-
Journal of Neuroinflammation Apr 2024Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating...
BACKGROUND
Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.
METHODS
Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD.
RESULTS
We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration.
CONCLUSIONS
This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.
Topics: Mice; Animals; Parkinson Disease; Metformin; Astrocytes; Dopaminergic Neurons; Nucleotidyltransferases; Mitochondria; GTP Phosphohydrolases
PubMed: 38566081
DOI: 10.1186/s12974-024-03072-0 -
BioRxiv : the Preprint Server For... Mar 2024The substantia nigra pars reticulata (SNr), a crucial basal ganglia output nucleus, contains a dense expression of dopamine D1 receptors (D1Rs), along with dendrites...
The substantia nigra pars reticulata (SNr), a crucial basal ganglia output nucleus, contains a dense expression of dopamine D1 receptors (D1Rs), along with dendrites belonging to dopaminergic neurons of substantia nigra pars compacta. These D1Rs are primarily located on the terminals of striatonigral medium spiny neurons, suggesting their involvement in the regulation of neurotransmitter release from the direct pathway in response to somatodendritic dopamine release. To explore the hypothesis that D1Rs modulate GABA release from striatonigral synapses, we conducted optical recordings of striatonigral activity and postsynaptic patch-clamp recordings from SNr neurons in the presence of dopamine and D1R agonists. We found that dopamine inhibits optogenetically triggered striatonigral GABA release by modulating vesicle fusion and Ca influx in striatonigral boutons. Notably, the effect of DA was independent of D1R activity but required activation of 5-HT1B receptors. Our results suggest a serotonergic mechanism involved in the therapeutic actions of dopaminergic medications for Parkinson's disease and psychostimulant-related disorders.
PubMed: 38559006
DOI: 10.1101/2024.03.14.584991 -
Neurochemical Research Jul 2024Currently, there are no effective therapies to cure Parkinson's disease (PD), which is the second most common neurodegenerative disease primarily characterized by motor...
Currently, there are no effective therapies to cure Parkinson's disease (PD), which is the second most common neurodegenerative disease primarily characterized by motor dysfunction and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Protopanaxadiols (PPDs), including 20 (R)- protopanaxadiol (R-PPD) and 20 (S)- protopanaxadiol (S-PPD), are main metabolites of ginsenosides. The role of ginsenosides in neurodegenerative diseases has been thoroughly studied, however, it is unknown whether PPDs can attenuate behavioral deficits and dopaminergic neuron injury in PD model mice to date. Here, we administered PPDs to MPTP-induced PD model mice and monitored the effects on behavior and dopaminergic neurons to investigate the effects of R-PPD and S-PPD against PD. Our results showed that R-PPD and S-PPD (at a dose of 20 mg/kg, i.g.) treatment alleviated MPTP (30 mg/kg, i.p.) induced behavioral deficits. Besides, R-PPD and S-PPD protected MPP-induced neuron injury and mitochondrial dysfunction, and reduced the abnormal expression of Cyt C, Bax, caspase-3 and Bcl-2. These findings demonstrate that R-PPD and S-PPD were potentially useful to ameliorate PD.
Topics: Animals; Male; Mitochondria; Mice, Inbred C57BL; Sapogenins; Mice; Neuroprotective Agents; Behavior, Animal; Dopaminergic Neurons; Disease Models, Animal; Parkinson Disease
PubMed: 38551796
DOI: 10.1007/s11064-024-04132-w -
Brain Sciences Feb 2024Increasing evidence suggests that the gut microbiota may represent potential strategies for Parkinson's disease (PD) treatment. Our previous research revealed a...
Increasing evidence suggests that the gut microbiota may represent potential strategies for Parkinson's disease (PD) treatment. Our previous research revealed a decreased abundance of (Akk) in PD mice; however, whether Akk is beneficial to PD is unknown. To answer this question, the mice received MPTP intraperitoneally to construct a subacute model of PD and were then supplemented with Akk orally for 21 consecutive days. Motor function, dopaminergic neurons, neuroinflammation, and neurogenesis were examined. In addition, intestinal inflammation, and serum and fecal short-chain fatty acids (SCFAs) analyses, were assessed. We found that Akk treatment effectively inhibited the reduction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and partially improved the motor function in PD mice. Additionally, Akk markedly alleviated neuroinflammation in the striatum and hippocampus and promoted hippocampal neurogenesis. It also decreased the level of colon inflammation. Furthermore, these aforementioned changes are mainly accompanied by alterations in serum and fecal isovaleric acid levels, and lower intestinal permeability. Our research strongly suggests that Akk is a potential neuroprotective agent for PD therapy.
PubMed: 38539626
DOI: 10.3390/brainsci14030238 -
European Journal of Medical Research Mar 2024Parkinson's disease (PD) is a progressive neurodegenerative disease as a result of the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc).... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative disease as a result of the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The fundamental features of PD are motor and non-motor symptoms. PD symptoms develop due to the disruption of dopaminergic neurotransmitters and other neurotransmitters such as γ-aminobutyric acid (GABA). The potential role of GABA in PD neuropathology concerning the motor and non-motor symptoms of PD was not precisely discussed. Therefore, this review intended to illustrate the possible role of GABA in PD neuropathology regarding motor and non-motor symptoms. The GABA pathway is essential in regulating the inhibitory tone to prevent excessive stimulation of the cerebral cortex. Degeneration of dopaminergic neurons in PD is linked with reducing GABAergic neurotransmission. Decreasing GABA activity promotes mitochondrial dysfunction and oxidative stress, which are highly related to PD neuropathology. Hence, restoring GABA activity by GABA agonists may attenuate the progression of PD motor symptoms. Therefore, dysregulation of GABAergic neurons in the SNpc contributes to developing PD motor symptoms. Besides, PD non-motor symptoms are also related to the dysfunction of the GABAergic pathway, and amelioration of this pathway may reduce PD non-motor symptoms. In conclusion, the deregulation of the GABAergic pathway in PD might be intricate in developing motor and non-motor symptoms. Improving this pathway might be a novel, beneficial approach to control PD symptoms.
Topics: Humans; Parkinson Disease; Neurodegenerative Diseases; gamma-Aminobutyric Acid; Neurotransmitter Agents
PubMed: 38539252
DOI: 10.1186/s40001-024-01779-7 -
NeuroImage May 2024Parkinson's disease (PD) is associated with the loss of neuromelanin (NM) and increased iron in the substantia nigra (SN). Magnetization transfer contrast (MTC) is...
BACKGROUND
Parkinson's disease (PD) is associated with the loss of neuromelanin (NM) and increased iron in the substantia nigra (SN). Magnetization transfer contrast (MTC) is widely used for NM visualization but has limitations in brain coverage and scan time. This study aimed to develop a new approach called Proton-density Enhanced Neuromelanin Contrast in Low flip angle gradient echo (PENCIL) imaging to visualize NM in the SN.
METHODS
This study included 30 PD subjects and 50 healthy controls (HCs) scanned at 3T. PENCIL and MTC images were acquired. NM volume in the SN pars compacta (SNpc), normalized image contrast (Cnorm), and contrast-to-noise ratio (CNR) were calculated. The change of NM volume in the SNpc with age was analyzed using the HC data. A group analysis compared differences between PD subjects and HCs. Receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculations were used to evaluate the diagnostic performance of NM volume and CNR in the SNpc.
RESULTS
PENCIL provided similar visualization and structural information of NM compared to MTC. In HCs, PENCIL showed higher NM volume in the SNpc than MTC, but this difference was not observed in PD subjects. PENCIL had higher CNR, while MTC had higher Cnorm. Both methods revealed a similar pattern of NM volume in SNpc changes with age. There were no significant differences in AUCs between NM volume in SNpc measured by PENCIL and MTC. Both methods exhibited comparable diagnostic performance in this regard.
CONCLUSIONS
PENCIL imaging provided improved CNR compared to MTC and showed similar diagnostic performance for differentiating PD subjects from HCs. The major advantage is PENCIL has rapid whole-brain coverage and, when using STAGE imaging, offers a one-stop quantitative assessment of tissue properties.
Topics: Humans; Parkinson Disease; Substantia Nigra; Pars Compacta; Magnetic Resonance Imaging; Melanins
PubMed: 38537765
DOI: 10.1016/j.neuroimage.2024.120588 -
Neural Regeneration Research Nov 2024Parkinson's disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Many studies have been performed...
Parkinson's disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson's disease. The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson's disease, which could substantially alleviate the symptoms of Parkinson's disease in clinical practice. However, ethical issues and tumor formation were limitations of its clinical application. Induced pluripotent stem cells can be acquired without sacrificing human embryos, which eliminates the huge ethical barriers of human stem cell therapy. Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons, without the need for intermediate proliferation states, thus avoiding issues of immune rejection and tumor formation. Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson's disease. However, there are also ethical concerns and the risk of tumor formation that need to be addressed. This review highlights the current application status of cell reprogramming in the treatment of Parkinson's disease, focusing on the use of induced pluripotent stem cells in cell replacement therapy, including preclinical animal models and progress in clinical research. The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson's disease, as well as the controversy surrounding in vivo reprogramming. These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson's disease.
PubMed: 38526281
DOI: 10.4103/1673-5374.390965 -
Heliyon Mar 2024Nanostructured materials with controllable properties have been used to cage and release various types of compounds. In the present study, iron-loaded nanostructured...
Nanostructured materials with controllable properties have been used to cage and release various types of compounds. In the present study, iron-loaded nanostructured sol-gel SiO-Fe materials were prepared and injected into the rat brain to develop a method for gradual iron delivery into the neurons with the aims to avoid acute iron toxicity and develop an animal model of gradual, metal-induced neurodegeneration. Nanoparticles were prepared by the traditional method of hydrolysis and condensation reactions of tetraethyl orthosilicate at room temperature and subsequent heat treatment at 200 °C. FeSO was added during the silica preparation. The resulting materials were characterized by UV-VIS and infrared spectroscopies, X-ray diffraction, and N adsorption-desorption. An ferrous sulfate release test was carried out in artificial cerebrospinal fluid as the release medium showing successful ferrous sulfate loading on nanostructured silica and sustained iron release during the test time of 10 h. Male Wistar rats administered with SiO-Fe nanoparticles in the () showed significant intraneuronal increase of iron, in contrast to the animals administered with FeSO that showed severe neuronal loss, 72 h post-treatment. Both treatments induced lipid fluorescent product formation in the ventral midbrain, in contrast to iron-free SiO and PBS-only injection controls. Circling behavior was evaluated six days after the intranigral microinjection, considered as a behavioral end-point of brain damage. The apomorphine-induced ipsilateral turns in the treated animals presented significant differences in relation to the control groups, with FeSO administration leading to a dramatic phenotype, compared to a milder impact in SiO-Fe administrated animals. Thus, the use of SiO-Fe nanoparticles represents a slow iron release system useful to model the gradual iron-accumulation process observed in the of patients with idiopathic Parkinson's disease.
PubMed: 38524581
DOI: 10.1016/j.heliyon.2024.e27786 -
Neurobiology of Disease May 2024A key pathological feature of Parkinson's Disease (PD) is the progressive degeneration of dopaminergic neurons (DAns) in the substantia nigra pars compacta. Considering...
A key pathological feature of Parkinson's Disease (PD) is the progressive degeneration of dopaminergic neurons (DAns) in the substantia nigra pars compacta. Considering the major role of EN1 in the development and maintenance of these DAns and the implications from En1 mouse models, it is highly interesting to study the molecular and protective effect of EN1 also in a human cellular model. Therefore, we generated EN1 knock-out (ko) human induced pluripotent stem cell (hiPSCs) lines and analyzed these during neuronal differentiation. Although the EN1 ko didn't interfere with neuronal differentiation and generation of tyrosine hydroxylase positive (TH+) neurons per se, the neurons exhibited shorter neurites. Furthermore, mitochondrial respiration, as well as mitochondrial complex I abundance was significantly reduced in fully differentiated neurons. To understand the implications of an EN1 ko during differentiation, we performed a transcriptome analysis of human neuronal precursor cells (hNPCs) which unveiled alterations in cilia-associated pathways. Further analysis of ciliary morphology revealed an elongation of primary cilia in EN1-deficient hNPCs. Besides, also Wnt signaling pathways were severely affected. Upon stimulating hNPCs with Wnt which drastically increased EN1 expression in WT lines, the phenotypes concerning mitochondrial function and cilia were exacerbated in EN1 ko hNPCs. They failed to enhance the expression of the complex I subunits NDUFS1 and 3, and now displayed a reduced mitochondrial respiration. Furthermore, Wnt stimulation decreased ciliogenesis in EN1 ko hNPCs but increased ciliary length even further. This further highlights the relevance of primary cilia next to mitochondria for the functionality and correct maintenance of human DAns and provides new possibilities to establish neuroprotective therapies for PD.
Topics: Mice; Animals; Humans; Induced Pluripotent Stem Cells; Cell Differentiation; Parkinson Disease; Dopaminergic Neurons; Mitochondria; Substantia Nigra
PubMed: 38518837
DOI: 10.1016/j.nbd.2024.106474 -
Cureus Feb 2024Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that originate from the mesenchymal cells of the gastrointestinal tract. Extra-GISTs (EGISTs) are...
Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that originate from the mesenchymal cells of the gastrointestinal tract. Extra-GISTs (EGISTs) are caused by sites outside the gastrointestinal tract. We reported a case of EGIST of the pancreas in a 51-year-old woman. Enhanced CT scan showed a rounded, slightly hypointense focus in the head of the pancreas and the right pars compacta of the descending duodenum. Routine laboratory and endocrine tests were unremarkable. The patient underwent laparoscopic surgery. The diagnosis of EGIST was confirmed through histopathological and immunohistochemical examination. The tumor was found to be CD117+, CD34+, and DOG+ with a high risk of malignancy. No recurrence was observed during the nine-month postoperative follow-up.
PubMed: 38516419
DOI: 10.7759/cureus.54514