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Open Medicine (Warsaw, Poland) 2024Parkinson's disease (PD), characterized by tremor, slowness of movement, stiffness, and poor balance, is due to a significant loss of dopaminergic neurons in the... (Review)
Review
Parkinson's disease (PD), characterized by tremor, slowness of movement, stiffness, and poor balance, is due to a significant loss of dopaminergic neurons in the substantia nigra pars compacta and dopaminergic nerve terminals in the striatum with deficit of dopamine. To date the mechanisms sustaining PD pathogenesis are under investigation; however, a solid body of experimental evidence involves neuroinflammation, mitochondrial dysfunction, oxidative stress, and apoptotic cell death as the crucial factors operating in the pathogenesis of PD. Nutrition is known to modulate neuroinflammatory processes implicated in the pathogenesis and progression of this neurodegenerative disorder. Consistent with this notion, the Burseraceae family, which includes the genera and , are attracting emerging interest in the treatment of a wide range of pathological conditions, including neuroinflammation and cognitive decline. Bioactive components present in these species have been shown to improve cognitive function and to protect neurons from degeneration in , animal, as well as clinical research. These effects are mediated through the anti-inflammatory, antiamyloidogenic, anti-apoptotic, and antioxidative properties of bioactive components. Although many studies have exploited possible therapeutic approaches, data from human studies are lacking and their neuroprotective potential makes them a promising option for preventing and treating major neurodegenerative disorders.
PubMed: 38911256
DOI: 10.1515/med-2024-0988 -
Tissue & Cell Jun 2024Paraquat (PQ), is an extensively used herbicide and is a well-established powerful neurotoxin. However, the mechanism underlying its neurotoxicity still needs further...
Effect of Selenium nanoparticles on Paraquat-induced-neuroinflammation and oligodendocyte modulation: Implication of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway.
BACKGROUND
Paraquat (PQ), is an extensively used herbicide and is a well-established powerful neurotoxin. However, the mechanism underlying its neurotoxicity still needs further investigation.
AIM OF WORK
The study investigated the pathogenesis of PQ-induced neuroinflammation of the substantia nigra pars compacta (SNPC) and cerebellum and evaluated the potential effect of selenium nanoparticles (SeN) against such neurotoxicity.
METHODS
Thirty-six mice were randomly divided into three groups; Control group, PQ group: mice received PQ 10 mg/kg (i.p), and PQ + SeN group; mice received PQ in addition to oral SeN 0.1 mg/kg. All regimens were administered for 14 days. The mice's brains were processed for biochemical, molecular, histological, and immune-histochemical assessment.
RESULTS
SeN increased the SNPC and cerebellum antioxidants (reduced glutathione, glutathione peroxidase, and superoxide dismutase 1) while decreasing malondialdehyde concentration. Also, SeN increased the anti-inflammatory interleukin (IL)-10 and decreased the pro-inflammatory IL-1β and -6 along with improving the angiogenic nitric oxide and reducing caspase-1. Further, western blots of phosphorylated Janus kinase (JAK2)/signal transducer and activator of transcription3 (STAT3) proteins showed a significant decline. Those improving effects of SeN on SNPC, and cerebellum were supported by the significantly preserved dopaminergic and Purkinje neurons, the enhanced myelin fibers on Luxol fast blue staining, and the marked increase in Olig-2, Platelet-derived growth factor-alpha, and tyrosine hydroxylase immunoreactivity.
CONCLUSION
SeN could mitigate PQ-induced neurotoxicity via its antioxidant, anti-inflammatory, and antiapoptotic properties.
PubMed: 38905876
DOI: 10.1016/j.tice.2024.102454 -
Parkinsonism & Related Disorders Jun 2024The substantia nigra pars compacta (SNc) is the key pathologic locus in neurodegenerative parkinsonian disorders. Recently, in vivo susceptibility MRI metrics were...
INTRODUCTION
The substantia nigra pars compacta (SNc) is the key pathologic locus in neurodegenerative parkinsonian disorders. Recently, in vivo susceptibility MRI metrics were associated with postmortem glial cell density and tau burden in the SNc of parkinsonism subjects. This study investigated the red nucleus (RN), another iron-rich region adjacent to the SNc and a potential site of higher functionality in parkinsonisms.
METHODS
In vivo MRI and postmortem data were obtained from 34 parkinsonism subjects and 3 controls. Neuron density, glial cell density, and percentages of area occupied by α-synuclein and tau were quantified using digitized midbrain slides. R2* and quantitative susceptibility mapping (QSM) metrics in the RN and SNc were derived from multi-gradient echo images. Histopathology data were compared between the RN and SNc using paired t-tests. MRI-histology associations were analyzed using partial Pearson correlations.
RESULTS
The RN had greater neuron (t = 3.169, P = 0.004) and glial cell densities (t = 2.407, P = 0.025) than the SNc, whereas the SNc had greater α-synuclein (t = 4.614, P < 0.0001) and tau burden (t = 4.513, P = 0.0001). In both the RN (R2*: r = 0.47, P = 0.043; QSM: r = 0.52, P = 0.024) and SNc (R2*: r = 0.57, P = 0.01; QSM: r = 0.58, P = 0.009), MRI values were associated with glial cell density but not neuron density or α-synuclein (Ps > 0.092). QSM associated with tau burden (r = 0.49, P = 0.038) in the SNc, but not the RN.
CONCLUSIONS
The RN is resilient to parkinsonian-related pathological processes compared to the SNc, and susceptibility MRI captured glial cell density in both regions. These findings help to further our understanding of the underlying pathophysiological processes in parkinsonisms.
PubMed: 38896976
DOI: 10.1016/j.parkreldis.2024.107043 -
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