ABSTRACT
INTRODUCTION: Reliable diagnosis of vascular parkinsonism (VaP) in the presence of a gait hypokinesia is an issue that is encountered in geriatrics. The EVAMAR-AGEX study was focusing on the phenomenon of recurrent falls in older persons (OP) with this parkinsonian gait. The present study is focusing on the diagnosis of VaP-related parkinsonian gait by developing a diagnostic guidance model adapted to OP. METHODS: Data from baseline and the 2-year follow-up visit were used to carry out univariate analysis and calculation of odds ratios, allowing to identify relevant variables to include in the diagnostic guidance model. To evaluate the model, confusion matrices were created, evaluating true positive, false negative, false positive and true negative incidences, sensitivity and specificity, and negative and positive predictive values. RESULTS: 79 patients included 58% male; average age 81.24 years. VaP diagnosis according to Zijlmans criteria occurred in 28%; neurodegenerative parkinsonian syndromes in 72%. A 4-criteria model was established to facilitate diagnostic: lack of prior hallucinations, lack of movement disorders tremor excluded, no cognitive fluctuations, and ≥75 years of age at diagnosis. In combination of 4/4 criteria, all of them were required to disclose a specificity of 91% in the diagnosis of VaP. In combination of 3/4, in case of negative test, a negative predictive value for VaP diagnosis of 0.97 was obtained. CONCLUSION: The challenge of our tool is both to be able to rule out what is probably not a VaP and to argue what makes a VaP diagnosis probable in OP.
Subject(s)
Movement Disorders , Parkinson Disease, Secondary , Parkinsonian Disorders , Vascular Diseases , Humans , Male , Aged , Aged, 80 and over , Female , Hypokinesia/diagnosis , Hypokinesia/etiology , Parkinsonian Disorders/complications , Parkinsonian Disorders/diagnosis , Tremor/epidemiology , Gait , Parkinson Disease, Secondary/diagnosis , Parkinson Disease, Secondary/etiologyABSTRACT
Ginsenoside Rg3, extracted from Panax ginseng C.A. Meyer, has been shown to possess neuroprotective properties. The present study aims to investigate the neuroprotective effects of ginsenoside Rg3 on rotenone-induced Parkinson's disease mice. Rotenone, a mitochondrial complex I inhibitor, leads to the augmentation of reactive oxygen species production in cells. Male C57/BL6 mice were intragastrically administered rotenone (30 mg/kg) and then treated with ginsenoside Rg3 (5, 10, or 20 mg/kg). Pole, rotarod, and open field tests were performed to evaluate motor function. Ginsenoside Rg3 decreased the climbing time in the pole test (p < 0.01), whereas it increased the latency in the rotarod test (p < 0.01) and the total distance (p < 0.01) and mean speed in the open field test (p < 0.01). Ginsenoside Rg3 treatment augmented the number of tyrosine hydroxylase-positive neurons in the substantia nigra (p < 0.01), mean density of tyrosine hydroxylase-positive nerve fibers (p < 0.01), and dopamine content (p < 0.01) in the striatum and reduced the reactive oxygen species level in the substantia nigra (p < 0.01). Glutathione cysteine ligase regulatory subunit and glutathione cysteine ligase modulatory subunit expression levels were elevated in the ginsenoside Rg3 groups. Ginsenoside Rg3 also improved motor function in rotenone-induced Parkinson's disease mice. The neuroprotective effects of ginsenoside Rg3 are at least partly associated with its anti-oxidative properties via regulation of glutathione cysteine ligase modulatory subunit and glutathione cysteine ligase regulatory subunit expression.
Subject(s)
Antioxidants/pharmacology , Ginsenosides/pharmacology , Neuroprotective Agents/pharmacology , Parkinson Disease, Secondary/drug therapy , Animals , Antioxidants/therapeutic use , Disease Models, Animal , Ginsenosides/therapeutic use , Humans , Male , Mice , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/therapeutic use , Oxidative Stress/drug effects , Parkinson Disease, Secondary/etiology , Parkinson Disease, Secondary/pathology , Reactive Oxygen Species/metabolism , Rotenone/toxicity , Substantia Nigra/drug effects , Substantia Nigra/pathologyABSTRACT
Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson's disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD, some hypotheses have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients, in general, and for the PD cases reported, in particular. Given the importance of this potential connection, we present here a molecular-level mechanistic hypothesis that explains well these findings and will serve to explore the potential CNS damage in COVID-19 patients. The model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins. Our hypothesis is supported by finding 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome. The molecular-level mechanistic hypothesis presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.
Subject(s)
COVID-19/complications , Parkinson Disease, Secondary/etiology , COVID-19/metabolism , Central Nervous System/virology , Exosomes/metabolism , Humans , Lung/metabolism , Models, Theoretical , Parkinson Disease/etiology , Parkinson Disease/metabolism , Parkinson Disease/virology , Parkinson Disease, Secondary/metabolism , Parkinson Disease, Secondary/virology , Protein Interaction Maps , SARS-CoV-2/pathogenicity , Viral Proteins/metabolismABSTRACT
Parkinson's disease (PD) is a deliberately progressive neurological disorder, arises due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of dopaminergic nerves and dopamine deficiency leads to motor symptoms characterized by rigidity, tremor, and bradykinesia. Heavy metals and trace elements play various physiological and pathological roles in the nervous system. Excessive exposure to toxic metals like mercury (Hg), lead (Pb), copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), aluminium (Al), arsenic (As), cadmium(cd), and selenium (Se) cross the blood-brain barrier to enter into the brain and leads to dopaminergic neuronal degeneration. Excessive concentrations of heavy metals in the brain promote oxidative stress, mitochondrial dysfunction, and the formation of α-synuclein leads to dopaminergic neuronal damage. There is increasing evidence that heavy metals normally present in the human body in minute concentration also cause accumulation to initiate the free radical formation and affecting the basal ganglia signaling. In this review, we explored how these metals affect brain physiology and their roles in the accumulation of toxic proteins (α-synuclein and Lewy bodies). We have also discussed the metals associated with neurotoxic effects and their prevention as management of PD. Our goal is to increase the awareness of metals as players in the onset and progression of PD.
Subject(s)
Brain/pathology , Chelating Agents/therapeutic use , Free Radical Scavengers/therapeutic use , Metals, Heavy/adverse effects , Parkinson Disease, Secondary/etiology , Brain/cytology , Brain/drug effects , Chelating Agents/pharmacology , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Environmental Exposure/adverse effects , Free Radical Scavengers/pharmacology , Humans , Metals, Heavy/antagonists & inhibitors , Oxidative Stress/drug effects , Parkinson Disease, Secondary/drug therapy , Parkinson Disease, Secondary/pathology , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , alpha-Synuclein/metabolismABSTRACT
Major depressive disorder (MDD) is one of the most prevalent forms of mental illness also affecting older adults. Recent evidence suggests a relationship between MDD and neurodegenerative diseases, including Parkinson's disease (PD). Individuals with PD have a predisposition to developing MDD, and both neurobiological conditions are associated with oxidative stress. Thus, we conducted this study to investigate depressive-like behavior and oxidative stress parameters using both animal models of PD and stress. Adult Wistar rats were subjected to chronic mild stress (CMS) protocol by 40 days and then it was used 6-hydroxydopamine (6-OHDA) as a model of PD, into the striatum. The experimental groups were: Control + Sham, Stress + Sham, Control+6-OHDA, and Stress+6-OHDA. Depressive like-behavior was evaluated by the forced swimming test (FST) and spontaneous locomotor activity by open-field test. Oxidative stress parameters were measured in the striatum, hippocampus, and prefrontal cortex (PFC). The results showed effects to increase immobility and decrease climbing times in the FST in Stress + Sham, Control+6-OHDA, and Stress+6-OHDA groups. The number of crossings and rearings were decreased in the Stress+6-OHDA group. The lipid peroxidation was increased in the PFC of Stress + Sham, and the hippocampus and striatum of Stress + Sham and Control+6-OHDA groups. Carbonyl protein levels increased in the PFC of Stress + Sham and striatum in Control+6-OHDA. Nitrite/Nitrate concentration was elevated in the PFC of Stress + Sham, in the hippocampus of Control+6-OHDA, the striatum of Stress + Sham, and Control+6-OHDA groups. Myeloperoxidase (MPO) activity was increased in the PFC and hippocampus of Stress + Sham and Control+6-OHDA groups. The activity of catalase decreased in the PFC of the Stress + Sham group. The activity of the superoxide dismutase (SOD) was decreased in the PFC of the Stress + Sham group, in the hippocampus of Stress + Sham and Control+6-OHDA groups, and the striatum of Control+6-OHDA group. These findings suggest that both stress and 6-OHDA induce depressive-like behavior and oxidative stress in the brain. The joining models have little evidence of the effects. Thus these findings suggest that other pathways are involved in the common point of the pathophysiology of PD and MDD.
Subject(s)
Adrenergic Agents/pharmacology , Behavior, Animal , Brain , Depressive Disorder, Major , Oxidative Stress , Oxidopamine/pharmacology , Parkinson Disease, Secondary , Stress, Psychological/complications , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Brain/drug effects , Brain/metabolism , Brain/physiopathology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/physiopathology , Depressive Disorder, Major/chemically induced , Depressive Disorder, Major/etiology , Depressive Disorder, Major/metabolism , Depressive Disorder, Major/physiopathology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/physiopathology , Male , Oxidative Stress/drug effects , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/etiology , Parkinson Disease, Secondary/metabolism , Parkinson Disease, Secondary/physiopathology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiopathology , Rats , Rats, WistarSubject(s)
COVID-19/complications , Parkinson Disease/complications , SARS-CoV-2 , Adult , Causality , Female , Humans , Male , Middle Aged , Parkinson Disease/diagnosis , Parkinson Disease, Secondary/diagnosis , Parkinson Disease, Secondary/etiology , Time Factors , Translational Research, BiomedicalABSTRACT
Cranial dural arteriovenous fistula (cDAVF) may rarely lead to parkinsonism and rapid cognitive decline. Dysfunction of the extrapyramidal system and the thalamus, due to venous congestion of the Galenic system with subsequent parenchymal edema, is likely to represent an important pathophysiological mechanism. Here, we report a case of a 57-year-old man with a cDAVF of the straight sinus (Borden type III; DES-Zurich bridging vein shunt [BVS] type with direct, exclusive, and strained leptomeningeal venous drainage [LVD]) and subsequent edema of both thalami, the internal capsule, the hippocampi, the pallidum, and the mesencephalon. Several attempts at venous embolization were unsuccessful, and the neurological condition of the patient further deteriorated with progressive parkinsonism and intermittent episodes of loss of consciousness (KPS 30). A suboccipital mini-craniotomy was performed and the culminal vein was disconnected from the medial tentorial sinus, achieving an immediate fistula occlusion. Three-month follow-up MRI revealed complete regression of the edema. Clinically, parkinsonism remitted completely, allowing for tapering of dopaminergic medication. His cognition markedly improved in further course. The purpose of this report is to highlight the importance of rapid and complete cDAVF occlusion to reverse venous hypertension and prevent progressive clinical impairment. The review of the literature underlines the high morbidity and mortality of these patients. Microsurgical disconnection of the fistula plays an important role in the management of these patients and, surprisingly, has not been reported so far.
Subject(s)
Antiparkinson Agents/therapeutic use , Central Nervous System Vascular Malformations/surgery , Craniotomy , Neurosurgical Procedures , Parkinson Disease, Secondary/drug therapy , Central Nervous System Vascular Malformations/complications , Central Nervous System Vascular Malformations/diagnostic imaging , Cognition , Cognitive Dysfunction/etiology , Cognitive Dysfunction/psychology , Humans , Male , Middle Aged , Parkinson Disease, Secondary/diagnosis , Parkinson Disease, Secondary/etiology , Parkinson Disease, Secondary/physiopathology , Treatment OutcomeABSTRACT
The sigma 1 receptor (S1R) is widely expressed in the CNS and is mainly located on the endoplasmic reticulum. The S1R is involved in the regulation of many neurotransmission systems and, indirectly, in neurodegenerative diseases. The S1R may therefore represent an interesting neuronal biomarker in neurodegenerative diseases such as Parkinson's (PD) or Alzheimer's diseases (AD). Here we present the characterisation of the S1R-specific 18F-labelled tracer 18F-IAM6067 in two animal models and in human brain tissue. Methods: Wistar rats were used for PET-CT imaging (60 min dynamic acquisition) and metabolite analysis (1, 2, 5, 10, 20, 60 min post-injection). To verify in vivo selectivity, haloperidol, BD1047 (S1R ligand), CM398 (S2R ligand) and SB206553 (5HT2B/C antagonist) were administrated for pre-saturation studies. Excitotoxic lesions induced by intra-striatal injection of AMPA were also imaged by 18F-IAM6067 PET-CT to test the sensitivity of the methods in a well-established model of neuronal loss. Tracer brain uptake was also verified by autoradiography in rats and in a mouse model of PD (intrastriatal 6-hydroxydopamine (6-OHDA) unilateral lesion). Finally, human cortical binding was investigated by autoradiography in three groups of subjects (control subjects with Braak ≤2, and AD patients, Braak >2 & ≤4 and Braak >4 stages). Results: We demonstrate that despite rapid peripheral metabolism of 18F-IAM6067, radiolabelled metabolites were hardly detected in brain samples. Brain uptake of 18F-IAM6067 showed differences in S1R anatomical distribution, namely from high to low uptake: pons-raphe, thalamus medio-dorsal, substantia nigra, hypothalamus, cerebellum, cortical areas and striatum. Pre-saturation studies showed 79-90% blockade of the binding in all areas of the brain indicated above except with the 5HT2B/C antagonist SB206553 and S2R ligand CM398 which induced no significant blockade, indicating good specificity of 18F-IAM6067 for S1Rs. No difference between ipsi- and contralateral sides of the brain in the mouse model of PD was detected. AMPA lesion induced a significant 69% decrease in 18F-IAM6067 uptake in the globus pallidus matching the neuronal loss as measured by NeuN, but only a trend to decrease (-16%) in the caudate putamen despite a significant 91% decrease in neuronal count. Moreover, no difference in the human cortical binding was shown between AD groups and controls. Conclusion: This work shows that 18F-IAM6067 is a specific and selective S1R radiotracer. The absence or small changes in S1R detected here in animal models and human tissue warrants further investigations and suggests that S1R might not be the anticipated ideal biomarker for neuronal loss in neurodegenerative diseases such as AD and PD.
Subject(s)
Alzheimer Disease/diagnosis , Brain/diagnostic imaging , Parkinson Disease, Secondary/diagnosis , Radiopharmaceuticals/administration & dosage , Receptors, sigma/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Animals , Autoradiography , Brain/pathology , Disease Models, Animal , Female , Fluorine Radioisotopes/administration & dosage , Humans , Male , Middle Aged , Molecular Imaging/methods , Oxidopamine/administration & dosage , Oxidopamine/toxicity , Parkinson Disease, Secondary/etiology , Parkinson Disease, Secondary/pathology , Positron Emission Tomography Computed Tomography/methods , Rats , Rats, Wistar , Sigma-1 ReceptorABSTRACT
Dengue fever continues to be an important cause of morbidity and mortality in tropical and subtropical countries. A wide range of neurological manifestations including dengue encephalopathy, Guillain-Barre syndrome, acute disseminated encephalomyelitis, transverse myelitis, cranial nerve palsies, and myositis have been reported following dengue infection. But parkinsonism secondary to dengue virus infection is uncommon, with only three published case reports in adults and one in children. We describe a 13-year-old pre-morbidly normal boy, who presented with bradykinesia, bradyphonia, mask-like facies, and cogwheel rigidity while recovering from uncomplicated DF. He responded favorably to levodopa/carbidopa supplementation and had resolution of symptoms over the next 2 weeks. We also did a comparative review of all published cases of dengue-induced parkinsonism. Post-dengue, parkinsonism is uncommon, and treating clinicians should be aware of this uncommon but treatable neurological complication of a common arboviral infection.
Subject(s)
Dengue/complications , Parkinson Disease, Secondary/etiology , Adolescent , Antiparkinson Agents/therapeutic use , Brain/diagnostic imaging , Carbidopa/therapeutic use , Diffusion Magnetic Resonance Imaging , Drug Combinations , Electroencephalography , Humans , India , Levodopa/therapeutic use , Magnetic Resonance Imaging , Male , Parkinson Disease, Secondary/diagnostic imaging , Parkinson Disease, Secondary/drug therapy , Parkinson Disease, Secondary/physiopathology , Treatment OutcomeABSTRACT
Environmental neurotoxins such as paraquat (PQ), manganese, and 1-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are associated with a higher risk of Parkinson's disease (PD). These parkinsonian toxins exert certain common toxicological effects on astroglia; however, their role in the regulatory functions of astroglial secretory proteins remains unclear. In a previous study, we observed that secretogranin II (SCG2) and secretogranin III (SCG3), which are important components of the regulated secretory pathway, were elevated in PQ-activated U118 astroglia. In the current study, we used the parkinsonian toxins dopamine (DA), active metabolite of MPTP (MPP+), MnCl2, and lipopolysaccharide (LPS) as inducers, and studied the potential regulation of SCG2 and SCG3. Our results showed that all the parkinsonian toxins except LPS affected astroglial viability but did not cause apoptosis. Exposure to DA, MPP+, and MnCl2 upregulated glial fibrillary acidic protein (GFAP), a marker for astrocyte activation, and stimulated the levels of several astrocytic-derived factors. Further, DA, MPP+, and MnCl2 exposure impeded astroglial cell cycle progression. Moreover, the expression of SCG3 was elevated, while its exosecretion was inhibited in astroglia activated by parkinsonian toxins. The level of SCG2 remained unchanged. In combination with our previous findings, the results of this study indicate that SCG3 may act as a cofactor in astrocyte activation stimulated by various toxins, and the regulation of SCG3 could be involved in the toxicological mechanism by which parkinsonian toxins affect astroglia.
Subject(s)
Astrocytes/drug effects , Astrocytes/metabolism , Chromogranins/physiology , MPTP Poisoning/complications , Neurotoxins/toxicity , Parkinson Disease, Secondary/etiology , Cell Cycle/drug effects , Chlorides/adverse effects , Chlorides/toxicity , Chromogranins/metabolism , Dopamine/administration & dosage , Dopamine/toxicity , Glial Fibrillary Acidic Protein/metabolism , Humans , Manganese Compounds/adverse effects , Paraquat/toxicity , Secretogranin II/metabolism , Secretogranin II/physiology , Tumor Cells, Cultured , Up-Regulation/drug effectsSubject(s)
Apathy , Basal Ganglia Diseases/complications , Brain Neoplasms/complications , Hemangioma, Cavernous, Central Nervous System/complications , Parkinson Disease, Secondary/etiology , Aged , Basal Ganglia Cerebrovascular Disease/complications , Basal Ganglia Cerebrovascular Disease/diagnostic imaging , Basal Ganglia Diseases/diagnostic imaging , Basal Ganglia Diseases/metabolism , Brain Neoplasms/diagnostic imaging , Caudate Nucleus/diagnostic imaging , Caudate Nucleus/metabolism , Cerebral Small Vessel Diseases/complications , Cerebral Small Vessel Diseases/diagnostic imaging , Diagnosis, Differential , Disease Progression , Dopamine Plasma Membrane Transport Proteins/metabolism , Female , Hemangioma, Cavernous, Central Nervous System/diagnostic imaging , Humans , Magnetic Resonance Imaging , Parkinson Disease/diagnosis , Parkinson Disease, Secondary/diagnosis , Parkinson Disease, Secondary/drug therapy , Parkinson Disease, Secondary/metabolismSubject(s)
Basal Ganglia/diagnostic imaging , Parkinson Disease, Secondary/etiology , Sinus Thrombosis, Intracranial/complications , Sinus Thrombosis, Intracranial/diagnostic imaging , Thalamus/diagnostic imaging , Anticoagulants/administration & dosage , Basal Ganglia/pathology , Humans , Male , Middle Aged , Parkinson Disease, Secondary/drug therapy , Parkinson Disease, Secondary/physiopathology , Sinus Thrombosis, Intracranial/drug therapy , Thalamus/pathology , Tomography, X-Ray ComputedSubject(s)
Fibrinolytic Agents/pharmacology , Parkinson Disease, Secondary/etiology , Sinus Thrombosis, Intracranial/diagnostic imaging , Female , Fibrinolytic Agents/administration & dosage , Heparin/pharmacology , Humans , Magnetic Resonance Imaging , Middle Aged , Parkinson Disease, Secondary/drug therapy , Sinus Thrombosis, Intracranial/complications , Sinus Thrombosis, Intracranial/drug therapyABSTRACT
In addition to neurodegenerative disorders, there are many secondary forms of parkinsonism. The most common cause for secondary parkinsonism is the intake of distinct drugs. Neuroleptics and calcium channel blockers have been mainly described to induce parkinsonism, but also other drugs were suspected to cause or worsen parkinsonism. Another common cause for secondary parkinsonism are vascular lesions (i.e. vascular parkinsonism). Furthermore, also brain tumors have been described as rare causes for parkinsonism. Moreover, parkinsonism can be caused by chronic traumatic encephalopathy, which is a special case, since secondary insults to the brain leads to the occurrence of a neuropathologically defined disease. Other rare causes for secondary parkinsonism are lesions caused by infectious or immunological diseases as well as toxins or street drugs.
Subject(s)
Brain Injuries, Traumatic/complications , Brain Neoplasms/complications , Cerebrovascular Disorders/complications , Drug-Related Side Effects and Adverse Reactions/etiology , Parkinson Disease, Secondary/etiology , Parkinson Disease, Secondary/physiopathology , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/physiopathology , Humans , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/diagnosisABSTRACT
This study explored the influence of long non-coding RNA (lncRNA) SNHG14 on α-synuclein (α-syn) expression and Parkinson's disease (PD) pathogenesis. Firstly, we found that the expression level of SNHG14 was elevated in brain tissues of PD mice. In MN9D cells, the rotenone treatment (1µmol/L) enhanced the binding between transcriptional factor SP-1 and SNHG14 promoter, thus promoting SNHG14 expression. Interference of SNHG14 ameliorated the DA neuron injury induced by rotenone. Next, we found an interaction between SNHG14 and miR-133b. Further study showed that miR-133b down-regulated α-syn expression by targeting its 3'-UTR of mRNA and SNHG14 could reverse the negative effect of miR-133b on α-syn expression. Interference of SNHG14 reduced rotenone-induced DA neuron damage through miR-133b in MN9D cells and α-syn was responsible for the protective effect of miR-133b. Similarly, interference of SNHG14 mitigated neuron injury in PD mouse model. All in all, silence of SNHG14 mitigates dopaminergic neuron injury by down-regulating α-syn via targeting miR-133b, which contributes to improving PD.
Subject(s)
Dopaminergic Neurons , Intracellular Signaling Peptides and Proteins/metabolism , MicroRNAs/metabolism , Nerve Tissue Proteins/metabolism , Parkinson Disease, Secondary/etiology , alpha-Synuclein/metabolism , Animals , Cell Line , Disease Models, Animal , Mice, Inbred C57BL , Parkinson Disease, Secondary/metabolism , RNA, Long Noncoding/metabolism , RotenoneABSTRACT
Cerebral vascular lesions are integral to the diagnosis of vascular parkinsonism (VP). The VP, also referred to as lower body parkinsonism, is frequently caused by subcortical white matter lesions, but lesions at any levels of the nigro-striato-thalamo-cortical pathway can also cause VP, thus giving rise to various symptoms other than gait disturbance. Previous dopamine transporter imaging studies using SPECT showed heterogeneous patterns suggesting diverse contributing lesions to VP. Here we present 3 cases of VP demonstrated by F-FP-CIT PET/CT, visualizing vascular lesions at different levels between the midbrain and motor cortex. Distinctive clinical manifestations of them recapitulate the pathogenesis of VP.
Subject(s)
Brain Infarction/complications , Parkinson Disease, Secondary/diagnostic imaging , Parkinson Disease, Secondary/etiology , Positron Emission Tomography Computed Tomography , Tropanes , Aged , Female , Humans , Parkinson Disease, Secondary/pathology , Parkinson Disease, Secondary/physiopathologyABSTRACT
Environmental factors may play a critical role in the etiology and pathogenesis of Parkinson's disease (PD). However, the association of PD with specific chemical species remains largely unknown. Here we prepared three kinds of iron oxide nanoparticles and examined their cytotoxicity in a cellular model of PD. We found that lysosome-targeted nanoparticles showed significant cytotoxicity in SH-SY5Y cells. Inhibition of AMPK could aggravate the neurotoxicity of lysosome-targeted nanoparticles as well as mitochondrion-targeted nanoparticles. Alteration of mitochondrial membrane potentials was found to be in agreement with the neurotoxicity of iron nanoparticles. These results suggested an important role of AMPK in regulating iron nanoparticle-associated neurotoxicity.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Ferric Compounds/toxicity , Lysosomes/drug effects , Mitochondria/drug effects , Nanoparticles/toxicity , Parkinson Disease, Secondary/etiology , Cell Line , Humans , Lysosomes/metabolism , Lysosomes/pathology , Mitochondria/metabolism , Mitochondria/pathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Parkinson Disease, Secondary/metabolism , Parkinson Disease, Secondary/pathologyABSTRACT
Survivors of blast-induced traumatic brain injury (bTBI) have increased susceptibility to Parkinson's disease (PD), characterized by α-synuclein aggregation and the progressive degeneration of nigrostriatal dopaminergic neurons. Using an established bTBI rat model, we evaluated the changes of α-synuclein and tyrosine hydroxylase (TH), known hallmarks of PD, and acrolein, a reactive aldehyde and marker of oxidative stress, with the aim of revealing key pathways leading to PD post-bTBI. Indicated in both animal models of PD and TBI, acrolein is likely a point of pathogenic convergence. Here we show that after a single mild bTBI, acrolein is elevated up to a week, systemically in urine, and in whole brain tissue, specifically the substantia nigra and striatum. Acrolein elevation is accompanied by heightened α-synuclein oligomerization, dopaminergic dysregulation, and acrolein/α-synuclein interaction in the same brain regions. We further show that acrolein can directly modify and oligomerize α-synuclein in vitro. Taken together, our data suggests acrolein likely plays an important role in inducing PD pathology following bTBI by encouraging α-synuclein aggregation. These results are expected to advance our understanding of the long-term post-bTBI pathological changes leading to the development of PD, and suggest intervention targets to curtail such pathology.