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British Journal of Pharmacology Jun 2021l-DOPA prolonged treatment leads to disabling motor complications as dyskinesia that could be decreased by drugs acting on 5-HT receptors. Since the internal segment of...
BACKGROUND AND PURPOSE
l-DOPA prolonged treatment leads to disabling motor complications as dyskinesia that could be decreased by drugs acting on 5-HT receptors. Since the internal segment of the globus pallidus, homologous to the entopeduncular nucleus in rodents, seems to be involved in the etiopathology of l-DOPA-induced dyskinesia, we investigated whether the entopeduncular nucleus is modulated by the 5-HT receptor partial and full agonists, buspirone, and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in control and 6-hydroxydopamine (6-OHDA)-lesioned rats with or without long-term l-DOPA treatment.
EXPERIMENTAL APPROACH
Extracellular single-unit electrocorticogram and local field potential recordings under anaesthesia, immunostaining assays and optogenetic manipulation coupled to electrophysiological recordings were performed.
KEY RESULTS
Systemic buspirone reduced the entopeduncular nucleus firing rate in the sham animals and burst activity in the 6-OHDA-lesioned rats (with or without l-DOPA treatment), while local administration reduced entopeduncular nucleus activity in all the groups, regardless of DA integrity. Systemic 8-OH-DPAT also induced inhibitory effects only in the sham animals. Effects triggered by buspirone and 8-OH-DPAT were reversed by the 5-HT receptor antagonist, WAY-100635. Neither buspirone nor 8-OH-DPAT modified the low-frequency oscillatory activity in the entopeduncular nucleus or its synchronization with the motor cortex. Buspirone did not alter the response induced by subthalamic nucleus opto-stimulation in the entopeduncular nucleus.
CONCLUSION AND IMPLICATIONS
Systemic 5-HT receptor activation elicits different effects on the electrophysiological properties of the entopeduncular nucleus depending on the integrity of the nigrostriatal pathway and it does not alter the relationship between subthalamic nucleus and entopeduncular nucleus neuron activity.
Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Buspirone; Entopeduncular Nucleus; Levodopa; Oxidopamine; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A
PubMed: 33686657
DOI: 10.1111/bph.15437 -
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 -
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 -
Molecules (Basel, Switzerland) Jun 20226-hydroxydopamine (6-OHDA) is used to induce oxidative damage in neuronal cells, which can serve as an experimental model of Parkinson's disease (PD). Jujuboside A and B...
6-hydroxydopamine (6-OHDA) is used to induce oxidative damage in neuronal cells, which can serve as an experimental model of Parkinson's disease (PD). Jujuboside A and B confer free radical scavenging effects but have never been examined for their neuroprotective effects, especially in PD; therefore, in this study, we aimed to investigate the feasibility of jujubosides as protectors of neurons against 6-OHDA and the underlying mechanisms. 6-OHDA-induced neurotoxicity in the human neuronal cell lines SH-SY5Y and SK-N-SH, was used to evaluate the protective effects of jujubosides. These findings indicated that jujuboside A and B were both capable of rescuing the 6-OHDA-induced loss of cell viability, activation of apoptosis, elevation of reactive oxygen species, and downregulation of the expression levels of superoxide dismutase, catalase, and glutathione peroxidase. In addition, jujuboside A and B can reverse a 6-OHDA-elevated Bax/Bcl-2 ratio, downregulate phosphorylated PI3K and AKT, and activate caspase-3, -7, and -9. These findings showed that jujubosides were capable of protecting both SH-SY5Y and SK-N-SH neuronal cells from 6-OHDA-induced toxicity via the rebalancing of the redox system, together with the resetting of the PI3K/AKT apoptotic signaling cascade. In conclusion, jujuboside may be a potential drug for PD prevention.
Topics: Apoptosis; Cell Line, Tumor; Humans; Neuroblastoma; Neuroprotective Agents; Neurotoxicity Syndromes; Oxidopamine; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species
PubMed: 35807356
DOI: 10.3390/molecules27134106 -
The Journal of Neuroscience : the... Aug 2017Parkinson's disease and experimentally induced hemiparkinsonism are characterized by increased beta synchronization between cortical and subcortical areas. This change...
Parkinson's disease and experimentally induced hemiparkinsonism are characterized by increased beta synchronization between cortical and subcortical areas. This change in beta connectivity might reflect either a symmetric increase in interareal influences or asymmetric changes in directed influences among brain areas. We assessed patterns of functional and directed connectivity within and between striatum and six cortical sites in each hemisphere of the hemiparkinsonian rat model. LFPs were recorded in resting and walking states, before and after unilateral 6-hydroxydopamine lesion. The hemiparkinsonian state was characterized by increased oscillatory activity in the 20-40 Hz range in resting and walking states, and increased interhemispheric coupling (phase lag index) that was more widespread at rest than during walking. Spectral Granger-causality analysis revealed that the change in symmetric functional connectivity comprised profound reorganization of hierarchical organization and directed influence patterns. First, in the lesioned hemisphere, the more anterior, nonprimary motor areas located at the top of the cortical hierarchy (i.e., receiving many directed influences) tended to increase their directed influence onto the posterior primary motor and somatosensory areas. This enhanced influence of "higher" areas may be related to the loss of motor control due to the 6-OHDA lesion. Second, the drive from the nonlesioned toward the lesioned hemisphere (in particular to striatum) increased, most prominently during walking. The nature of these adaptations (disturbed signaling or compensation) is discussed. The present study demonstrates that hemiparkinsonism is associated with a profound reorganization of the hierarchical organization of directed influence patterns among brain areas, perhaps reflecting compensatory processes. Parkinson's disease classically first becomes manifest in one hemibody before affecting both sides, suggesting that degeneration is asymmetrical. Our results suggest that asymmetrical degeneration of the dopaminergic system induces an increased drive from the nonlesioned toward the lesioned hemisphere and a profound reorganization of functional cortical hierarchical organization, leading to a stronger directed influence of hierarchically higher placed cortical areas over primary motor and somatosensory cortices. These changes may represent a compensatory mechanism for loss of motor control as a consequence of dopamine depletion.
Topics: Animals; Corpus Striatum; Male; Motor Cortex; Nerve Net; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Wistar; Somatosensory Cortex
PubMed: 28687605
DOI: 10.1523/JNEUROSCI.3257-16.2017 -
Cells Sep 2023Defective autophagy is one of the cellular hallmarks of Parkinson's disease (PD). Therefore, a therapeutic strategy could be a modest enhancement of autophagic activity...
Defective autophagy is one of the cellular hallmarks of Parkinson's disease (PD). Therefore, a therapeutic strategy could be a modest enhancement of autophagic activity in dopamine (DA) neurons to deal with the clearance of damaged mitochondria and abnormal protein aggregates. Syringin (SRG) is a phenolic glycoside derived from the root of . It has antioxidant, anti-apoptotic, and anti-inflammatory properties. However, whether it has a preventive effect on PD remains unclear. The present study found that SRG reversed the increase in intracellular ROS-caused apoptosis in SH-SY5Y cells induced by neurotoxin 6-OHDA exposure. Likewise, in degeneration of DA neurons, DA-related food-sensitive behaviors, longevity, and accumulation of α-synuclein were also improved. Studies of neuroprotective mechanisms have shown that SRG can reverse the suppressed expression of SIRT1, Beclin-1, and other autophagy markers in 6-OHDA-exposed cells. Thus, these enhanced the formation of autophagic vacuoles and autophagy activity. This protective effect can be blocked by pretreatment with wortmannin (an autophagosome formation blocker) and bafilomycin A1 (an autophagosome-lysosome fusion blocker). In addition, 6-OHDA increases the acetylation of Beclin-1, leading to its inactivation. SRG can induce the expression of SIRT1 and promote the deacetylation of Beclin-1. Finally, we found that SRG reduced the 6-OHDA-induced expression of miR-34a targeting . The overexpression of miR-34a mimic abolishes the neuroprotective ability of SRG. In conclusion, SRG induces autophagy via partially regulating the miR-34a/SIRT1/Beclin-1 axis to prevent 6-OHDA-induced apoptosis and α-synuclein accumulation. SRG has the opportunity to be established as a candidate agent for the prevention and cure of PD.
Topics: Humans; Animals; Oxidopamine; Caenorhabditis elegans; alpha-Synuclein; Beclin-1; Sirtuin 1; Neuroblastoma; Autophagy; Neurotoxicity Syndromes; Parkinson Disease; MicroRNAs
PubMed: 37759532
DOI: 10.3390/cells12182310 -
International Journal of Molecular... Mar 2022With the increase in life expectancy and consequent aging of the world's population, the prevalence of many neurodegenerative diseases is increasing, without concomitant...
With the increase in life expectancy and consequent aging of the world's population, the prevalence of many neurodegenerative diseases is increasing, without concomitant improvement in diagnostics and therapeutics. These diseases share neuropathological hallmarks, including mitochondrial dysfunction. In fact, as mitochondrial alterations appear prior to neuronal cell death at an early phase of a disease's onset, the study and modulation of mitochondrial alterations have emerged as promising strategies to predict and prevent neurotoxicity and neuronal cell death before the onset of cell viability alterations. In this work, differentiated SH-SY5Y cells were treated with the mitochondrial-targeted neurotoxicants 6-hydroxydopamine and rotenone. These compounds were used at different concentrations and for different time points to understand the similarities and differences in their mechanisms of action. To accomplish this, data on mitochondrial parameters were acquired and analyzed using unsupervised (hierarchical clustering) and supervised (decision tree) machine learning methods. Both biochemical and computational analyses resulted in an evident distinction between the neurotoxic effects of 6-hydroxydopamine and rotenone, specifically for the highest concentrations of both compounds.
Topics: Apoptosis; Cell Death; Cell Line, Tumor; Cell Survival; Humans; Neuroprotective Agents; Neurotoxicity Syndromes; Oxidopamine; Rotenone
PubMed: 35328430
DOI: 10.3390/ijms23063009 -
Journal of Food and Drug Analysis Jan 2020The incidence of neurodegeneration leading to the conditions such as Alzheimer's and Parkinson's diseases are on the increase, they require the approaches that focus on...
The incidence of neurodegeneration leading to the conditions such as Alzheimer's and Parkinson's diseases are on the increase, they require the approaches that focus on protection prevention rather than treatment. Plants are rich sources of many compounds which possess medicinal properties. We sought to investigate the neuroprotective effects of Uncariahirsuta and its compounds on d-galactose-induced stress in BALB/c mice as well as 6-hydroxydopamine (6-OHDA)-induced stress in mouse nerve growth factor (mNGF)-differentiated PC12 cells. Our results demonstrate that the 95% ethanol extract of U. hirsuta reversed the d-galactose-induced learning and memory dysfunctions and decreased the malodialdehyde levels. Furthermore, the isolated compounds, 5β-carboxystrictosidine (1) and chlorogenic acid (2), protected mNGF-differentiated PC12 cells against toxicity induced by 6-OHDA by acting as antiapoptotic agents. The 50% inhibitory concentration (IC) for intracellular reactive oxygen species (ROS) scavenging was found to be 24.5 (for 1) and 19.7 μM (for 2), and both 1 and 2 reduced intracellular calcium levels with respective IC values of 46.9 and 27 μM. Interestingly, both compounds inhibited caspase 3 and 9 activities with respective IC values of 25.6 and 24.5 μM for 1 and 19.4 and 16.3 μM for 2. Our results identify U. hirsuta and its active compounds as potential neuroprotective agents and deserve further evaluation for drug development for neuroprotection in the future.
Topics: Animals; Cell Survival; Learning; Memory; Mice; Mice, Inbred BALB C; Neuroprotective Agents; Oxidative Stress; Oxidopamine; PC12 Cells; Plant Extracts; Rats; Reactive Oxygen Species; Uncaria
PubMed: 31883603
DOI: 10.1016/j.jfda.2019.10.004 -
Molecular and Cellular Neurosciences May 2022The sympathetic nervous system (SNS) regulates skeletal muscle motor innervation and stabilizes the NMJ in health, disease and aging. Previous studies using both...
The sympathetic nervous system (SNS) regulates skeletal muscle motor innervation and stabilizes the NMJ in health, disease and aging. Previous studies using both chemical (6-hydroxydopamine, 6-OHDA) and microsurgically-induced sympathetic denervation examined the NMJ organization and transmission in the mouse; however, a detailed quantification of the postterminal on larger hindlimb muscles involved in gait mechanics and posture is lacking. The purpose of this study was to determine whether targets of the sympathetic neuron (SN) exhibiting different intrinsic composition such as the fast-twitch extensor digitorum longus (EDL) and the slow-twitch soleus muscles differ in their response to SN deprivation, and to develop a strategy to accurately quantify the impact of sympathectomy on the NMJ postterminal including those fibers located deeper in the muscle. This approach included muscle fixed ex vivo or through transcardial perfusion in mice treated with 6-OHDA or control ascorbic acid. We measured NMJ postterminal mean terminal total area, number of postterminal fragments, mean fragment area, and mean distance between fragments in free-floating alpha-bungarotoxin-stained in 1038 isolated muscle fibers. We found that muscle fiber sympathetic innervation plays a crucial role in the structural organization of the motorneuron-myofiber synapse postterminal and its deprivation leads to AChR cluster dispersion or shrinking as described in various neuromuscular diseases and aging.
Topics: Animals; Mice; Motor Neurons; Muscle, Skeletal; Neuromuscular Junction; Oxidopamine; Sympathectomy
PubMed: 35489637
DOI: 10.1016/j.mcn.2022.103730 -
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