Mouse Model Of Parkinson's Disease Research Articles

Decreased cellular excitability of pyramidal tract neurons in primary motor cortex leads to paradoxically increased network activity in simulated parkinsonian motor cortex.

Decreased excitability of pyramidal tract neurons in layer 5B (PT5B) of primary motor cortex (M1) has recently been shown in a dopamine-depleted mouse model of parkinsonism. We hypothesized that decreased PT5B neuron excitability would substantially disrupt oscillatory and non-oscillatory firing patterns of neurons in layer 5 (L5) of primary motor cortex (M1). To test this hypothesis, we performed computer simulations using a previously validated computer model of mouse M1. Inclusion of the experimentally identified parkinsonism-associated decrease of PT5B excitability into our computational model produced a paradoxical increase in rest-state PT5B firing rate, as well as an increase in beta-band oscillatory power in local field potential (LFP). In the movement-state, PT5B population firing and LFP showed reduced beta and increased high-beta, low-gamma activity of 20-35 Hz in the parkinsonian, but not in control condition. The appearance of beta-band oscillations in parkinsonism would be expected to disrupt normal M1 motor output and contribute to motor activity deficits seen in patients with Parkinson's disease (PD).

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.

Rhein alleviates MPTP-induced Parkinson's disease by suppressing neuroinflammation via MAPK/IκB pathway.

Parkinson's disease (PD) is a common neurodegenerative disease with a rapid increase in incidence in recent years. Existing treatments cannot slow or stop the progression of PD. It was proposed that neuroinflammation leads to neuronal death, making targeting neuroinflammation a promising therapeutic strategy. Our previous studies have demonstrated that rhein protects neurons in vitro by inhibiting neuroinflammation, and it has been found to exhibit neuroprotective effects in Alzheimer's disease and epilepsy, but its neuroprotective mechanisms and effects on PD are still unclear. PD animal model was induced by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP). ELISA, RT-qPCR, western blot and Immunofluorescence were used to detect the levels of inflammatory cytokines and M1 polarization markers. The protein expression levels of signaling pathways were measured by western blot. Hematoxylin-eosin (HE) staining showed that rhein did not damage the liver and kidney. Two behavioral tests, pole test and rotarod test, were used to evaluate the improvement effect of rhein on movement disorders. The number of neurons in the substantia nigra was evaluated by Nissl staining. Immunohistochemistry and western blot were used to detect tyrosine hydroxylase (TH) and α-synuclein. Rhein inhibited the activation of MAPK/IκB signaling pathway and reduced the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and M1 polarization markers of microglia in vivo. In a mouse model of PD, rhein ameliorated movement disorders, reduced dopaminergic neuron damage and α-synuclein deposition. Rhein inhibits neuroinflammation through MAPK/IκB signaling pathway, thereby reducing neurodegeneration, α-synuclein deposition, and improving movement disorders in Parkinson's disease.

TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons

Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival invivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD.

α-Synuclein Overexpression and the Microbiome Shape the Gut and Brain Metabolome in Mice.

Pathological forms of the protein α-synuclein contribute to a family of disorders termed synucleinopathies, which includes Parkinson's disease (PD). Most cases of PD are believed to arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms and pathology in animal models. To explore how the microbiome may impact PD-associated genetic risks, we quantitatively profiled nearly 630 metabolites from 26 biochemical classes in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice with or without microbiota. We observe tissue-specific changes driven by genotype, microbiome, and their interaction. Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. Notably, levels of the microbial metabolite trimethylamine N-oxide (TMAO) strongly correlate from the gut to the plasma to the brain, identifying a product of gene-environment interactions that may influence PD-like outcomes in mice. TMAO is elevated in the blood and cerebral spinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and the microbiome in a mouse model of PD.

Sensory-Behavioral Deficits in Parkinson's Disease: Insights from a 6-OHDA Mouse Model.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the striatum, predominantly associated with motor symptoms. However, non-motor deficits, particularly sensory symptoms, often precede motor manifestations, offering a potential early diagnostic window. The impact of non-motor deficits on sensation behavior and the underlying mechanisms remains poorly understood. In this study, we examined changes in tactile sensation within a Parkinsonian state by employing a mouse model of PD induced by 6-hydroxydopamine (6-OHDA) to deplete striatal dopamine (DA). Leveraging the conserved mouse whisker system as a model for tactile-sensory stimulation, we conducted psychophysical experiments to assess sensory-driven behavioral performance during a tactile detection task in both the healthy and Parkinson-like states. Our findings reveal that DA depletion induces pronounced alterations in tactile sensation behavior, extending beyond expected motor impairments. We observed diverse behavioral deficits, spanning detection performance, task engagement, and reward accumulation, among lesioned individuals. While subjects with extreme DA depletion consistently showed severe sensory behavioral deficits, others with substantial DA depletion displayed minimal changes in sensory behavior performance. Moreover, some exhibited moderate degradation of behavioral performance, likely stemming from sensory signaling loss rather than motor impairment. The implementation of a sensory detection task is a promising approach to quantify the extent of impairments associated with DA depletion in the animal model. This facilitates the exploration of early non-motor deficits in PD, emphasizing the importance of incorporating sensory assessments in understanding the diverse spectrum of PD symptoms.

Discovery of novel benzimidazole derivatives as selective and reversible monoamine oxidase B inhibitors for Parkinson's disease treatment

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 IC50 value of 67.3 nM, comparable to safinamide (IC50 = 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 (Ki = 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.

Lipid and Transcriptional Regulation in a Parkinson's Disease Mouse Model by Intranasal Vesicular and Hexosomal Plasmalogen‐Based Nanomedicines (Adv. Healthcare Mater. 14/2024)

Lipid and Transcriptional Regulation in a Parkinson's Disease Mouse Model by Intranasal Vesicular and Hexosomal Plasmalogen‐Based Nanomedicines (Adv. Healthcare Mater. 14/2024)

ICAM-1 may promote the loss of dopaminergic neurons by regulating inflammation in MPTP-induced Parkinson’s disease mouse models

Parkinson’s disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis. Intercellular adhesion molecule-1 (ICAM-1), an inflammatory marker, participates in neuroinflammation during dopaminergic neuronal damage. However, the explicit mechanisms of action of ICAM-1 in PD have not been elucidated. We established a subacute PD mouse model by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed motor symptoms and gastrointestinal dysfunction in mice. Immunofluorescence was used to examine the survival of dopaminergic neurons, expression of microglial and astrocyte markers, and intestinal tight junction-associated proteins. Then, we use 16 S rRNA sequencing to identify alterations in the microbiota. Our findings revealed that ICAM-1-specific antibody (Ab) treatment relieved behavioural defects, gastrointestinal dysfunction, and dopaminergic neuronal death in MPTP-induced PD mice. Further mechanistic investigations indicated that ICAM-1Ab might suppress neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra and relieving colon barrier impairment and intestinal inflammation. Furthermore, 16 S rRNA sequencing revealed that the relative abundances of bacterial Firmicutes, Clostridia, and Lachnospiraceae were elevated in the PD mice. However, ICAM-1Ab treatment ameliorated the MPTP-induced disorders in the intestinal microbiota. Collectively, we concluded that the suppressing ICAM-1 might lead to the a significant decrease of inflammation and restore the gut microbial community, thus ameliorating the damage of DA neurons.

Aerobic exercise improves motor dysfunction in Parkinson's model mice via differential regulation of striatal medium spiny neuron.

The striatum plays a crucial role in providing input to the basal ganglia circuit and is implicated in the pathological process of Parkinson's disease (PD). Disruption of the dynamic equilibrium in the basal ganglia loop can be attributed to the abnormal functioning of the medium spiny neurons (MSNs) within the striatum, potentially acting as a trigger for PD. Exercise has been shown to mitigate striatal neuronal dysfunction through neuroprotective and neurorestorative effects and to improve behavioral deficits in PD model mice. In addition, this effect is offset by the activation of MSNs expressing dopamine D2 receptors (D2-MSNs). In the current study, we investigated the underlying neurobiological mechanisms of this effect. Our findings indicated that exercise reduces the power spectral density of the beta-band in the striatum and decreases the overall firing frequency of MSNs, particularly in the case of striatal D2-MSNs. These observations were consistent with the results of molecular biology experiments, which revealed that aerobic training specifically enhanced the expression of striatal dopamineD2 receptors (D2R). Taken together, our results suggest that aerobic training aimed at upregulating striatal D2R expression to inhibit the functional activity of D2-MSNs represents a potential therapeutic strategy for the amelioration of motor dysfunction in PD.

In Vivo Study of Moringa oleifera Seed Extracts as Potential Sources of Neuroprotection against Rotenone-Induced Neurotoxicity.

Parkinson's disease (PD) is a leading neurodegenerative disorder affecting 1-3 percent of the elderly population. Oxidative stress is the primary factor for the neurodegeneration of Substantia Nigra (SN). The current study aims to assess the seed extracts of Moringa oleifera (MO) on rotenone-mediated motor function impairments in a PD mouse model. For this purpose, two different seed extracts of MO were prepared, including aqueous MO (AqMO) and ethanolic MO (EthMO). Male Swiss albino mice were grouped into five groups. Mice received 2.5 mg/kg rotenone for 21 consecutive days, and control mice received the vehicle. Extract-treated mice received 200 mg/kg AqMO and EthMO separately, orally and daily for 28 days. Sinemet-treated mice received 20 mg/kg, oral dose, as a positive group. The motor function performance was evaluated using standard neurobehavioral tests. The antioxidant potentials of MO seed extracts were estimated by lipid peroxidation (LPO), reduced glutathione (GSH), glutathione-s-transferase (GST) and catalase (CAT) activities in mice brain homogenates. The PD mice brain SN sections were investigated for neurodegeneration. MO seed extract-treated mice showed a significant reduction in motor dysfunction compared to rotenone-treated mice as assessed through the open field, beam walk, pole climb-down, tail suspension, stride length and stepping tests. Increased antioxidant capacities of the PD mice brains of MO extract-administered groups were observed compared to the control. A histological study showed reduced signs of neurodegeneration, vacuolation around multipolar cells and cytoplasmic shrinkage in MO extract-treated mice SN brain sections. Collectively, MO seed extracts protected the animals from locomotor deficits induced by rotenone, possibly through antioxidant means, and seem to have potential applications in neurodegenerative diseases.

A pilot study on the mechanism of Guasha in treating Parkinson's disease based on molecular level and ultra-trace proteomics analysis

Guasha is a widely applied non-pharmacological therapy of traditional Chinese medicine (TCM), which has been proved to be effective in the treatment of Parkinson's disease (PD). The objective of this study was to explore the mechanisms of Guasha therapy in the pathological processes including neuroinflammation in PD. After 3 Guasha courses, a reduction in α-synuclein aggregation and alleviation of microglia activation were observed in the substantia nigra pars compacta (SNpc). Furthermore, levels of TNF-α, IL-1β and IFN-γ in the SNpc decreased, while plasma TGF-β, IL-4 and IL-10 increased. Moreover, both TH protein and mRNA levels in the SNpc, as well as dopamine levels in the striatum, exhibited an increase. The proteomics analysis results based on plasma-derived exosomes revealed a total of 943 differentially expressed proteins identified. Compared to the model group, the Guasha group screened for 82 differential proteins, with 30 upregulated and 52 downregulated. The improvement of pathological changes in the PD model mice treated with Guasha primarily involves biological processes such as oxidative stress, immune response and inflammation, and cellular structure regulation. It involves signaling pathways related to aldosterone synthesis and secretion, adrenergic signaling in myocardial cells, COVID-19-related inflammatory signaling, and neurotrophic signaling. Collectively, the mechanisms of Guasha for treating PD might be closely related to inhibiting microglial cell activation-mediated neuroinflammation, regulating oxidative stress, cellular structure, aldosterone synthesis and secretion-mediated electrolyte balance, as well as noradrenergic signaling-mediated neuroprotection. These findings provided new insight for Guasha in treating PD and would potentially enhance therapeutic interventions.

Utilizing a Disposable Sensor with Polyaniline-Doped Multi-Walled Carbon Nanotubes to Enable Dopamine Detection in Ex Vivo Mouse Brain Tissue Homogenates.

Disposable sensors are inexpensive, user-friendly sensing tools designed for rapid single-point measurements of a target. Disposable sensors have become more and more essential as diagnostic tools due to the growing demand for quick, easy-to-access, and reliable information related to the target. Dopamine (DA), a prevalent catecholamine neurotransmitter in the human brain, is associated with central nervous system activities and directly promotes neuronal communication. For the sensitive and selective estimation of DA, an enzyme-free amperometric sensor based on polyaniline-doped multi-walled carbon nanotubes (PANI-MWCNTs) drop-coated disposable screen-printed carbon electrodes (SPCEs) was fabricated. This PANI-MWCNTs-2/SPCE sensor boasts exceptional accuracy and sensitivity when working directly with ex vivo mouse brain homogenates. The sensor exhibited a detection limit of 0.05 μM (S/N = 3), and a wide linear range from 1.0 to 200 μM. The sensor's high selectivity to DA amidst other endogenous interferents was recognized. Since the constructed sensor is enzyme-free yet biocompatible, it exhibited high stability in DA detection using ex vivo mouse brain homogenates extracted from both Parkinson's disease and control mice models. This research thus presents new insights into understanding DA release dynamics at the tissue level in both of these models.

MiR-101a-3p/ROCK2 axis regulates neuronal injury in Parkinson's disease models.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). This study focuses on deciphering the role of microRNA (miR)-101a-3p in the neuronal injury of PD and its regulatory mechanism. We constructed a mouse model of PD by intraperitoneal injection of 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP), and used 1-methyl-4-phenylpyridinium (MPP+) to treat Neuro-2a cells to construct an in-vitro PD model. Neurological dysfunction in mice was evaluated by swimming test and traction test. qRT-PCR was utilized to examine miR-101a-3p expression and ROCK2 expression in mouse brain tissues and Neuro-2a cells. Western blot was conducted to detect the expression of α-synuclein protein and ROCK2 in mouse brain tissues and Neuro-2a cells. The targeting relationship between miR-101a-3p and ROCK2 was determined by dual-luciferase reporter gene assay. The apoptosis of neuro-2a cells was assessed by flow cytometry. Low miR-101a-3p expression and high ROCK2 expression were found in the brain tissues of PD mice and MPP+-treated Neuro-2a cells; PD mice showed decreased neurological disorders, and apoptosis of Neuro-2a cells was increased after MPP+ treatment, both of which were accompanied by increased accumulation of α-synuclein protein. After miR-101a-3p was overexpressed, the neurological function of PD mice was improved, and the apoptosis of Neuro-2a cells induced by MPP+ was alleviated, and the accumulation of α-synuclein protein was reduced; ROCK2 overexpression counteracted the protective effect of miR-101a-3p. Additionally, ROCK2 was identified as the direct target of miR-101a-3p. MiR-101a-3p can reduce neuronal apoptosis and neurological deficit in PD mice by inhibiting ROCK2 expression, suggesting that miR-101a-3p is a promising therapeutic target for PD.

Neuroprotection effects of kynurenic acid-loaded micelles for the Parkinson’s disease models

Anti-glutamatergic agents may have neuroprotective effects against excitotoxicity that is known to be involved in the pathogenesis of Parkinson’s disease (PD). One of these agents is kynurenic acid (KYNA), a tryptophan metabolite, which is an endogenous N-methyl-D-aspartic acid (NMDA) receptor antagonist. However, its pharmacological properties of poor water solubility and limited blood–brain barrier (BBB) permeability rules out its systemic administration in disorders affecting the central nervous system. Our aim in the present study was to investigate the neuroprotective effects of KYNA-loaded micelles (KYNA-MICs) against PD in vitro and in vivo. Lipid-based micelles (MICs) in conjunction with KYNA drug delivery have the potential to enhance the penetration of therapeutic drugs into a diseased brain without BBB obstacles. KYNA-MICs were characterized by particle size (105.8 ± 12.1 nm), loading efficiency (78.3 ± 4.23%), and in vitro drug release (approximately 30% at 24 h). The in vitro experiments showed that KYNA-MICs effectively reduced 2-fold protein aggregation. The in vivo studies revealed that KYNA was successfully delivered by 5-fold increase in neurotoxin-induced PD brains. The results showed significant enhancement of KYNA delivery into brain. We also found that the KYNA-MICs exhibited several therapeutic effects. The KYNA-MICs reduced protein aggregation of an in vitro PD model, ameliorated motor functions, and prevented loss of the striatal neurons in a PD animal model. The beneficial effects of KYNA-MICs are probably explained by the anti-excitotoxic activity of the treatment’s complex. As the KYNA-MICs did not induce any appreciable side-effects at the protective dose applied to a chronic PD mouse model, our results demonstrate that KYNA provides neuroprotection and attenuates PD pathology.

Bmal1 mediates the neuroprotective effect of sodium butyrate in a mouse model of Parkinson's disease

To investigate the mechanisms that mediate the neuroprotective effect of the intestinal microbial metabolite sodium butyrate (NaB) in a mouse model of Parkinson's disease (PD) via the gut-brain axis. Thirty-nine 7-week-old male C57BL/6J mice were randomized equally into control group, PD model group, and NaB treatment group. In the latter two groups, PD models were established by intraperitoneal injection of 30 mg/kg 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) once daily for 5 consecutive days, and normal saline was injected in the control group. After modeling, the mice received daily gavage of NaB (300 mg/kg) or an equal volume of saline for 14 days. Behavioral tests were carried out to assess the changes in motor function of the mice, and Western blotting was performed to detect the expressions of tyrosine hydroxylase (TH) and α-synuclein (α-syn) in the striatum and nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and the tight junction proteins ZO-1, Occludin, and Claudinin the colon. HE staining was used to observe inflammatory cell infiltration in the colon of the mice. RNA sequencing analysis was performed to identify the differentially expressed genes in mouse colon tissues, and their expressions were verified using qRT-PCR and Western blotting. The mouse models of PD with NaB treatment showed significantly increased movement speed and pulling strength of the limbs with obviously upregulated expressions of TH, Occludin, and Claudin and downregulated expressions of α-syn, NF-κB, TNF-α, and IL-6 (all P < 0.05). HE staining showed that NaB treatment significantly ameliorated inflammatory cell infiltration in the colon of the PD mice. RNA sequencing suggested that Bmal1 gene probably mediated the neuroprotective effect of NaB in PD mice (P < 0.05). NaB can improve motor dysfunction, reduce dopaminergic neuron loss in the striatum, and ameliorate colonic inflammation in PD mice possibly through a mechanism involving Bmal1.

Evaluating the Neuroprotective Potential of Novel Benzodioxole Derivatives in Parkinson's Disease via AMPA Receptor Modulation.

Parkinson's disease (PD) is a significant health issue because it gradually damages the nervous system. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play a significant role in the development of PD. The current investigation employed hybrid benzodioxole-propanamide (BDZ-P) compounds to get information on AMPA receptors, analyze their biochemical and biophysical properties, and assess their neuroprotective effects. Examining the biophysical characteristics of all the subunits of the AMPA receptor offers insights into the impact of BDZ-P on the desensitization and deactivation rate. It demonstrates a partial improvement in the locomotor capacities in a mouse model of Parkinson's disease. In addition, the in vivo experiment assessed the locomotor activity by utilizing the open-field test. Our findings demonstrated that BDZ-P7 stands out with its remarkable potency, inhibiting the GluA2 subunit nearly 8-fold with an IC50 of 3.03 μM, GluA1/2 by 7.5-fold with an IC50 of 3.14 μM, GluA2/3 by nearly 7-fold with an IC50 of 3.19 μM, and GluA1 by 6.5-fold with an IC50 of 3.2 μM, significantly impacting the desensitization and deactivation rate of the AMPA receptor. BDZ-P7 showed an in vivo impact of partially reinstating locomotor abilities in a mouse model of PD. The results above suggest that the BDZ-P7 compounds show great promise as top contenders for the development of novel neuroprotective therapies.

(+)-Borneol Protects Dopaminergic Neuronal Loss in Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson's Disease Mice: A Study of Dopamine Level using In Vivo Brain Microdialysis.

Considerable research efforts have been directed toward the symptom relief of Parkinson's disease (PD) by attenuating dopamine (DA) depletion. One common feature of these existing therapies is their unavailability of preventing the neurodegenerative process of dopaminergic neurons. (+)-Borneol, a natural highly lipid-soluble bicyclic monoterpene, has been reported to regulate the levels of monoamine neurotransmitters in the central nervous system and exhibit neuroprotective effects. However, the effect of (+)-borneol on the dopaminergic neuronal loss of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice is not defined. Herein, we first report that 30 mg/kg (+)-borneol significantly attenuated the motor deficits of PD mice, which benefits from markedly increasing the level of DA and decreasing the metabolic rate of DA in the striatum of conscious and freely moving mouse detected by ultraperformance liquid chromatography tandem mass spectrometry online combined with in vivo brain microdialysis sampling. It is worth noting that the enhanced level of DA by (+)-borneol was enabled by the reduction in loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons in the substantia nigra and striatum and promotion of reserpine- or nomifensine-induced DA release in PD mice. Interestingly, (+)-borneol evidently inhibited the decreased expression levels of DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) on the MPTP mouse model of PD. Moreover, (+)-borneol suppressed the neuroinflammation by inhibiting the production of IL-1β, IL-6, and TNF-α and attenuated oxidative stress by decreasing the level of MDA and increasing the activities of SOD and GSH-px in PD mice. These findings demonstrate that (+)-borneol protects DA neurons by inhibiting neuroinflammation and oxidative stress. Further research work for the neuroprotection mechanism of (+)-borneol will focus on reactive oxygen species-mediated apoptosis. Therefore, (+)-borneol is a potential therapeutic candidate for retarding the neurodegenerative process of PD.

RND3 modulates microglial polarization and alleviates neuroinflammation in Parkinson's disease by suppressing NLRP3 inflammasome activation

Neuroinflammation mediated by microglia plays an important role in the etiology of Parkinson's disease (PD). Rho family GTPase 3 (RND3) exerts anti-inflammatory effects and may act as a potential new inducer of neuroprotective phenotypes in microglia. However, whether RND3 can be used to regulate microglia activation or reduce neuroinflammation in PD remains elusive. The study investigated the microglia modulating effects and potential anti-inflammatory effects of RND3 in vivo and in vitro, using animal models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and cell models of BV-2 cells stimulated by LPS plus IFN-γ with or without RND3-overexpression. The results showed that RND3 was highly expressed in the MPTP-induced PD mouse model and BV-2 cells treated with LPS and IFN-γ. In vivo experiments confirmed that RND3 overexpression could modulate microglia phenotype and ameliorate MPTP-induced neuroinflammation through inhibiting activation of the NLRP3 inflammasome in substantia nigra pars compacta (SNpc). In vitro study showed that RND3 overexpression could attenuate the production of pro-inflammatory factors in BV2 cells stimulated by LPS and IFN-γ. Mechanistically, RND3 reduced the activation of the NLRP3 inflammasome upon LPS and IFN-γ stimulation. Taken together, these findings suggest that RND3 modulates microglial polarization and alleviates neuroinflammation in Parkinson's disease by suppressing NLRP3 inflammasome activation.

VGluT2 neuron subtypes in the paraventricular thalamic nucleus regulate depression in paraquat-induced Parkinson’s disease

Parkinson's disease (PD) is a prevalent neurodegenerative disease and approximately one third of patients with PD are estimated to experience depression. Paraquat (PQ) is the most widely used herbicide worldwide and PQ exposure is reported to induce PD with depression. However, the specific brain region and neural networks underlying the etiology of depression in PD, especially in the PQ-induced model, have not yet been elucidated. Here, we report that the VGluT2-positive glutamatergic neurons in the paraventricular thalamic nucleus (PVT) promote depression in the PQ-induced PD mouse model. Our results show that PVTVGluT2 neurons are activated by PQ and their activation increases the susceptibility to depression in PD mice. Conversely, inhibition of PVTVGluT2 neurons reversed the depressive-behavioral changes induced by PQ. Similar to the effects of intervention the soma of PVTVGluT2 neurons, stimulation of their projections into the central amygdaloid nucleus (CeA) also strongly influenced depression in PD mice. PQ induced malfunctioning of the glutamate system and changes in the dendritic and synaptic morphology in the CeA through its role on PVTVGluT2 neuronal activation. In summary, our results demonstrate that PVTVGluT2 neurons are key neuronal subtypes for depression in PQ-induced PD and promote depression processes through the PVTVGluT2-CeA pathway.