-
NPJ Parkinson's Disease Jun 2024Dopaminergic neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease (PD), while those in the dorsal tier...
Dopaminergic neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease (PD), while those in the dorsal tier and ventral tegmental area are relatively spared. The factors determining why these neurons are more vulnerable than others are still unrevealed. Neuroinflammation and immune cell infiltration have been demonstrated to be a key feature of neurodegeneration in PD. However, the link between selective dopaminergic neuron vulnerability, glial and immune cell response, and vascularization and their interactions has not been deciphered. We aimed to investigate the contribution of glial cell activation and immune cell infiltration in the selective vulnerability of ventral dopaminergic neurons within the midbrain in a non-human primate model of PD. Structural characteristics of the vasculature within specific regions of the midbrain were also evaluated. Parkinsonian monkeys exhibited significant microglial and astroglial activation in the whole midbrain, but no major sub-regional differences were observed. Remarkably, the ventral substantia nigra was found to be typically more vascularized compared to other regions. This feature might play some role in making this region more susceptible to immune cell infiltration under pathological conditions, as greater infiltration of both T- and B- lymphocytes was observed in parkinsonian monkeys. Higher vascular density within the ventral region of the SNc may be a relevant factor for differential vulnerability of dopaminergic neurons in the midbrain. The increased infiltration of T- and B- cells in this region, alongside other molecules or toxins, may also contribute to the susceptibility of dopaminergic neurons in PD.
PubMed: 38886348
DOI: 10.1038/s41531-024-00735-w -
IBRO Neuroscience Reports Dec 2024Parkinson's disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Death of... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Death of dopaminergic cells in the SNpc leads to manifestations of motor dysfunction and non-motor symptoms of PD. The progression of PD symptoms severely affects the quality of life of patients and poses socio-economic problems to families and society at large. The clinical and neuropathological characteristics of PD are triggered by multiple factors such as oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein aggregation. Notwithstanding the advancements in pharmacological therapy in PD management, there is burgeoning interest in alternative and complementary approaches, essentially nutrition and plant extracts strategies. This review gives widespread analysis of the role of nutrition and plant extracts in the management of PD. Studies that investigated the effects of various dietary compounds and plant extract on PD symptoms and progression were reviewed from existing literatures. Nutraceuticals, including vitamins and phytochemicals such as have shown potential neuroprotective functions in preclinical and clinical studies. Indeed, these strategies ameliorate mitochondrial dysfunction, oxidative stress, and neuroinflammation, all which are implicated in the pathogenesis of PD. The neuroprotective mechanisms of nutrition and plant extracts in PD, with emphasis on their capacity to target multiple pathways implicated in PD are discussed. Additionally, challenges and limitations related with translating preclinical findings into clinical practice including standardization of dosing regimens, bioavailability, and inter-individual variability are discussed. Largely, this review elucidates on the role of nutrition and plant extracts as adjunctive therapy in PD management.
PubMed: 38872839
DOI: 10.1016/j.ibneur.2024.05.011 -
Neuropharmacology Jun 2024The anteroventral bed nucleus of stria terminalis (avBNST) is a limbic forebrain region involved in the regulation of anxiety, and expresses GABA receptors, which are...
Blockade of pre- and post-synaptic GABA receptors in the anteroventral bed nucleus of stria terminalis produces anxiolytic-like and anxiety-like effects in parkinsonian rats respectively.
The anteroventral bed nucleus of stria terminalis (avBNST) is a limbic forebrain region involved in the regulation of anxiety, and expresses GABA receptors, which are located at both pre- and post-synaptic sites. However, it is unclear how blockade of these receptors affects anxiety-like behaviors, particularly in Parkinson's disease (PD)-related anxiety. In the present study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, and increased GABA release and decreased glutamate release in the avBNST, as well as decreased level of dopamine (DA) in the basolateral amygdala (BLA). Intra-avBNST injection of pre-synaptic GABA receptor antagonist CGP36216 produced anxiolytic-like effects, while the injection of post-synaptic GABA receptor antagonist CGP35348 induced anxiety-like responses in both sham and 6-OHDA rats. Intra-avBNST injection of CGP36216 inhibited the GABAergic neurons and increased GABA/glutamate ratio in the avBNST and increased levels of DA and serotonin (5-HT) in the BLA; conversely, CGP35348 produced opposite effects on the firing activity of avBNST GABAergic neurons and levels of the neurotransmitters in the avBNST and BLA. Moreover, the doses of the antagonists producing significant behavioral effects in 6-OHDA rats were lower than those in sham rats, and the duration of action of the antagonists on the firing rate of the neurons and release of the neurotransmitters was prolonged in 6-OHDA rats. Altogether, these findings suggest that pre- and post-synaptic GABA receptors in the avBNST are implicated in PD-related anxiety-like behaviors, and degeneration of the nigrostriatal pathway enhances functions and/or upregulates expression of these receptors.
PubMed: 38866066
DOI: 10.1016/j.neuropharm.2024.110033 -
Neuroscience Letters Jun 2024Parkinson's disease (PD) entails the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), leading to movement-related impairments....
Parkinson's disease (PD) entails the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), leading to movement-related impairments. Accurate assessment of DA neuron health is vital for research applications. Manual analysis, however, is laborious and subjective. To address this, we introduce TrueTH, a user-friendly and robust pipeline for unbiased quantification of DA neurons. Existing deep learning tools for tyrosine hydroxylase-positive (TH) neuron counting often lack accessibility or require advanced programming skills. TrueTH bridges this gap by offering an open-sourced and user-friendly solution for PD research. We demonstrate TrueTH's performance across various PD rodent models, showcasing its accuracy and ease of use. TrueTH exhibits remarkable resilience to staining variations and extreme conditions, accurately identifying TH neurons even in lightly stained images and distinguishing brain section fragments from neurons. Furthermore, the evaluation of our pipeline's performance in segmenting fluorescence images shows strong correlation with ground truth and outperforms existing models in accuracy. In summary, TrueTH offers a user-friendly interface and is pretrained with a diverse range of images, providing a practical solution for DA neuron quantification in Parkinson's disease research.
PubMed: 38857698
DOI: 10.1016/j.neulet.2024.137871 -
ELife Jun 2024Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). However, whether LRRK2 mutations cause PD and...
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). However, whether LRRK2 mutations cause PD and degeneration of dopaminergic (DA) neurons via a toxic gain-of-function or a loss-of-function mechanism is unresolved and has pivotal implications for LRRK2-based PD therapies. In this study, we investigate whether and its functional homolog play a cell-intrinsic role in DA neuron survival through the development of DA neuron-specific conditional double knockout (cDKO) mice. Unlike germline DKO mice, DA neuron-restricted cDKO mice exhibit normal mortality but develop age-dependent loss of DA neurons, as shown by the progressive reduction of DA neurons in the substantia nigra pars compacta (SNpc) at the ages of 20 and 24 months. Moreover, DA neurodegeneration is accompanied with increases in apoptosis and elevated microgliosis in the SNpc as well as decreases in DA terminals in the striatum, and is preceded by impaired motor coordination. Taken together, these findings provide the unequivocal evidence for the cell-intrinsic requirement of LRRK in DA neurons and raise the possibility that LRRK2 mutations may impair its protection of DA neurons, leading to DA neurodegeneration in PD.
Topics: Animals; Dopaminergic Neurons; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice, Knockout; Mice; Cell Survival; Protein Serine-Threonine Kinases; Parkinson Disease; Apoptosis
PubMed: 38856715
DOI: 10.7554/eLife.92673 -
Research Square May 2024Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia...
Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Pink1 and Parkin are proteins that function together in mitochondrial quality control, and when they carry loss-of-function mutations lead to familial forms of PD. While much research has focused on central nervous system alterations in PD, peripheral contributions to PD pathogenesis are increasingly appreciated. We report Pink1/Parkin regulate glycolytic and mitochondrial oxidative metabolism in peripheral blood mononuclear cells (PBMCs) from rats. Pink1/Parkin deficiency induces changes in the circulating lymphocyte populations, namely increased CD4 + T cells and decreased CD8 + T cells and B cells. Loss of Pink1/Parkin leads to elevated platelet counts in the blood and increased platelet-T cell aggregation. Platelet-lymphocyte aggregates are associated with increased thrombosis risk, and venous thrombosis is a cause of sudden death in PD, suggesting targeting the Pink1/Parkin pathway in the periphery has therapeutic potential.
PubMed: 38854001
DOI: 10.21203/rs.3.rs-4431604/v1 -
Neurobiology of Disease Aug 2024Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal...
Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
Topics: Animals; Dyskinesia, Drug-Induced; Levodopa; Oxidopamine; Mice; Male; Mice, Inbred C57BL; Serotonin 5-HT4 Receptor Agonists; Antiparkinson Agents; Corpus Striatum; Receptors, Serotonin, 5-HT4; Parkinsonian Disorders; Pyridines; Neurons; Piperidines; Pyrimidines
PubMed: 38852753
DOI: 10.1016/j.nbd.2024.106559 -
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