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Neurochemical Research Jun 2024Parkinson's disease (PD) is a complex multifactorial progressive neurodegenerative disease characterized by locomotor alteration due to the specific deterioration of...
Parkinson's disease (PD) is a complex multifactorial progressive neurodegenerative disease characterized by locomotor alteration due to the specific deterioration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). Mounting evidence shows that human LRRK2 (hLRRK2) kinase activity is involved in oxidative stress (OS)-induced neurodegeneration, suggesting LRRK2 inhibition as a potential therapeutic target. We report that the hLRRK2 inhibitor PF-06447475 (PF-475) prolonged lifespan, increased locomotor activity, maintained DAergic neuronal integrity, and reduced lipid peroxidation (LPO) in female Drosophila melanogaster flies chronically exposed to paraquat (PQ), a redox cycling compound, compared to flies treated with vehicle only. Since LRRK2 is an evolutionary conserved kinase, the present findings reinforce the idea that either reduction or inhibition of the LRRK2 kinase might decrease OS and locomotor alterations associated with PD. Our observations highlight the importance of uncovering the function of the hLRRK2 orthologue dLrrk2 in D. melanogaster as an excellent model for pharmacological screenings.
PubMed: 38847910
DOI: 10.1007/s11064-024-04141-9 -
Behavioural Brain Research Jun 2024Parkinson's is the most common neurodegenerative disease after Alzheimer's. Motor findings in Parkinson's occur as a result of the degeneration of dopaminergic neurons... (Review)
Review
Parkinson's is the most common neurodegenerative disease after Alzheimer's. Motor findings in Parkinson's occur as a result of the degeneration of dopaminergic neurons starting in the substantia nigra pars compacta and ending in the putamen and caudate nucleus. Loss of neurons and the formation of inclusions called Lewy bodies in existing neurons are characteristic histopathological findings of Parkinson's. The disease primarily impairs the functional capacity of the person with cardinal findings such as tremor, bradykinesia, etc., as a result of the loss of dopaminergic neurons in the substantia nigra. Experimental animal models of Parkinson's have been used extensively in recent years to investigate the pathology of this disease. These models are generally based on systemic or local(intracerebral) administration of neurotoxins, which can replicate many features of Parkinson's mammals. The development of transgenic models in recent years has allowed us to learn more about the modeling of Parkinson's. Applying animal modeling, which shows the most human-like effects in studies, is extremely important. It has been demonstrated that oxidative stress increases in many neurodegenerative diseases such as Parkinson's and various age-related degenerative diseases in humans and that neurons are sensitive to it. In cases where oxidative stress increases and antioxidant systems are inadequate, natural molecules such as flavonoids and polyphenols can be used as a new antioxidant treatment to reduce neuronal reactive oxygen species and improve the neurodegenerative process. Therefore, in this article, we examined experimental animal modeling in Parkinson's disease and the effect of green chemistry approaches on Parkinson's disease.
PubMed: 38844056
DOI: 10.1016/j.bbr.2024.115092 -
Neuroscience Jun 2024Transient nigrostriatal dopaminergic signalling is well known for its role in reinforcement learning and increasingly so for its role in the initiation of voluntary...
Transient nigrostriatal dopaminergic signalling is well known for its role in reinforcement learning and increasingly so for its role in the initiation of voluntary movement. However, how transient bursts of dopamine modulate voluntary movement remains unclear, likely due to the heterogeneity of the nigrostriatal system, the focus of optogenetic studies on locomotion at sub-sec time intervals, and the overlapping roles of phasic dopamine in behaviour and novelty signalling. In this study we investigated how phasic activity in the lateral substantia nigra pars compacta (lateral SNc) over time affects voluntary behaviours during exploration. Using a transgenic mouse model of both sexes expressing channelrhodopsin (ChR2) in dopamine transporter-expressing cells, we stimulated the lateral SNc while mice explored an open field over two consecutive days. We found that phasic activation of the lateral SNc induced an increase in exploratory behaviours including horizontal movement activity, locomotion initiation, and rearing specifically on the first open field exposure, but not on the second day. In addition, stimulated animals did not habituate to the same extent as their ChR2-negative counterparts, as indicated by a lack of decrease in baseline activity. These findings suggest that rather than prompting voluntary movement in general, phasic nigrostriatal dopamine prompts context-appropriate behaviours. In addition, dopamine signalling that modulates movement acts over longer timescales than the transient signal, affecting behaviour even after the signal has ended.
PubMed: 38838978
DOI: 10.1016/j.neuroscience.2024.05.025 -
European Journal of Medicinal Chemistry Aug 2024Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development...
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development of novel scaffolds for human monoamine oxidase B (hMAO-B) inhibitors with reversible properties represents an important strategy to improve the efficacy and safety for PD treatment. In the current work, we have devised and assessed two innovative derivative series serving as hMAO-B inhibitors. These series have utilized benzimidazole as a scaffold and strategically incorporated a primary amide group, which is recognized as a pivotal pharmacophore in subsequent activity screening and reversible mode of action. Among these compounds, 16d has emerged as the most potent hMAO-B inhibitor with an IC value of 67.3 nM, comparable to safinamide (IC = 42.6 nM) in vitro. Besides, 16d demonstrated good selectivity towards hMAO-B isoenzyme with a selectivity index over 387. Importantly, in line with the design purpose, 16d inhibited hMAO-B in a competitive and reversible manner (K = 82.50 nM). Moreover, 16d exhibited a good safety profile in both cellular and acute toxicity assays in mice. It also displayed ideal pharmacokinetic properties and blood-brain barrier permeability in vivo, essential prerequisites for central nervous system medicines. In the MPTP-induced PD mouse model, 16d significantly alleviated the motor impairment, especially muscle relaxation and motor coordination. Therefore, 16d, serving as a lead compound, holds instructive significance for subsequent investigations regarding its application in the treatment of PD.
Topics: Monoamine Oxidase Inhibitors; Monoamine Oxidase; Humans; Animals; Structure-Activity Relationship; Mice; Benzimidazoles; Parkinson Disease; Molecular Structure; Drug Discovery; Dose-Response Relationship, Drug; Male; Mice, Inbred C57BL; Antiparkinson Agents
PubMed: 38838545
DOI: 10.1016/j.ejmech.2024.116566 -
Nature Communications Jun 2024Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent...
Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.
Topics: Animals; Deep Brain Stimulation; Mice; Hippocampus; Ultrasonic Waves; Mice, Inbred C57BL; Dopaminergic Neurons; Male; Dopamine; Proto-Oncogene Proteins c-fos; Substantia Nigra; Neurons; Transducers
PubMed: 38834558
DOI: 10.1038/s41467-024-48748-6 -
Frontiers in Aging Neuroscience 2024The altered neuromelanin in substantia nigra pars compacta (SNpc) is a valuable biomarker in the detection of early-stage Parkinson's disease (EPD). Diagnosis via visual...
OBJECTIVES
The altered neuromelanin in substantia nigra pars compacta (SNpc) is a valuable biomarker in the detection of early-stage Parkinson's disease (EPD). Diagnosis via visual inspection or single radiomics based method is challenging. Thus, we proposed a novel hybrid model that integrates radiomics and deep learning methodologies to automatically detect EPD based on neuromelanin-sensitive MRI, namely short-echo-time Magnitude (setMag) reconstructed from quantitative susceptibility mapping (QSM).
METHODS
In our study, we collected QSM images including 73 EPD patients and 65 healthy controls, which were stratified into training-validation and independent test sets with an 8:2 ratio. Twenty-four participants from another center were included as the external validation set. Our framework began with the detection of the brainstem utilizing YOLO-v5. Subsequently, a modified LeNet was applied to obtain deep learning features. Meanwhile, 1781 radiomics features were extracted, and 10 features were retained after filtering. Finally, the classified models based on radiomics features, deep learning features, and the hybrid of both were established through machine learning algorithms, respectively. The performance was mainly evaluated using accuracy, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). The saliency map was used to visualize the model.
RESULTS
The hybrid feature-based support vector machine (SVM) model showed the best performance, achieving ACC of 96.3 and 95.8% in the independent test set and external validation set, respectively. The model established by hybrid features outperformed the one radiomics feature-based (NRI: 0.245, IDI: 0.112). Furthermore, the saliency map showed that the bilateral "swallow tail" sign region was significant for classification.
CONCLUSION
The integration of deep learning and radiomic features presents a potent strategy for the computer-aided diagnosis of EPD. This study not only validates the accuracy of our proposed model but also underscores its interpretability, evidenced by differential significance across various anatomical sites.
PubMed: 38832074
DOI: 10.3389/fnagi.2024.1397896 -
BioRxiv : the Preprint Server For... May 2024Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males....
BACKGROUND
Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males. Dopamine modulation of the basal ganglia is implicated in numerous neuropsychiatric conditions, including TS. Motivated by an unexpected genetic finding in a family with TS, we previously characterized the modulation of striatal dopamine by histamine.
METHODS
We used microdialysis to analyze striatal dopamine response to the targeted infusion of histamine and histamine agonists. siRNA knockdown of histamine receptors was used to identify the cellular mediators of observed effects.
RESULTS
Intracerebroventricular histamine reduced striatal dopamine in male mice, replicating previous work. Unexpectedly, histamine increased striatal dopamine in females. Targeted infusion of selected agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, in contrast, H2R had no role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing in estrus/proestrus but not in metestrus/diestrus.
CONCLUSIONS
These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of other sex differences in the striatal circuitry, perhaps including the marked sex differences seen in TS and related neuropsychiatric conditions.
PubMed: 38826392
DOI: 10.1101/2024.05.20.595049 -
Molecular Neurobiology Jun 2024MicroRNA (miRNA) are usually 18-25 nucleotides long non-coding RNA targeting post-transcriptional regulation of genes involved in various biological processes. The... (Review)
Review
MicroRNA (miRNA) are usually 18-25 nucleotides long non-coding RNA targeting post-transcriptional regulation of genes involved in various biological processes. The function of miRNA is essential for maintaining a homeostatic cellular condition, regulating autophagy, cellular motility, and inflammation. Dysregulation of miRNA is responsible for multiple disorders, including neurodegeneration, which has emerged as a severe problem in recent times and has verified itself as a life-threatening condition that can be understood by the continuous destruction of neurons affecting various cognitive and motor functions. Parkinson's disease (PD) is the second most common, permanently debilitating neurodegenerative disorder after Alzheimer's, mainly characterized by uncontrolled tremor, stiffness, bradykinesia or akinesia (slowness in movement), and post-traumatic stress disorder. PD is mainly caused by the demolition of the primary dopamine neurotransmitter secretory cells and dopaminergic or dopamine secretory neurons in the substantia nigra pars compacta of the midbrain, which are majorly responsible for motor functions. In this study, a systematic evaluation of research articles from year 2017 to 2022 was performed on multiple search engines, and lists of miRNA being dysregulated in PD in different body components were generated. This study highlighted miR-7, miR-124, miR-29 family, and miR-425, showing altered expression levels during PD's progression, further regulating the expression of multiple genes responsible for PD.
PubMed: 38823001
DOI: 10.1007/s12035-024-04261-x -
Neuroscience Bulletin May 2024Knowledge about the neuronal dynamics and the projectome are both essential for understanding how the neuronal network functions in concert. However, it remains...
Knowledge about the neuronal dynamics and the projectome are both essential for understanding how the neuronal network functions in concert. However, it remains challenging to obtain the neural activity and the brain-wide projectome for the same neurons, especially for neurons in subcortical brain regions. Here, by combining in vivo microscopy and high-definition fluorescence micro-optical sectioning tomography, we have developed strategies for mapping the brain-wide projectome of functionally relevant neurons in the somatosensory cortex, the dorsal hippocampus, and the substantia nigra pars compacta. More importantly, we also developed a strategy to achieve acquiring the neural dynamic and brain-wide projectome of the molecularly defined neuronal subtype. The strategies developed in this study solved the essential problem of linking brain-wide projectome to neuronal dynamics for neurons in subcortical structures and provided valuable approaches for understanding how the brain is functionally organized via intricate connectivity patterns.
PubMed: 38819707
DOI: 10.1007/s12264-024-01232-z -
Neural Regeneration Research Feb 2025JOURNAL/nrgr/04.03/01300535-202502000-00033/figure1/v/2024-05-28T214302Z/r/image-tiff There is a need to develop interventions to slow or reverse the degeneration of...
JOURNAL/nrgr/04.03/01300535-202502000-00033/figure1/v/2024-05-28T214302Z/r/image-tiff There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson's disease after diagnosis. Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids, such as docosahexaenoic acid, and exercise in Parkinson's disease, we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway. First, mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation. Four weeks after lesion, animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks. During this period, the animals had access to a running wheel, which they could use or not. Docosahexaenoic acid treatment, voluntary exercise, or the combination of both had no effect on (i) distance traveled in the open field test, (ii) the percentage of contraversive rotations in the apomorphine-induction test or (iii) the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta. However, the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum. Compared to docosahexaenoic acid treatment or exercise alone, the combination of docosahexaenoic acid and exercise (i) improved forelimb balance in the stepping test, (ii) decreased the striatal DOPAC/dopamine ratio and (iii) led to increased dopamine transporter levels in the lesioned striatum. The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson's disease.
PubMed: 38819068
DOI: 10.4103/NRR.NRR-D-23-00595