model with respect to the opioid system, using naloxone, a pan-opioid receptor antagonist, in unilateral 6-hydroxydopamine-lesioned male rats, treated with 6 mg/kg levodopa (l-DOPA) to establish a model of l-DOPA-induced dyskinesia (LID). As previously reported, we showed that ketamine (20 mg/kg) is highly efficacious in reducing LID and now report that the magnitude of this effect is resistant to naloxone (3 and 5 mg/kg). The higher naloxone dose of 5 mg/kg, however, led to an extension of the time-course of the LID, indicating that opioid receptor activation, while not a prerequisite for the anti-dyskinetic effects of ketamine, still exerts an acute modulatory effect. In contrast to the mild modulatory effect on LID, we found that naloxone added to the anti-parkinsonian activity of ketamine, further reducing the akinetic phenotype. In conclusion, our data show opioid receptor blockade differentially modulates the acute anti-parkinsonian and anti-dyskinetic actions of ketamine, providing novel mechanistic information to support repurposing ketamine for individuals with LID.
PubMed: 38889877
DOI: 10.1016/j.neuropharm.2024.110047 -
Chemical Communications (Cambridge,... Jul 2024An electrochemical sensor based on porous aromatic cages was reported, which can achieve chiral sensing of DOPA enantiomers. The prepared sensor can achieve a...
An electrochemical sensor based on porous aromatic cages was reported, which can achieve chiral sensing of DOPA enantiomers. The prepared sensor can achieve a recognition efficiency of up to 2.6 for DOPA enantiomers. The enhanced recognition efficiency could be attributed to the cooperation of intermolecular interactions, and the efficient charge transfer process.
PubMed: 38887804
DOI: 10.1039/d4cc02622e -
Microbiome Jun 2024Despite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. The development of novel therapeutic...
BACKGROUND
Despite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. The development of novel therapeutic and preventative approaches is highly desirable. Accumulating evidence in the past several years has established associations between the gut microbiome and microbial metabolites with drinking behavior, but druggable targets and their underlying mechanism of action are understudied.
RESULTS
Here, using a drink-in-the-dark mouse model, we identified a microbiome metabolite-based novel treatment (sodium valerate) that can reduce excessive alcohol drinking. Sodium valerate is a sodium salt of valeric acid short-chain fatty acid with a similar structure as γ-aminobutyric acid (GABA). Ten days of oral sodium valerate supplementation attenuates excessive alcohol drinking by 40%, reduces blood ethanol concentration by 53%, and improves anxiety-like or approach-avoidance behavior in male mice, without affecting overall food and water intake. Mechanistically, sodium valerate supplementation increases GABA levels across stool, blood, and amygdala. It also significantly increases H4 acetylation in the amygdala of mice. Transcriptomics analysis of the amygdala revealed that sodium valerate supplementation led to changes in gene expression associated with functional pathways including potassium voltage-gated channels, inflammation, glutamate degradation, L-DOPA degradation, and psychological behaviors. 16S microbiome profiling showed that sodium valerate supplementation shifts the gut microbiome composition and decreases microbiome-derived neuroactive compounds through GABA degradation in the gut microbiome.
CONCLUSION
Our findings suggest that sodium valerate holds promise as an innovative therapeutic avenue for the reduction of habitual binge drinking, potentially through multifaceted mechanisms. Video Abstract.
Topics: Animals; Male; Mice; Gastrointestinal Microbiome; gamma-Aminobutyric Acid; Fatty Acids, Volatile; Alcohol Drinking; Amygdala; Ethanol; Mice, Inbred C57BL; Disease Models, Animal; Binge Drinking; Pentanoic Acids
PubMed: 38886761
DOI: 10.1186/s40168-024-01829-6 -
Frontiers in Aging Neuroscience 2024This meta-analysis aims to assess the effectiveness and safety of robot-assisted deep brain stimulation (DBS) surgery for Parkinson's disease(PD).
OBJECTIVE
This meta-analysis aims to assess the effectiveness and safety of robot-assisted deep brain stimulation (DBS) surgery for Parkinson's disease(PD).
METHODS
Four databases (Medline, Embase, Web of Science and CENTRAL) were searched from establishment of database to 23 March 2024, for articles studying robot-assisted DBS in patients diagnosed with PD. Meta-analyses of vector error, complication rate, levodopa-equivalent daily dose (LEDD), Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS II, UPDRS III, and UPDRS IV were performed.
RESULTS
A total of 15 studies were included in this meta-analysis, comprising 732 patients with PD who received robot-assisted DBS. The pooled results revealed that the vector error was measured at 1.09 mm (95% CI: 0.87 to 1.30) in patients with Parkinson's disease who received robot-assisted DBS. The complication rate was 0.12 (95% CI, 0.03 to 0.24). The reduction in LEDD was 422.31 mg (95% CI: 68.69 to 775.94). The improvement in UPDRS, UPDRS III, and UPDRS IV was 27.36 (95% CI: 8.57 to 46.15), 14.09 (95% CI: 4.67 to 23.52), and 3.54 (95% CI: -2.35 to 9.43), respectively.
CONCLUSION
Robot-assisted DBS is a reliable and safe approach for treating PD. Robot-assisted DBS provides enhanced accuracy in contrast to conventional frame-based stereotactic techniques. Nevertheless, further investigation is necessary to validate the advantages of robot-assisted DBS in terms of enhancing motor function and decreasing the need for antiparkinsonian medications, in comparison to traditional frame-based stereotactic techniques.: PROSPERO(CRD42024529976).
PubMed: 38882524
DOI: 10.3389/fnagi.2024.1419152 -
Heliyon Jun 2024We developed novel and optimal Q10-NLC/SLN formulations as antioxidant and anti-tyrosinase agents. The formulations were analyzed for particle size, morphology,...
Preparation and characterization of novel nanostructured lipid carriers (NLC) and solid lipid nanoparticles (SLN) containing coenzyme Q10 as potent antioxidants and antityrosinase agents.
We developed novel and optimal Q10-NLC/SLN formulations as antioxidant and anti-tyrosinase agents. The formulations were analyzed for particle size, morphology, entrapment efficiency (EE %), and long-term stability. The drug release and skin penetration were evaluated using dialysis bag diffusion and Sprague Dawley (SD) rats, respectively. Cytotoxicity and protecting effects were assessed by AlamarBlue® assay, ROS level by DCFH-DA, and tyrosinase activity by l-DOPA assay, measuring the absorbance at 470 nm. The selected formulations had optimal surface characterizations, including Z-average size, PDI, and Zeta potential ranging from 125 to 207 nm, 0.09-0.22, and -7 to -24, respectively. They also exhibited physiochemical stability for up to 6 months and EE% above 80 %. The lipids ratio and co-Q10 amount as variable factors significantly affected particle size and zeta potential but were insignificant on PDI. The release diagram showed that Q10-NLC/SLN revealed a fast release during the first 8 h and prolonged release afterward. The skin permeation revealed a higher accumulative uptake of co-Q10 in the skin for Q10-NLC/SLN compared to Q10 emulsions. Both selected Q10-NLC and Q10-SLN could reduce intracellular ROS after exposure to HO. The Q10-NLC was found to be more potent for inhibiting the tyrosinase activity compared to O10-SLN. The results suggest that the new formulations are promising carriers for topical delivery of co-Q10 as an anti-aging and skin-whitening agent.
PubMed: 38882272
DOI: 10.1016/j.heliyon.2024.e31429