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PeerJ 2022We assessed whether ICT can alleviate 6-OHDA-induced cell damage inhibition of oxidative stress by evaluating the protective effect of icaritin (ICT) against...
BACKGROUND
We assessed whether ICT can alleviate 6-OHDA-induced cell damage inhibition of oxidative stress by evaluating the protective effect of icaritin (ICT) against 6-hydroxydopamine (6-OHDA)-induced MN9D cell damage and further determined the mechanism by which ICT reduces oxidative stress.
METHODS
MN9D cells were treated with 6-OHDA, to study the mechanism underlying the neuroprotective effect of ICT. MN9D cell damage was assessed by the CCK-8 assay, flow cytometry was performed to measure the content of reactive oxygen species (ROS) in cells, a superoxide dismutase (SOD) kit was used to evaluate SOD activity, and Western blotting was used to measure the expression of α-synuclein (α-Syn), Tyrosine hydroxylase (TH), nuclear factor erythroid-2 related factor 2 (Nrf2), and heme oxygenase-1 (HO-1).
RESULTS
ICT reduced damage to MN9D cells induced by 6-OHDA. ICT increased SOD activity and TH expression and reduced ROS production and α-Syn expression. ICT promoted the translocation of Nrf2 from the cytoplasm to the nucleus and further increased the protein expression of HO-1.
CONCLUSIONS
ICT protects against 6-OHDA-induced dopaminergic neuronal cell injury by attenuating oxidative stress, and the mechanism is related to modulate the activities of Nrf2, HO-1 protein, and SOD.
Topics: Dopaminergic Neurons; NF-E2-Related Factor 2; Oxidative Stress; Oxidopamine; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase; Animals; Mice; Flavonoids
PubMed: 35433120
DOI: 10.7717/peerj.13256 -
Proceedings of the National Academy of... Oct 2021In Parkinson's disease (PD), the loss of midbrain dopaminergic cells results in severe locomotor deficits, such as gait freezing and akinesia. Growing evidence indicates...
In Parkinson's disease (PD), the loss of midbrain dopaminergic cells results in severe locomotor deficits, such as gait freezing and akinesia. Growing evidence indicates that these deficits can be attributed to the decreased activity in the mesencephalic locomotor region (MLR), a brainstem region controlling locomotion. Clinicians are exploring the deep brain stimulation of the MLR as a treatment option to improve locomotor function. The results are variable, from modest to promising. However, within the MLR, clinicians have targeted the pedunculopontine nucleus exclusively, while leaving the cuneiform nucleus unexplored. To our knowledge, the effects of cuneiform nucleus stimulation have never been determined in parkinsonian conditions in any animal model. Here, we addressed this issue in a mouse model of PD, based on the bilateral striatal injection of 6-hydroxydopamine, which damaged the nigrostriatal pathway and decreased locomotor activity. We show that selective optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus in mice expressing channelrhodopsin in a Cre-dependent manner in Vglut2-positive neurons (Vglut2-ChR2-EYFP mice) increased the number of locomotor initiations, increased the time spent in locomotion, and controlled locomotor speed. Using deep learning-based movement analysis, we found that the limb kinematics of optogenetic-evoked locomotion in pathological conditions were largely similar to those recorded in intact animals. Our work identifies the glutamatergic neurons of the cuneiform nucleus as a potentially clinically relevant target to improve locomotor activity in parkinsonian conditions. Our study should open avenues to develop the targeted stimulation of these neurons using deep brain stimulation, pharmacotherapy, or optogenetics.
Topics: Animals; Biomechanical Phenomena; Corpus Striatum; Disease Models, Animal; Glutamic Acid; Light; Locomotion; Mice; Mice, Transgenic; Midbrain Reticular Formation; Neurons; Optogenetics; Oxidopamine; Parkinson Disease; Rhodopsin
PubMed: 34670837
DOI: 10.1073/pnas.2110934118 -
Current Neuropharmacology 2015Vocal communication is negatively affected by neurodegenerative diseases, such as Parkinson disease, and by aging. The neurological and sensorimotor mechanisms... (Review)
Review
Vocal communication is negatively affected by neurodegenerative diseases, such as Parkinson disease, and by aging. The neurological and sensorimotor mechanisms underlying voice deficits in Parkinson disease and aging are not well-understood. Rat ultrasonic vocalizations provide a unique behavioral model for studying communication deficits and the mechanisms underlying these deficits in these conditions. The purpose of this review was to examine the existing literature for methods using rat ultrasonic vocalization with regard to the primary disease pathology of Parkinson disease, dopamine denervation, and aging. Although only a small amount of papers were found for each of these topics, results suggest that both shared and unique acoustic deficits in ultrasonic vocalizations exist across conditions and that these acoustic deficits are due to changes in either dopamine signaling or denervation and in aging models changes to the nucleus ambiguus, at the level of the neuromuscular junction, and the composition of the vocal folds in the larynx. We conclude that ultrasonic vocalizations are a useful tool for studying biologic mechanisms underlying vocal communication deficits in neurodegenerative diseases and aging.
Topics: Adrenergic Agents; Aging; Animals; Denervation; Dopamine; Neurodegenerative Diseases; Oxidopamine; Parkinson Disease; Rats; Vocalization, Animal
PubMed: 26411763
DOI: 10.2174/1570159x1302150525122416 -
Brain Research Bulletin May 2023Alterations of electrophysiological activities, such as changed spike firing rates, reshaping the firing patterns, and aberrant frequency oscillations between the...
Alterations of electrophysiological activities, such as changed spike firing rates, reshaping the firing patterns, and aberrant frequency oscillations between the subthalamic nucleus (STN) and the primary motor cortex (M1), are thought to contribute to motor impairment in Parkinson's disease (PD). However, the alterations of electrophysiological characteristics of STN and M1 in PD are still unclear, especially under specific treadmill movement. To examine the relationship between electrophysiological activity in the STN-M1 pathway, extracellular spike trains and local field potential (LFPs) of STN and M1 were simultaneously recorded during resting and movement in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. The results showed that the identified STN neurons and M1 neurons exhibited abnormal neuronal activity after dopamine loss. The dopamine depletion altered the LFP power in STN and M1 whatever in rest or movement states. Furthermore, the enhanced synchronization of LFP oscillations after dopamine loss was found in 12-35 Hz (beta frequencies) between the STN and M1 during rest and movement. In addition, STN neurons were phase-locked firing to M1 oscillations at 12-35 Hz during rest epochs in 6-OHDA lesioned rats. The dopamine depletion also impaired the anatomical connectivity between the M1 and STN by injecting anterograde neuroanatomical tracing virus into M1 in control and PD rats. Collectively, impairment of' electrophysiological activity and anatomical connectivity in the M1-STN pathway may be the basis for dysfunction of the cortico-basal ganglia circuit, correlating with motor symptoms of PD.
Topics: Animals; Humans; Rats; Dopamine; Neural Pathways; Oxidopamine; Parkinson Disease; Subthalamic Nucleus
PubMed: 36878325
DOI: 10.1016/j.brainresbull.2023.03.002 -
Brain Research Sep 2023Physical exercise benefits Parkinson's disease (PD) patients but the mechanism is unclear. Cannabinoid receptor type 1 (CB1R) is known to be reduced in PD patients and...
Physical exercise benefits Parkinson's disease (PD) patients but the mechanism is unclear. Cannabinoid receptor type 1 (CB1R) is known to be reduced in PD patients and animal models. We test the hypothesis that binding of the CB1R inverse agonist, [H]SR141716A, is normalized by treadmill exercise in the toxin-induced 6-hydroxydopamine (6-OHDA) model of PD. Male rats had unilateral striatal injections of 6-OHDA or saline. After 15 days, half were submitted to treadmill exercise and half remained sedentary. [H]SR141716A autoradiography was performed in postmortem tissue from striatum, substantia nigra (SN) and hippocampus. There was a 41% decrease of [H]SR141716A specific binding in the ipsilateral SN of 6-OHDA-injected sedentary animals which was attenuated to 15% by exercise, when compared to saline-injected animals. No striatal differences were observed. A 30% bilateral hippocampal increase was observed in both healthy and 6-OHDA exercised groups. In addition, a positive correlation between nigral [H]SR141716A binding and nociceptive threshold was observed in PD-exercised animals (p = 0.0008), suggesting a beneficial effect of exercise in the pain associated with the model. Chronic exercise can reduce the detrimental effects of PD on nigral [H]SR141716A binding, similar to the reported reduction after dopamine replacement therapy, so should be considered as an adjunct therapy for PD.
Topics: Rats; Male; Animals; Parkinson Disease; Oxidopamine; Rats, Wistar; Drug Inverse Agonism; Rimonabant; Substantia Nigra; Corpus Striatum; Hippocampus; Receptors, Cannabinoid; Disease Models, Animal
PubMed: 37268248
DOI: 10.1016/j.brainres.2023.148436 -
Experimental Neurology Aug 2021Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor...
BACKGROUND
Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including synaptic regeneration.
OBJECTIVES
In a parkinsonian rat model, we test the hypotheses that exercise: (a) increases synaptic density and reduces neuroinflammation and (b) lowers the nociceptive threshold by increasing μ-opioid receptor expression.
METHODS
Brain autoradiography was performed on rats unilaterally injected with either 6-hydroxydopamine (6-OHDA) or saline and subjected to treadmill exercise over 5 weeks. [H]UCB-J was used to measure synaptic vesicle glycoprotein 2A (SV2A) density. Dopamine D2/3 receptor and μ-opioid receptor availability were assessed with [H]Raclopride and [H]DAMGO, respectively, while neuroinflammation was detected with the 18kDA translocator protein (TSPO) marker [H]PK11195. The nociceptive threshold was determined prior to and throughout the exercise protocol.
RESULTS
We confirmed a dopaminegic deficit with increased striatal [H]Raclopride D2/3 receptor availability and reduced nigral tyrosine hydroxylase immunoreactivity in the ipsilateral hemisphere of all 6-OHDA-injected rats. Sedentary rats lesioned with 6-OHDA showed significant reduction of ipsilateral striatal and substantia nigra [H]UCB-J binding while [H]PK11195 showed increased ipsilateral striatal neuroinflammation. Lesioned rats who exercised had higher levels of ipsilateral striatal [H]UCB-J binding and lower levels of neuroinflammation compared to sedentary lesioned rats. Striatal 6-OHDA injections reduced thalamic μ-opioid receptor availability but subsequent exercise restored binding. Exercise also raised thalamic and hippocampal SV2A synaptic density in 6-OHDA lesioned rats, accompanied by a rise in nociceptive threshold.
CONCLUSION
These data suggest that treadmill exercise protects nigral and striatal synaptic integrity in a rat lesion model of PD - possibly by promoting compensatory mechanisms. Exercise was also associated with reduced neuroinflammation post lesioning and altered opioid transmission resulting in an increased nociceptive threshold.
Topics: Animals; Brain; Exercise Test; Male; Oxidopamine; Parkinsonian Disorders; Physical Conditioning, Animal; Rats; Rats, Wistar; Synapses
PubMed: 33965411
DOI: 10.1016/j.expneurol.2021.113741 -
Neurologia (Barcelona, Spain) Oct 2017The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used to induce models of Parkinson's disease (PD). We now know that the model induced by 6-OHDA does not include all... (Review)
Review
The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used to induce models of Parkinson's disease (PD). We now know that the model induced by 6-OHDA does not include all PD symptoms, although it does reproduce the main cellular processes involved in PD, such as oxidative stress, neurodegeneration, neuroinflammation, and neuronal death by apoptosis. In this review we analyse the factors affecting the vulnerability of dopaminergic neurons as well as the close relationships between neuroinflammation, neurodegeneration, and apoptosis in the 6-OHDA model. Knowledge of the mechanisms involved in neurodegeneration and cell death in this model is the key to identifying potential therapeutic targets for PD.
Topics: Adrenergic Agents; Animals; Cells, Cultured; Disease Models, Animal; Dopaminergic Neurons; Humans; Nervous System; Oxidative Stress; Oxidopamine; Parkinson Disease; Substantia Nigra
PubMed: 26304655
DOI: 10.1016/j.nrl.2015.06.011 -
Cell Death & Disease Dec 2018Autophagy is a regulated, intracellular degradation process that delivers unnecessary or dysfunctional cargo to the lysosome. Autophagy has been viewed as an adaptive...
Autophagy is a regulated, intracellular degradation process that delivers unnecessary or dysfunctional cargo to the lysosome. Autophagy has been viewed as an adaptive survival response to various stresses, whereas in other cases, it promotes cell death. Therefore, both deficient and excessive autophagy may lead to cell death. In this study, we specifically attempted to explore whether and how dysregulated autophagy contributes to caspase-dependent neuronal cell death induced by the neurotoxin 6-hydroxydopamine (6-OHDA). Ultrastructural and biochemical analyses indicated that MN9D neuronal cells and primary cultures of cortical neurons challenged with 6-OHDA displayed typical features of autophagy. Cotreatment with chloroquine and monitoring autophagic flux by a tandem mRFP-EGFP-tagged LC3 probe indicated that the autophagic phenomena were primarily caused by dysregulated autophagic flux. Consequently, cotreatment with an antioxidant but not with a pan-caspase inhibitor significantly blocked 6-OHDA-stimulated dysregulated autophagy. These results indicated that 6-OHDA-induced generation of reactive oxygen species (ROS) played a critical role in triggering neuronal death by causing dysregulated autophagy and subsequent caspase-dependent apoptosis. The results of the MTT reduction, caspase-3 activation, and TUNEL assays indicated that pharmacological inhibition of autophagy using 3-methyladenine or deletion of the autophagy-related gene Atg5 significantly inhibited 6-OHDA-induced cell death. Taken together, our results suggest that abnormal induction of autophagic flux promotes apoptotic neuronal cell death, and that the treatments limiting dysregulated autophagy may have a strong neuroprotective potential.
Topics: Animals; Antioxidants; Apoptosis; Autophagy; Autophagy-Related Protein 5; Caspase 3; Caspase Inhibitors; Chloroquine; Humans; Mice; Neurons; Oxidopamine; Primary Cell Culture; Reactive Oxygen Species; Signal Transduction
PubMed: 30538224
DOI: 10.1038/s41419-018-1229-y -
Cells Apr 2022Intrastriatal embryonic ventral mesencephalon grafts have been shown to integrate, survive, and reinnervate the host striatum in clinical settings and in animal models...
Intrastriatal embryonic ventral mesencephalon grafts have been shown to integrate, survive, and reinnervate the host striatum in clinical settings and in animal models of Parkinson's disease. However, this ectopic location does not restore the physiological loops of the nigrostriatal pathway and promotes only moderate behavioral benefits. Here, we performed a direct comparison of the potential benefits of intranigral versus intrastriatal grafts in animal models of Parkinson's disease. We report that intranigral grafts promoted better survival of dopaminergic neurons and that only intranigral grafts induced recovery of fine motor skills and normalized cortico-striatal responses. The increase in the number of toxic activated glial cells in host tissue surrounding the intrastriatal graft, as well as within the graft, may be one of the causes of the increased cell death observed in the intrastriatal graft. Homotopic localization of the graft and the subsequent physiological cell rewiring of the basal ganglia may be a key factor in successful and beneficial cell transplantation procedures.
Topics: Animals; Brain Tissue Transplantation; Cell Transplantation; Fetal Tissue Transplantation; Mesencephalon; Oxidopamine; Parkinson Disease; Substantia Nigra
PubMed: 35406755
DOI: 10.3390/cells11071191 -
Neurobiology of Disease Oct 2013One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in... (Review)
Review
One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in patients with Parkinson's disease (PD) and in animal models such as the rat with 6-hydroxydopamine (6-OHDA)-induced lesion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, all of which are associated with severe striatal dopamine depletion. Neuronal hyper-synchronization in the beta (or any other) band is not present despite the presence of bradykinetic features in the rat and monkey models, suggesting that increased beta band power may arise when nigro-striatal lesion is advanced and that it is not an essential feature of the early parkinsonian state. Similar observations and conclusions have been previously made for increased neuronal firing rate in the subthalamic and globus pallidus pars interna nuclei. Accordingly, it is suggested that early parkinsonism may be associated with dynamic changes in basal ganglia output activity leading to reduced movement facilitation that may be an earlier feature of the parkinsonian state.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Basal Ganglia; Biological Clocks; Disease Models, Animal; Humans; Neurons; Oxidopamine; Parkinson Disease; Rats
PubMed: 23727447
DOI: 10.1016/j.nbd.2013.05.010