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Clinics (Sao Paulo, Brazil) 2023The 6-OHDA nigro-striatal lesion model has already been related to disorders in the excitability and synchronicity of neural networks and variation in the expression of...
BACKGROUND
The 6-OHDA nigro-striatal lesion model has already been related to disorders in the excitability and synchronicity of neural networks and variation in the expression of transmembrane proteins that control intra and extracellular ionic concentrations, such as cation-chloride cotransporters (NKCC1 and KCC2) and Na+/K+-ATPase and, also, to the glial proliferation after injury. All these non-synaptic mechanisms have already been related to neuronal injury and hyper-synchronism processes.
OBJECTIVE
The main objective of this study is to verify whether mechanisms not directly related to synaptic neurotransmission could be involved in the modulation of nigrostriatal pathways.
METHODS
Male Wistar rats, 3 months old, were submitted to a unilateral injection of 24 µg of 6-OHDA, in the striatum (n = 8). The animals in the Control group (n = 8) were submitted to the same protocol, with the replacement of 6-OHDA by 0.9% saline. The analysis by optical densitometry was performed to quantify the immunoreactivity intensity of GFAP, NKCC1, KCC2, Na+/K+-ATPase, TH and Cx36.
RESULTS
The 6-OHDA induced lesions in the striatum, were not followed by changes in the expression cation-chloride cotransporters and Na+/K+-ATPase, but with astrocytic reactivity in the lesioned and adjacent regions of the nigrostriatal. Moreover, the dopaminergic degeneration caused by 6-OHDA is followed by changes in the expression of connexin-36.
CONCLUSIONS
The use of the GJ blockers directly along the nigrostriatal pathways to control PD motor symptoms is conjectured. Electrophysiology of the striatum and the substantia nigra, to verify changes in neuronal synchronism, comparing brain slices of control animals and experimental models of PD, is needed.
Topics: Rats; Animals; Male; Parkinson Disease; Oxidopamine; Rats, Wistar; Chlorides; Disease Models, Animal; Adenosine Triphosphatases; Symporters
PubMed: 37480642
DOI: 10.1016/j.clinsp.2023.100242 -
Neurobiology of Disease Apr 2024A common adverse effect of Parkinson's disease (PD) treatment is L-dopa-induced dyskinesia (LID). This condition results from both dopamine (DA)-dependent and...
A common adverse effect of Parkinson's disease (PD) treatment is L-dopa-induced dyskinesia (LID). This condition results from both dopamine (DA)-dependent and DA-independent mechanisms, as glutamate inputs from corticostriatal projection neurons impact DA-responsive medium spiny neurons in the striatum to cause the dyskinetic behaviors. In this study, we explored whether suppression of presynaptic corticostriatal glutamate inputs might affect the behavioral and biochemical outcomes associated with LID. We first established an animal model in which 6-hydroxydopamine (6-OHDA)-lesioned mice were treated daily with L-dopa (10 mg/kg, i.p.) for 2 weeks; these mice developed stereotypical abnormal involuntary movements (AIMs). When the mice were pretreated with the NMDA antagonist, amantadine, we observed suppression of AIMs and reductions of phosphorylated ERK1/2 and NR2B in the striatum. We then took an optogenetic approach to manipulate glutamatergic activity. Slc17a6 (vGluT2)-Cre mice were injected with pAAV5-Ef1a-DIO-eNpHR3.0-mCherry and received optic fiber implants in either the M1 motor cortex or dorsolateral striatum. Optogenetic inactivation at either optic fiber implant location could successfully reduce the intensity of AIMs after 6-OHDA lesioning and L-dopa treatment. Both optical manipulation strategies also suppressed phospho-ERK1/2 and phospho-NR2B signals in the striatum. Finally, we performed intrastriatal injections of LDN 212320 in the dyskenesic mice to enhance expression of glutamate uptake transporter GLT-1. Sixteen hours after the LDN 212320 treatment, L-dopa-induced AIMs were reduced along with the levels of striatal phospho-ERK1/2 and phospho-NR2B. Together, our results affirm a critical role of corticostriatal glutamate neurons in LID and strongly suggest that diminishing synaptic glutamate, either by suppression of neuronal activity or by upregulation of GLT-1, could be an effective approach for managing LID.
Topics: Rats; Mice; Animals; Levodopa; Parkinson Disease; Oxidopamine; Glutamic Acid; Rats, Sprague-Dawley; Dopamine; Corpus Striatum; Dyskinesias; Disease Models, Animal; Antiparkinson Agents
PubMed: 38401650
DOI: 10.1016/j.nbd.2024.106452 -
Brain Stimulation 2024This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the development of systemic lupus erythematosus (SLE) in...
Locus coeruleus tyrosine hydroxylase positive neurons mediated the peripheral and central therapeutic effects of transcutaneous auricular vagus nerve stimulation (taVNS) in MRL/lpr mice.
OBJECTIVE
This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the development of systemic lupus erythematosus (SLE) in MRL/lpr mice.
METHODS
MRL/lpr mice were treated with taVNS for ten weeks. Locus coeruleus (LC) tyrosine hydroxylase positive (TH) neurons were selectively lesioned by stereotactic injection of 6-hydroxydopamine (6-OHDA) or selectively activated by chemogenetic methods. Sympathetic denervation was conducted by intraperitoneal injection of 6-OHDA.
RESULTS
TaVNS activated the TH neurons in LC. TaVNS produced central therapeutic effects by reducing the number of hippocampal microglia, and increasing the number of surviving LC TH neurons in MRL/lpr mice. TaVNS also retarded the development of lymphadenectasis and splenomegaly, decreased the proportion of double-negative T (DNT) cells, and alleviated nephritis in MRL/lpr mice. The lesion of LC TH neurons eliminated both these central and peripheral therapeutic effects of taVNS, while chemogenetic activation of LC TH neurons mimicked most central and peripheral protective effects of taVNS in MRL/lpr mice. Furthermore, taVNS regulated the autonomic nervous system in MRL/lpr mice.
CONCLUSION
This study provides direct evidence that taVNS can retard the development of peripheral and central symptoms of SLE, which is mediated by the LC TH neurons.
Topics: Mice; Animals; Locus Coeruleus; Tyrosine 3-Monooxygenase; Vagus Nerve Stimulation; Mice, Inbred MRL lpr; Oxidopamine; Transcutaneous Electric Nerve Stimulation; Lupus Erythematosus, Systemic; Neurons; Vagus Nerve
PubMed: 38145753
DOI: 10.1016/j.brs.2023.12.008 -
ELife Apr 2024Midbrain dopamine (mDA) neurons comprise diverse cells with unique innervation targets and functions. This is illustrated by the selective sensitivity of mDA neurons of...
Midbrain dopamine (mDA) neurons comprise diverse cells with unique innervation targets and functions. This is illustrated by the selective sensitivity of mDA neurons of the substantia nigra compacta (SNc) in patients with Parkinson's disease, while those in the ventral tegmental area (VTA) are relatively spared. Here, we used single nuclei RNA sequencing (snRNA-seq) of approximately 70,000 mouse midbrain cells to build a high-resolution atlas of mouse mDA neuron diversity at the molecular level. The results showed that differences between mDA neuron groups could best be understood as a continuum without sharp differences between subtypes. Thus, we assigned mDA neurons to several 'territories' and 'neighborhoods' within a shifting gene expression landscape where boundaries are gradual rather than discrete. Based on the enriched gene expression patterns of these territories and neighborhoods, we were able to localize them in the adult mouse midbrain. Moreover, because the underlying mechanisms for the variable sensitivities of diverse mDA neurons to pathological insults are not well understood, we analyzed surviving neurons after partial 6-hydroxydopamine (6-OHDA) lesions to unravel gene expression patterns that correlate with mDA neuron vulnerability and resilience. Together, this atlas provides a basis for further studies on the neurophysiological role of mDA neurons in health and disease.
Topics: Adult; Humans; Animals; Mice; Dopaminergic Neurons; Gene Expression Profiling; Parkinsonian Disorders; Ascomycota; Mesencephalon; Oxidopamine
PubMed: 38587883
DOI: 10.7554/eLife.89482 -
International Journal of Molecular... Jul 2023Parkinson's-disease (PD) is an incurable, age-related neurodegenerative disease, and its global prevalence of disability and death has increased exponentially. Although...
Parkinson's-disease (PD) is an incurable, age-related neurodegenerative disease, and its global prevalence of disability and death has increased exponentially. Although motor symptoms are the characteristic manifestations of PD, the clinical spectrum also contains a wide variety of non-motor symptoms, which are the main cause of disability and determinants of the decrease in a patient's quality of life. Noteworthy in this regard is the stress on the cardiac system that is often observed in the course of PD; however, its effects have not yet been adequately researched. Here, an untargeted metabolomics approach was used to assess changes in cardiac metabolism in the 6-hydroxydopamine model of PD. Beta-sitosterol, campesterol, cholesterol, monoacylglycerol, α-tocopherol, stearic acid, beta-glycerophosphoric acid, o-phosphoethanolamine, myo-inositol-1-phosphate, alanine, valine and allothreonine are the metabolites that significantly discriminate parkinsonian rats from sham counterparts. Upon analysis of the metabolic pathways with the aim of uncovering the main biological pathways involved in concentration patterns of cardiac metabolites, the biosynthesis of both phosphatidylethanolamine and phosphatidylcholine, the glucose-alanine cycle, glutathione metabolism and plasmalogen synthesis most adequately differentiated sham and parkinsonian rats. Our results reveal that both lipid and energy metabolism are particularly involved in changes in cardiac metabolism in PD. These results provide insight into cardiac metabolic signatures in PD and indicate potential targets for further investigation.
Topics: Rats; Animals; Parkinson Disease; Oxidopamine; Neurodegenerative Diseases; Quality of Life; Alanine
PubMed: 37569578
DOI: 10.3390/ijms241512202 -
Clinics (Sao Paulo, Brazil) 2023Although reduced life expectancy in Parkinson's Disease (PD) patients has been related to severe cardiac arrhythmias due to autonomic dysfunctions, its molecular...
AIMS
Although reduced life expectancy in Parkinson's Disease (PD) patients has been related to severe cardiac arrhythmias due to autonomic dysfunctions, its molecular mechanisms remain unclear. To investigate the role of cardiac β-Adrenergic (βAR) and A-Adenosine (AR) receptors in these dysfunctions, the pharmacological effects of stimulation of cardiac βAR (isoproterenol, ISO), in the absence and presence of cardiac βAR (atenolol, AT) or AR (1,3-dipropyl-8-cyclopentyl xanthine, DPCPX) blockade, on the arrhythmias induced by Ischemia/Reperfusion (CIR) in an animal PD model were studied.
METHODS
PD was produced by dopaminergic lesions (confirmed by immunohistochemistry analysis) caused by the injection of 6-hydroxydopamine (6-OHDA, 6 μg) in rat striatum. CIR was produced by a surgical interruption for 10 min followed by reestablishment of blood circulation in the descendent left coronary artery. On the incidence of CIR-Induced Ventricular Arrhythmias (VA), Atrioventricular Block (AVB), and Lethality (LET), evaluated by Electrocardiogram (ECG) analysis, the effects of intravenous treatment with ISO, AT and DPCPX (before CIR) were studied.
RESULTS
VA, AVB and LET incidences were significantly higher in 6-OHDA (83%, 92%, 100%, respectively) than in control rats (58%, 67% and 67%, respectively). ISO treatment significantly reduced these incidences in 6-OHDA (33%, 33% and 42%, respectively) and control rats (25%, 25%, 33%, respectively), indicating that stimulation of cardiac βAR induced cardioprotection. This response was prevented by pretreatment with AT and DPCPX, confirming the involvement of cardiac βAR and AR.
CONCLUSION
Pharmacological modulation of cardiac βAR and AR could be a potential therapeutic strategy to reduce severe arrhythmias and increase life expectancy in PD patients.
Topics: Rats; Animals; Adrenergic Agents; Parkinson Disease; Oxidopamine; Arrhythmias, Cardiac; Receptors, Purinergic P1
PubMed: 37459671
DOI: 10.1016/j.clinsp.2023.100243 -
Acta Neuropathologica Communications Jan 2024Parthanatos represents a critical molecular aspect of Parkinson's disease, wherein AIMP2 aberrantly activates PARP-1 through direct physical interaction. Although AIMP2...
BACKGROUND
Parthanatos represents a critical molecular aspect of Parkinson's disease, wherein AIMP2 aberrantly activates PARP-1 through direct physical interaction. Although AIMP2 ought to be a therapeutic target for the disease, regrettably, it is deemed undruggable due to its non-enzymatic nature and predominant localization within the tRNA synthetase multi-complex. Instead, AIMP2 possesses an antagonistic splice variant, designated DX2, which counteracts AIMP2-induced apoptosis in the p53 or inflammatory pathway. Consequently, we examined whether DX2 competes with AIMP2 for PARP-1 activation and is therapeutically effective in Parkinson's disease.
METHODS
The binding affinity of AIMP2 and DX2 to PARP-1 was contrasted through immunoprecipitation. The efficacy of DX2 in neuronal cell death was assessed under 6-OHDA and H2O2 in vitro conditions. Additionally, endosomal and exosomal activity of synaptic vesicles was gauged in AIMP2 or DX2 overexpressed hippocampal primary neurons utilizing optical live imaging with VAMP-vGlut1 probes. To ascertain the role of DX2 in vivo, rotenone-induced behavioral alterations were compared between wild-type and DX2 transgenic animals. A DX2-encoding self-complementary adeno-associated virus (scAAV) was intracranially injected into 6-OHDA induced in vivo animal models, and their mobility was examined. Subsequently, the isolated brain tissues were analyzed.
RESULTS
DX2 translocates into the nucleus upon ROS stress more rapidly than AIMP2. The binding affinity of DX2 to PARP-1 appeared to be more robust compared to that of AIMP2, resulting in the inhibition of PARP-1 induced neuronal cell death. DX2 transgenic animals exhibited neuroprotective behavior in rotenone-induced neuronal damage conditions. Following a single intracranial injection of AAV-DX2, both behavior and mobility were consistently ameliorated in neurodegenerative animal models induced by 6-OHDA.
CONCLUSION
AIMP2 and DX2 are proposed to engage in bidirectional regulation of parthanatos. They physically interact with PARP-1. Notably, DX2's cell survival properties manifest exclusively in the context of abnormal AIMP2 accumulation, devoid of any tumorigenic effects. This suggests that DX2 could represent a distinctive therapeutic target for addressing Parkinson's disease in patients.
Topics: Animals; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Nuclear Proteins; Hydrogen Peroxide; Oxidopamine; Parkinson Disease; Parthanatos; Rotenone; Cell Line, Tumor
PubMed: 38172953
DOI: 10.1186/s40478-023-01697-5 -
Pharmacology Research & Perspectives Oct 2023The importance of vesicular monoamine transporter 2 (VMAT2) in dopamine regulation, which is considered crucial for neuropsychiatric disorders, is currently being...
The importance of vesicular monoamine transporter 2 (VMAT2) in dopamine regulation, which is considered crucial for neuropsychiatric disorders, is currently being studied. Moreover, the development of disease treatments using histone deacetylase (HDAC) inhibitors (HDACi) is actively progressing in various fields. Recently, research on the possibility of regulating neuropsychiatric disorders has been conducted. In this study, we evaluated whether VMAT2 expression increased by an HDACi can fine-tune neuropsychotic behavior, such as attention deficit hyperactivity disorder (ADHD) and protect against the cell toxicity through oxidized dopamine. First, approximately 300 candidate HDACi compounds were added to the SH-SY5Y dopaminergic cell line to identify the possible changes in the VMAT2 expression levels, which were measured using quantitative polymerase chain reaction. The results demonstrated, that treatment with pimelic diphenylamide 106 (TC-H 106), a class I HDACi, increased VMAT2 expression in both the SH-SY5Y cells and mouse brain. The increased VMAT2 expression induced by TC-H 106 alleviated the cytotoxicity attributed to 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP ) and free dopamine treatment. Moreover, dopamine concentrations, both intracellularly and in the synaptosomes, were significantly elevated by increased VMAT2 expression. These results suggest that dopamine concentration regulation by VMAT2 expression induced by TC-H 106 could alter several related behavioral aspects that was confirmed by attenuation of hyperactivity and impulsivity, which were major characteristics of animal model showing ADHD-like behaviors. These results indicate that HDACi-increased VMAT2 expression offers sufficient protections against dopaminergic cell death induced by oxidative stress. Thus, the epigenetic approach could be considered as therapeutic candidate for neuropsychiatric disease regulation.
Topics: Humans; Animals; Mice; Histone Deacetylase Inhibitors; Vesicular Monoamine Transport Proteins; Cytoprotection; Dopamine; Neuroblastoma; Oxidopamine
PubMed: 37740715
DOI: 10.1002/prp2.1135 -
CNS Neuroscience & Therapeutics Feb 2024Induced pluripotent stem cells (iPSCs) hold a promising potential for rescuing dopaminergic neurons in therapy for Parkinson's disease (PD). This study clarifies a...
TREM2 gene induces differentiation of induced pluripotent stem cells into dopaminergic neurons and promotes neuronal repair via TGF-β activation in 6-OHDA-lesioned mouse model of Parkinson's disease.
OBJECTIVE
Induced pluripotent stem cells (iPSCs) hold a promising potential for rescuing dopaminergic neurons in therapy for Parkinson's disease (PD). This study clarifies a TREM2-dependent mechanism explaining the function of iPSC differentiation in neuronal repair of PD.
METHODS
PD-related differentially expressed genes were screened by bioinformatics analyses and their expression was verified using RT-qPCR in nigral tissues of 6-OHDA-lesioned mice. Following ectopic expression and depletion experiments in iPSCs, cell differentiation into dopaminergic neurons as well as the expression of dopaminergic neuronal markers TH and DAT was measured. Stereotaxic injection of 6-OHDA was used to develop a mouse model of PD, which was injected with iPSC suspension overexpressing TREM2 to verify the effect of TREM2 on neuronal repair.
RESULTS
TREM2 was poorly expressed in the nigral tissues of 6-OHDA-lesioned mice. In the presence of TREM2 overexpression, the iPSCs showed increased expression of dopaminergic neuronal markers TH and DAT, which facilitated the differentiation of iPSCs into dopaminergic neurons. Mechanistic investigations indicated that TREM2 activated the TGF-β pathway and induced iPSC differentiation into dopaminergic neurons. In vivo data showed that iPSCs overexpressing TREM2 enhanced neuronal repair in 6-OHDA-lesioned mice.
CONCLUSION
This work identifies a mechanistic insight for TREM2-mediated TGF-β activation in the regulation of neuronal repair in PD and suggests novel strategies for neurodegenerative disorders.
Topics: Animals; Mice; Cell Differentiation; Disease Models, Animal; Dopaminergic Neurons; Induced Pluripotent Stem Cells; Oxidopamine; Parkinson Disease; Transforming Growth Factor beta
PubMed: 38348765
DOI: 10.1111/cns.14630 -
Neuroscience Letters Nov 2023Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopamine (DA) neurons and the presence of alpha-synuclein (αSyn)-positive Lewy body (LB)...
Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopamine (DA) neurons and the presence of alpha-synuclein (αSyn)-positive Lewy body (LB) pathology. In this study, we attempted to recapitulate both these features in a novel in vitro model for PD. To achieve this, we combined the αSyn pre-formed fibril (PFF)-seeded LB-like pathology with 6-hydroxydopamine (6-OHDA)-induced mitochondrial toxicity in mouse embryonic midbrain cultures. To pilot the model for therapeutics testing, we assessed the effects of cerebral dopamine neurotrophic factor (CDNF) on αSyn aggregation and neuron survival. PFF-seeded pathology did not lead to DA neuron loss even with the highest dose of PFFs. The combination of PFFs and 6-OHDA did not trigger additional neurodegeneration or LB-like pathology and instead presented DA neuron loss to a similar extent as with 6-OHDA only. CDNF did not affect the PFF-seeded αSyn pathology or the DA neuron survival in the combination model but showed a trend toward neuroprotection in the 6-OHDA-only cultures.
Topics: Mice; Animals; alpha-Synuclein; Oxidopamine; Dopamine; Feasibility Studies; Parkinson Disease; Synucleinopathies; Nerve Degeneration; Mesencephalon
PubMed: 37802418
DOI: 10.1016/j.neulet.2023.137510