Deep Brain Stimulation Mechanisms in Parkinson's Disease: Immediate and Long-Term Effects.

Deep brain stimulation (DBS) is a common therapy for managing Parkinson's disease (PD) in clinical practice. However, a complete understanding of its mode of action is still needed. DBS is believed to work primarily through electrical and neurochemical pathways. Furthermore, DBS has other mechanisms of action. This review explores the fundamental concepts and applications of DBS in treating PD, including its mechanisms, clinical implications, and recent research.

Electroacupuncture Improves Neuronal Damage and Mitochondrial Dysfunction Through the TRPC1 and SIRT1/AMPK Signaling Pathways to Alleviate Parkinson's Disease in Mice.

Parkinson's disease (PD) is a neurodegenerative disease that mainly manifests as cognitive decline and motor dysfunction, the treatment of which is still a major challenge in the clinical field. Acupuncture therapy has been shown in many studies to enhance the body's own immunity and disease resistance. This study mainly discusses the specific mechanism underlying electroacupuncture intervention in improving PD. Male C57BL/6 mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce a mouse PD model, and the chorea trembling control area of the head of PD mice was treated by electroacupuncture. Western blotting was used to detect the expression of related proteins in mouse pathological samples; TUNEL measured neuronal apoptosis levels; Nissl staining observed neuronal damage; immunofluorescence and immunohistochemistry were used to detect the expression of Iba-1, TH, and α-syn in substantia nigra denser (SN). The expression levels of oxidative stress factors and inflammatory factors were measured by kits. Flow cytometry measured mitochondrial membrane potential and Ca2+ levels. MPTP intraperitoneal injection induced an increase in inflammatory factors in PD mice and promoted the oxidative stress response, and the inflammatory response was alleviated after electroacupuncture treatment. Electroacupuncture intervention effectively alters the decrease in oxidative stress levels and alleviates neuronal damage in PD mice. Electroacupuncture improves mitochondrial dysfunction induced by MPTP in PD mice by activating the SIRT1/AMPK signaling pathway. We also confirmed that knocking down TRPC1 can inhibit the SIRT1/AMPK signaling pathway, weaken the Ca2+ content in mouse neuronal tissue, and promote cell apoptosis. Electroacupuncture improves neuronal damage and alleviates PD in mice through the TRPC1 and SIRT1/AMPK signaling pathways. In addition, electroacupuncture therapy can improve MPTP-induced mitochondrial dysfunction in PD mice and alleviate the PD process.

Mesenchymal stem cell exosomes rich in miR-23b-3p affect the Wnt signaling pathway and promote neuronal autophagy to alleviate PD symptoms.

This study aims to elucidate the role of miR-23b-3p in mesenchymal stem cell exosomes in regulating the Wnt signaling pathway to promote autophagy of neurons and alleviate Parkinson's disease (PD) symptoms. We generated rat and cellular PD models with 6-OHDA, treated them with mesenchymal stem cell exosomes rich in miR-23b-3p and determined the expression of α-syn and Wnt/ß-catenin pathway and autophagy-related genes. In the plasma of PD patients, the levels of miR-23b-3p and the Wnt/ß-catenin pathway-related genes ß-catenin and DAT were low, while α-syn expression was high. In the PD cell model, miR-23b-3p was downregulated, the Wnt pathway was inhibited, α-syn was upregulated, neuron autophagy was inhibited, and the revitalization of the Wnt/ß-catenin pathway could promote the autophagy of neurons. Coculture of miR-23b-3p-enriched exosomes with MN9D cells confirmed that miR-23b-3p-enriched exosomes could promote autophagy in MN9D cells in a PD cell model. Moreover, animal experiments confirmed the results of the cell experiments. Therefore, miR-23b-3p-enriched mesenchymal stem cell exosomes promote neuronal autophagy by regulating the Wnt signaling pathway, thus alleviating PD progression and providing an important basis for the clinical treatment of PD.

BDNF alleviates Parkinson's disease by promoting STAT3 phosphorylation and regulating neuronal autophagy.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual death of dopaminergic neurons. Brain-derived neurotrophic factor (BDNF) and its receptors are widely distributed throughout the central nervous system, which can promote the survival and growth of neurons and protect neurons. This study revealed that BDNF promotes STAT3 phosphorylation and regulates autophagy in neurons. The PD mouse model was established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Moreover, SH-SY5Y cells were treated with 1-methyl-4-phenyl-pyridinium (MPP+) to establish a PD cell model. The level of BDNF was low in PD model mice and SH-SY5Y cells treated with MPP+. BDNF enhanced the levels of p-TrkB, P-STAT3, PINK1, and DJ-1. BDNF promoted autophagy, inhibited the level of p-α-syn (Ser129) and enhanced cell proliferation. The autophagy inhibitor 3-Methyladenine (3-methyladenine, 3-MA) reversed the protective effects of BDNF on neurons. BiFC assay results showed that there was a direct physical interaction between BDNF and STAT3, and coimmunoprecipitation experiments indicated an interaction between STAT3 and PI3K. The PI3K agonist Recilisib activated the PI3K/AKT/mTOR pathway, promoted autophagy, and alleviated neuronal cell damage. BDNF alleviates PD pathology by promoting STAT3 phosphorylation and regulating neuronal autophagy in SH-SY5Y cells and cultured primary neurons. Finally, BDNF has neuroprotective effects on PD model mice.

MALAT1 Mediates α-Synuclein Expression through miR-23b-3p to Induce Autophagic Impairment and the Inflammatory Response in Microglia to Promote Apoptosis in Dopaminergic Neuronal Cells.

Background: Parkinson's disease (PD) is a very common neurodegenerative disease that adversely affects the physical and mental health of many patients, but there is currently no effective treatment. Objective: To this end, this study focused on investigating the potential mechanisms leading to dopaminergic neuronal apoptosis in PD. Methods: Rotenone induces damage in dopaminergic neuronal MN9D cells. Apoptosis was detected by flow cytometry, and the expression of apoptosis-related proteins was detected by western blot. RT-qPCR was used to detect the expression of MALAT1 and miR-23b-3p. The expression of α-synuclein was detected by ELISA. A dual luciferase gene reporter assay was used to determine the targeted regulatory relationship between MALAT1 and miR-23b-3p and miR-23b-3p and α-synuclein. MN9D supernatant was cocultured with BV-2 cells, or BV-2 cells were treated with exogenous α-synuclein and then treated with an autophagy inhibitor (3-MA) and autophagy activator (RAPA). The expression of α-synuclein in BV-2 cells was detected by immunofluorescence. The expression of MIP-1α, a marker of microglial activation, was detected by ELISA. The nuclear translocation of NF-κB p65 was detected by immunofluorescence. The expression of proinflammatory cytokines was detected by ELISA. Western blotting was used to detect the expression of autophagy-related proteins. Apoptosis of MN9D cells was detected after coculture of BV-2 supernatant with MN9D. Results: The expression of MALAT1 and α-synuclein was upregulated, while the expression of miR-23b-3p was downregulated in damaged MN9D cells, resulting in cell apoptosis. MALAT1 can negatively regulate the expression of miR-23b-3p, while miR-23b-3p negatively regulates the expression of α-synuclein. α-synuclein can enter BV-2 cells through cell phagocytosis. Coculture of BV-2 cells with α-synuclein or with MN9D supernatant overexpressing MALAT1 resulted in a decrease in the autophagy level of BV-2 cells and an inflammatory reaction. However, miR-23b-3p mimics and knockdown of α-synuclein reversed the effect of MALAT1 on autophagy and the inflammatory response of BV-2 cells. In addition, after coculture of BV-2 cells with α-synuclein, the level of autophagy further decreased when 3-MA was added, while the opposite result occurred when RAPA was added. After coculture of α-synuclein-treated BV-2 cell supernatant with MN9D cells, autophagy-impaired BV-2 promoted the apoptosis of MN9D cells, and 3-MA aggravated the autophagy disorder of BV-2 and further promoted the apoptosis of MN9D cells, while RAPA reversed the autophagy disorder of BV-2 and alleviated the apoptosis of MN9D cells. Conclusion: MALAT1 can promote α-synuclein expression by regulating miR-23b-3p, thereby inducing microglial autophagy disorder and an inflammatory response leading to apoptosis of dopaminergic neurons. This newly discovered molecular mechanism may provide a potential target for the treatment of PD.

Preparation of gastrodin-modified dendrimer-entrapped gold nanoparticles as a drug delivery system for cerebral ischemia-reperfusion injury.

OBJECTIVE: This study sought to evaluate the feasibility of multifunctional gastrodin (GAS)-containing nano-drug carrier system against cerebral ischemia-reperfusion injury (CIRI). METHODS: The drug-loaded nanocomposite (Au-G5.NHAc-PS/GAS) with certain encapsulation efficiency (EE) was prepared by physical adsorption method using different proportions of GAS and drug-carrying system (Au-G5.NHAc-PS). High-performance liquid chromatography was used to determine the drug loading and EE. Cultured rat astrocytes and hypothalamic neurons were assigned into four groups: PBS, Au-G5.NHAc-PS, Au-G5.NHAc-PS/GAS, and GAS. CCK-8 assay, flow cytometry, and quantitative real-time PCR were performed to examine the cell viability, apoptosis, and the expression of tumor necrosis factor-α (TNF-α), IL-1ß, and IL-6 in the astrocytes and hypothalamic neurons, respectively. Cellular uptake of GAS and Au-G5.NHAc-PS/GAS was analyzed by using Hoechst 33342 staining. The animal model with focal cerebral ischemia was generated by middle cerebral artery occlusion (MCAO) in healthy male Sprague Dawley (SD) rats, and pathological changes of brain tissue and major organs in the rats were identified by hematoxylin and eosin (HE) staining. Apoptosis in rat astrocytes and hypothalamic neurons was detected by TUNEL staining and flow cytometry. RESULTS: Au-G5.NHAc-PS had a spherical shape with a uniform size of 157.3 nm. Among the nanoparticles, Au-G5.NHAc-PS/GAS with an EE of 70.3% displayed the best release delay effect. Moreover, we observed that in vitro cytotoxicity and cellular uptake of Au-G5.NHAc-PS/GAS were higher than those of GAS, whereas the expression of TNF-α, IL-1ß, and IL-6 was significantly downregulated in Au-G5.NHAc-PS/GAS group as compared to G5.NHAc-PS group. Notably, HE staining revealed that although Au-G5.NHAc-PS/GAS had no toxic and side effects on the main organs of rats, it alleviated the damage of brain tissue in the MCAO rats. Besides, Au-G5.NHAc/GAS markedly reduced MCAO-induced apoptosis. CONCLUSION: Au-G5.NHAc-PS showed favorable surface morphology, sustained drug release ability, no measurable toxicity, and good biocompatibility, indicating that GAS exerts anti-inflammatory and antiapoptotic effects on CIRI.

The Reactive Astrocytes After Surgical Brain Injury Potentiates the Migration, Invasion, and Angiogenesis of C6 Glioma.

BACKGROUND: Surgical resection is a key method for glioma treatment. This inherently invasive procedure alters the tumor microenvironment of glioma cells that cannot be removed by surgery. However, few studies have focused on the impact of this microenvironment change on the growth of glioma cells. METHODS: The authors preconstructed a surgical brain injury model, and then C6 glioma cells were transplanted. HE staining was used to observe the general morphology of tumor cells, and immunohistochemistry of MMP-2, MMP-9, GFAP, and CD31 was used to evaluate the invasiveness of glioma cells and activation of astrocytes and calculate microvessel density. In vitro, primary rat astrocytes were exposed to different temperature gradients. The supernatant was made into conditioned medium for culturing C6 glioma cells. The scratch test and transwell test were used to evaluate the migration and invasion of tumor cells. RESULTS: GFAP expression was stronger in surgical brain injury rats, C6 cells implanted in these rats showed stronger expression of MMP-2 and MMP-9, and CD31 was expressed in more microvessels. Astrocytes exposed to high temperatures of 40°C and 43°C expressed stronger GFAP, and C6 cells cultured in their supernatants had stronger scratch healing ability and the ability to cross transwell chambers. CONCLUSIONS: The microenvironment changes caused by surgical brain injury will enhance the migration and invasion of glioma cells and increase the microvessel density in the tumor. This effect may be related to the activation of astrocytes caused by the thermal injury of bipolar coagulation during surgery.

Single coil endovascular embolization of very tiny (≤2 mm) intracranial aneurysms: one center's experience.

Background: To investigate the safety and efficacy of endovascular embolization of very tiny (≤2 mm) intracranial aneurysms with single coil and summarize experience. Methods: A retrospective analysis was performed for 15 consecutive patients with very tiny aneurysms treated by coil embolization alone or stent-assisted coil embolization between January 2017 and January 2020. 15 patients with six unruptured aneurysms and nine ruptured aneurysms were included in this study. There were eight males and seven females with a mean age of 50.0 ± 5.2 years (range 41 to 57 years old). Intraoperative complications, imaging outcomes, clinical outcomes and follow-up data were analyzed. Results: All aneurysms were embolized with a single coil. Lvis stents were used in all coil assisted embolizations. The embolization success rate was 100%. The average volume embolization ratio (VER) of aneurysm embolization was 53.7 ± 25.5%. An intraoperative aneurysm re-rupture complication occurred in one patient (6.7%). 11 patients (73.3%) had immediate complete occlusion after embolization. After a mean follow-up period of 6.7 ± 1.4 months, 13 patients (86.7%) had complete occlusion. No patients had aneurysm re-rupture, an ischemic event or recurrence during follow-up. All patients achieved favorable clinical outcomes with a modified rankin scale (MRS) of 0-2. Conclusions: This study demonstrates that endovascular embolization of very tiny intracranial aneurysms with a single coil is safe and effective. However, the follow-up period was not long enough and studies with larger numbers of patients are required. The summary of experience reported here is expected to provide significant patient benefits.

A pilot behavioural and neuroimaging investigation on photothrombotic stroke models in rhesus monkeys.

BACKGROUND: Ischemic stroke leads to a long-term disability in humans and no efficient clinical therapy exists to date. The middle cerebral artery occlusion (MCAO) model in non-human primates has shown to be of value for translational stroke research. New method In the current study, a photothrombotic (PT) stroke model was established in rhesus monkeys with either a proximal or distal segment of middle cerebral artery (MCA) thrombosis. This study is the first that compares the two approaches of PT stroke in monkeys using behavioral and physiological measurements and MRI scans. RESULTS: The experiment found that infarct occurred in the MCA target regions, with all monkeys having impaired behavior reflected by deficits in neurologic function, and motor and cognition in object retrieval detour (ORD) task. The monkeys with distal MCA thrombosis developed with sequential photo-irritations of the Sylvian fissure zone, adjacent central anterior gyrus and central posterior gyrus, had similar impairments with respect to behavior and showed a tendency of a small edema volume with proximal MCA thrombosis at days 4 and 7 post PT stroke. COMPARISON WITH EXISTING METHODS: The distal MCA thrombosis developed with sequential photo-irritations might provide a consistent and well-tolerated focal ischemia in rhesus monkeys, compared with other PT stroke models which usually were singly conducted on the animal's motor cortex and had a temporal effect. CONCLUSIONS: The sequentially photo-irritated PT stroke model is a promising ischemic stroke model in rhesus monkey for studying human stroke pathology and physiology and for new therapies development.

Electroacupuncture promotes the recovery of rats with spinal cord injury by suppressing the Notch signaling pathway via the H19/EZH2 axis.

BACKGROUND: Spinal cord injury (SCI) is a life-changing event with an extremely poor prognosis. In our preliminary studies, electroacupuncture (EA) was found to promote the repair of SCI, which was closely related to the Notch signaling pathway. Therefore, in the present study, we hypothesized that EA protects against SCI by inhibiting the Notch signaling pathway and sought to investigate the underlying molecular mechanisms. METHODS: Rat and cell models of SCI were established. The expression of long non-coding RNA H19 was measured by real-time quantitative polymerase chain reaction. The expression levels of EZH2, Notch1, Notch3, Notch4, Hes1, and PS1 protein were measured by western blot. Cell apoptosis and viability were analyzed using flow cytometry and Cell Counting Kit-8 assays, respectively. The expressions of glial fibrillary acidic protein (GFAP) and nestin were detected by immunofluorescence staining. RESULTS: The expressions of H19, EZH2, and GFAP were significantly increased after SCI but were inhibited by EA; in contrast, nestin expression was significantly decreased by SCI but was restored by EA. Moreover, oxygen-glucose deprivation (OGD) treatment elevated the expression of H19, EZH2, and Notch-related factors as well as apoptosis in PC-12 cells, while suppressing cell viability. Suppressing H19 alleviated the effects of OGD on cell viability and apoptosis, and inhibited the expression of EZH2 and Notch-related factors expression; these effects were reversed by EZH2 overexpression. Finally, EA promoted the recovery of SCI rats and neural stem cell (NSC) proliferation by inhibiting the Notch signaling pathway, which was reversed by H19 overexpression. CONCLUSIONS: Our results demonstrated that EA promotes the recovery of SCI rats and increases the proliferation and differentiation of NSCs by suppressing the Notch signaling pathway via modulating the H19/EZH2 axis.

CircRNAs as potential biomarkers for the clinicopathology and prognosis of glioma patients: a meta-analysis.

BACKGROUND: An increasing number of studies have reported circular RNAs (circRNAs) as new potential biomarkers for the prognosis of gliomas. However, the overall prognostic value of circRNAs for glioma remains unclear. Therefore, this study is the first comprehensive evaluation of the clinicopathological and prognostic value of dysregulated circRNAs in the treatment of glioma patients. METHODS: We systematically reviewed the online databases of PubMed, Web of Science, EMBASE, and Cochrane Library to identify studies that explored the relationship between circRNA expression and clinicopathological and prognostic factors in glioma through April 11, 2020. The quality of the included studies was evaluated by the Newcastle-Ottawa Scale (NOS) checklists. Clinicopathological features were assessed by pooled odds ratios (ORs) and 95% confidence intervals (CIs), and overall survival (OS) was assessed by hazard ratios (HRs) and 95% CIs. RESULTS: Twenty-four eligible studies, including 22 studies of clinicopathological features, 1 diagnostic study, and 18 studies of prognosis, that included a total of 1390 patients were ultimately included in this study. Meta-analysis showed that highly expressed oncogenic circRNAs were significantly related to poor clinicopathological features (age: P = 0.026; tumor size: P ≤ 0.001; tumor grade: P ≤ 0.001; KPS: P = 0.012) and worse overall survival (OS) (HR = 2.01, 95% CI: 1.61-2.50, P ≤ 0.001). Moreover, we found that highly expressed tumor-suppressor circRNAs were related to better clinicopathological features (gender: P = 0.042; age: P = 0.014; tumor size: P = 0.022; tumor grade: P ≤ 0.001) and longer OS (HR = 2.70, 95% CI: 1.82-3.99, P ≤ 0.001). CONCLUSIONS: In conclusion, there is a significant correlation between the dysregulated expression of circRNAs and the clinicopathology and prognosis of glioma patients.

Outcomes of STN-DBS in PD Patients With Different Rates of Disease Progression Over One Year of Follow-Up.

Parkinson's disease (PD) is a progressive neurodegenerative disorder, and the rate of progression is different across individuals. Subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to produce long-term symptom improvement in PD. In this retrospective study, we wanted to explore the effects of bilateral STN-DBS in PD patients with different rates of disease progression. Forty patients with PD were included. An index of progression rate was calculated by the ratio of the Unified Parkinson Disease Rating Scale, part III (UPDRS-III), score in the off-medication condition at baseline and disease duration. The patients were divided into fast-, medium-, and slow-progression groups by this index. The outcome measurements at the 1st, 6th, and 12th months after surgery were the changes in UPDRS-III scores in the off-medication/on-stimulation condition compared with the baseline. We found the following. (1). Motor functions in the different PD progression groups were improved by bilateral STN-DBS treatment at 1 year of follow-up. (2). However, compared to the slow- and medium-progression groups, the fast-progression group had less improvement at the 6th- and 12th-month follow-up. The results indicated that bilateral STN-DBS can improve motor functions of Parkinson's patients over the 1-year follow-up. Moreover, the outcomes in the slow- and medium-progression patients were better than those with fast-progression rates.