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Brain Research Jul 2023L-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to L-DOPA-induced dyskinesia (LID). LID involves a complex...
L-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to L-DOPA-induced dyskinesia (LID). LID involves a complex interaction between the remaining dopamine (DA) system and the semi-homologous serotonin (5-HT) system. Since serotonin transporters (SERT) have some affinity for DA uptake, they may serve as a functional compensatory mechanism when DA transporters (DAT) are scant. DAT and SERT's functional contributions in the dyskinetic brain have not been well delineated. The current investigation sought to determine how DA depletion and L-DOPA treatment affect DAT and SERT transcriptional processes, translational processes, and functional DA uptake in the 6-hydroxydopamine-lesioned hemi-parkinsonian rat. Rats were counterbalanced for motor impairment into equally lesioned treatment groups then given daily L-DOPA (0 or 6 mg/kg) for 2 weeks. At the end of treatment, the substantia nigra was processed for tyrosine hydroxylase (TH) and DAT gene expression and dorsal raphe was processed for SERT gene expression. The striatum was processed for synaptosomal DAT and SERT protein expression and ex vivo DA uptake. Nigrostriatal DA loss severely reduced DAT mRNA and protein expression in the striatum with minimal changes in SERT. L-DOPA treatment, while not significantly affecting DAT or SERT alone, did increase striatal SERT:DAT protein ratios. Using ex vivo microdialysis, L-DOPA treatment increased DA uptake via SERT when DAT was depleted. Overall, these results suggest that DA loss and L-DOPA treatment uniquely alter DAT and SERT, revealing implications for monoamine transporters as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.
Topics: Rats; Animals; Levodopa; Serotonin Plasma Membrane Transport Proteins; Serotonin; Gain of Function Mutation; Rats, Sprague-Dawley; Dopamine; Corpus Striatum; Parkinson Disease; Oxidopamine
PubMed: 37127174
DOI: 10.1016/j.brainres.2023.148381 -
European Journal of Pharmaceutical... Mar 2024Parkinson's disease is the second most prevalent age-related neurodegenerative disease and disrupts the lives of people aged >60 years. Meanwhile, single-target drugs...
Parkinson's disease is the second most prevalent age-related neurodegenerative disease and disrupts the lives of people aged >60 years. Meanwhile, single-target drugs becoming inapplicable as PD pathogenesis diversifies. Mitochondrial dysfunction and neurotoxicity have been shown to be relevant to the pathogenesis of PD. The novel synthetic compound J24335 (11-Hydroxy-1-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-one oxime), which has been researched similarly to J2326, has the potential to be a multi-targeted drug and alleviate these lesions. Therefore, we investigated the mechanism of action and potential neuroprotective function of J24335 against 6-OHDA-induced neurotoxicity in mice, and in PC12 cell models. The key target of action of J24335 was also screened. MTT assay, LDH assay, flow cytometry, RT-PCR, LC-MS, OCR and ECAR detection, and Western Blot analysis were performed to characterize the neuroprotective effects of J24335 on PC12 cells and its potential mechanism. Behavioral tests and immunohistochemistry were used to evaluate behavioral changes and brain lesions in mice. Moreover, bioinformatics was employed to assess the drug-likeness of J24335 and screen its potential targets. J24335 attenuated the degradation of mitochondrial membrane potential and enhanced glucose metabolism and mitochondrial biosynthesis to ameliorate 6-OHDA-induced mitochondrial dysfunction. Animal behavioral tests demonstrated that J24335 markedly improved motor function and loss of TH-positive neurons and dopaminergic nerve fibers, and contributed to an increase in the levels of dopamine and its metabolites in brain tissue. The activation of both the CREB/PGC-1α/NRF-1/TFAM and PKA/Akt/GSK-3β pathways was a major contributor to the neuroprotective effects of J24335. Furthermore, bioinformatics predictions revealed that J24335 is a low toxicity and highly BBB permeable compound targeting 8 key genes (SRC, EGFR, ERBB2, SYK, MAPK14, LYN, NTRK1 and PTPN1). Molecular docking suggested a strong and stable binding between J24335 and the 8 core targets. Taken together, our results indicated that J24335, as a multi-targeted neuroprotective agent with promising therapeutic potential for PD, could protect against 6-OHDA-induced neurotoxicity via two potential pathways in mice and PC12 cells.
Topics: Humans; Rats; Mice; Animals; Oxidopamine; Neuroprotective Agents; PC12 Cells; Neurodegenerative Diseases; Glycogen Synthase Kinase 3 beta; Molecular Docking Simulation; Dopamine; Mitochondrial Diseases; Dopaminergic Neurons
PubMed: 38199443
DOI: 10.1016/j.ejps.2024.106696 -
Brain Research Feb 2024Parkinson's disease (PD) is the most prevalent disorder of the basal ganglia, propagated by the degeneration of axon terminals within the striatum and subsequent loss of...
INTRODUCTION
Parkinson's disease (PD) is the most prevalent disorder of the basal ganglia, propagated by the degeneration of axon terminals within the striatum and subsequent loss of dopaminergic neurons in the substantia nigra (SN). Exposure of environmental neurotoxins and mutations of several mitochondrial and proteasomal genes are primarily responsible.
METHODS
To determine whether signal transducer and activator of transcription 3 (STAT3) could protect dopaminergic neurons against degeneration, we first screened it in the in vitro capacity using immortalized rat dopaminergic N27 cells under 6-OHDA neurotoxicity. We then evaluated the effectiveness of constitutively active (ca) STAT3 as a neuroprotective agent on N27 cells in a 6-hydroxydopamine (6-OHDA) induced rat model of PD and compared it to control animals or animals where AAV/caRheb was expressed in SN. Behavioral outcomes were assessed using rotational and cylinder assays and mitochondrial function using reactive oxygen species (ROS) levels.
RESULTS
Using flow cytometry, the in vitro analysis determined caSTAT3 significantly decreased dopaminergic neuronal death under 6-OHDA treatment conditions. Importantly, in vivo overexpression of caSTAT3 in SN dopaminergic neurons using AAV-mediated expression demonstrated significant neuroprotection of dopaminergic neurons following 6-OHDA. Both caSTAT3 and caRheb + caSTAT3 co-injection into substantia nigra reduced D-amphetamine-induced rotational behavior and increased ipsilateral forelimb function when compared to control animals. In addition, caSTAT3 decreased mitochondrial ROS production following 6-OHDA induced neurotoxicity.
CONCLUSION
caSTAT3 confers resistance against ROS production in mitochondria of susceptible SN dopaminergic neurons potentially offering a new avenue for treatment against PD.
Topics: Rats; Animals; Parkinson Disease; Dopaminergic Neurons; Oxidopamine; Rats, Sprague-Dawley; Reactive Oxygen Species; STAT3 Transcription Factor; Disease Models, Animal; Substantia Nigra; Neuroprotective Agents
PubMed: 38030102
DOI: 10.1016/j.brainres.2023.148691 -
Molecular Metabolism Jul 2023Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of...
OBJECTIVE
Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model.
METHODS
Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals.
RESULTS
Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus.
CONCLUSIONS
Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.
Topics: Rats; Humans; Male; Animals; Rodentia; Oxidopamine; Rats, Sprague-Dawley; Body Weight; Weight Loss; Gastrectomy; Glucose; Energy Metabolism
PubMed: 37187239
DOI: 10.1016/j.molmet.2023.101739 -
Neuropharmacology Oct 2023The anteroventral bed nucleus of the stria terminalis (avBNST) is widely acknowledged as a key brain structure that regulates negative emotional states, such as anxiety....
The α1 and γ2 subunit-containing GABA receptor-mediated inhibitory transmission in the anteroventral bed nucleus of stria terminalis is involved in the regulation of anxiety in rats with substantia nigra lesions.
The anteroventral bed nucleus of the stria terminalis (avBNST) is widely acknowledged as a key brain structure that regulates negative emotional states, such as anxiety. At present, it is still unclear whether GABA receptor-mediated inhibitory transmission in the avBNST is involved in Parkinson's disease (PD)-related anxiety. In this study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in rats induced anxiety-like behaviors, increased GABA synthesis and release, and upregulated expression of GABA receptor subunits in the avBNST, as well as decreased level of dopamine (DA) in the basolateral amygdala (BLA). In both sham and 6-OHDA rats, intra-avBNST injection of GABA receptor agonist muscimol induced the following changes: (i) anxiolytic-like responses, (ii) inhibition of the firing activity of GABAergic neurons in the avBNST, (iii) excitation of dopaminergic neurons in the ventral tegmental area (VTA) and serotonergic neurons in the dorsal raphe nucleus (DRN), and (iv) increase of DA and 5-HT release in the BLA, whereas antagonist bicuculline induced the opposite effects. Collectively, these findings suggest that degeneration of the nigrostriatal pathway enhances GABA receptor-mediated inhibitory transmission in the avBNST, which is involved in PD-related anxiety. Further, activation and blockade of avBNST GABA receptors affect the firing activity of VTA dopaminergic and DRN serotonergic neurons, and then change release of BLA DA and 5-HT, thereby regulating anxiety-like behaviors.
Topics: Rats; Animals; Receptors, GABA-A; Septal Nuclei; Serotonin; Oxidopamine; Rats, Sprague-Dawley; Anxiety; Substantia Nigra; Parkinson Disease; Dopamine; Dorsal Raphe Nucleus; gamma-Aminobutyric Acid
PubMed: 37392819
DOI: 10.1016/j.neuropharm.2023.109645 -
Cellular Signalling Jun 2024Parkinson's disease patients on chronic levodopa often suffer from motor complications, which tend to reduce their quality of life. Levodopa-induced dyskinesia (LID) is...
BACKGROUND
Parkinson's disease patients on chronic levodopa often suffer from motor complications, which tend to reduce their quality of life. Levodopa-induced dyskinesia (LID) is one of the most prevalent motor complications, often characterized by abnormal involuntary movements, and the pathogenesis of LID is still unclear but recent studies have suggested the involvement of autophagy.
METHODS
The onset of LID was mimicked by chronic levodopa treatment in a unilateral 6-hydroxydopamine (6-OHDA) -lesion rat model. Overexpression of ΔFosB in HEK293 cells to mimic the state of ΔFosB accumulation. The modulation of the AMP-activated protein kinase (AMPK)-mediated autophagy pathway using by metformin, AICAR (an AMPK activator), Compound C (an AMPK inhibitor) and chloroquine (an autophagy pathway inhibitor). The severity of LID was assessed by axial, limb, and orofacial (ALO) abnormal involuntary movements (AIMs) score and in vivo electrophysiology. The activity of AMPK pathway as well as autophagy markers and FosB-ΔFosB levels were detected by western blotting. RT-qPCR was performed to detect the transcription level of FosB-ΔFosB. The mechanism of autophagy dysfunction was further explored by immunofluorescence and transmission electron microscopy.
RESULTS
In vivo experiments demonstrated that chronic levodopa treatment reduced AMPK phosphorylation, impaired autophagosome-lysosomal fusion and caused FosB-ΔFosB accumulation in the striatum of PD rats. Long-term metformin intervention improved ALO AIMs scores as well as reduced the mean power of high gamma (hγ) oscillations and the proportion of striatal projection neurons unstable in response to dopamine for LID rats. Moreover, the intervention of metformin promoted AMPK phosphorylation, ameliorated the impairment of autophagosome-lysosomal fusion, thus, promoting FosB-ΔFosB degradation to attenuate its accumulation in the striatum of LID rats. However, the aforementioned roles of metformin were reversed by Compound C and chloroquine. The results of in vitro studies demonstrated the ability of metformin and AICAR to attenuate ΔFosB levels by promoting its degradation, while Compound C and chloroquine could block this effect.
CONCLUSIONS
In conclusion, our results suggest that long-term metformin treatment could promote ΔFosB degradation and thus attenuate the development of LID through activating the AMPK-mediated autophagy pathway. Overall, our results support the AMPK-mediated autophagy pathway as a novel therapeutic target for LID and also indicate that metformin is a promising therapeutic candidate for LID.
Topics: Humans; Rats; Animals; Levodopa; Antiparkinson Agents; AMP-Activated Protein Kinases; HEK293 Cells; Quality of Life; Dyskinesia, Drug-Induced; Proto-Oncogene Proteins c-fos; Oxidopamine; Autophagy; Chloroquine; Metformin; Disease Models, Animal
PubMed: 38432574
DOI: 10.1016/j.cellsig.2024.111125 -
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 -
Brain Research Jan 2024Parkinson's Disease (PD) is characterized by classic motor symptoms related to movement, but PD patients can experience symptoms associated with impaired autonomic...
Parkinson's Disease (PD) is characterized by classic motor symptoms related to movement, but PD patients can experience symptoms associated with impaired autonomic function, such as respiratory disturbances. Functional respiratory deficits are known to be associated with brainstem neurodegeneration in the mice model of PD induced by 6-hydroxydopamine (6-OHDA). Understanding the causes of neuronal death is essential for identifying specific targets to prevent degeneration. Many mechanisms can explain why neurons die in PD, and neuroinflammation is one of them. To test the influence of inflammation, mediated by microglia and astrocytes cells, in the respiratory disturbances associated with brainstem neurons death, we submitted wild-type (WT) and TNF receptor 1 (TNFR1) knockout male mice to the 6-OHDA model of PD. Also, male C57BL/6 animals were induced using the same PD model and treated with minocycline (45 mg/kg), a tetracycline antibiotic with anti-inflammatory properties. We show that degeneration of brainstem areas such as the retrotrapezoid nucleus (RTN) and the pre-Botzinger Complex (preBotC) were prevented in both protocols. Notably, respiratory disturbances were no longer observed in the animals where inflammation was suppressed. Thus, the data demonstrate that inflammation is responsible for the breathing impairment in the 6-OHDA-induced PD mouse model.
Topics: Humans; Mice; Animals; Male; Parkinson Disease; Oxidopamine; Receptors, Tumor Necrosis Factor, Type I; Neuroinflammatory Diseases; Mice, Inbred C57BL; Inflammation; Disease Models, Animal; Dopaminergic Neurons
PubMed: 37757967
DOI: 10.1016/j.brainres.2023.148586 -
Parkinsonism & Related Disorders Dec 2023Parkinson's disease represents a neurodegenerative condition characterized by the progressive loss of dopaminergic neurons within the Substantia Nigra pars compacta...
β-Caryophyllene decreases neuroinflammation and exerts neuroprotection of dopaminergic neurons in a model of hemiparkinsonism through inhibition of the NLRP3 inflammasome.
INTRODUCTION
Parkinson's disease represents a neurodegenerative condition characterized by the progressive loss of dopaminergic neurons within the Substantia Nigra pars compacta (SNpc), resulting in diminished dopamine levels in the striatum (STR) and chronic neuroinflammation. Recent investigations have proposed the neuroprotective potential of the endocannabinoid system in neurodegenerative disorders. β-caryophyllene (BCP) is recognized for its antioxidant and anti-inflammatory properties, attributed to its activation of the type 2 cannabinoid receptor. This study aimed to assess the neuroprotective impact of BCP on dopaminergic neurons, with a particular focus on inhibiting the NLRP3 inflammasome.
METHODS
A model of hemiparkinsonism, induced by 6-hydroxydopamine (6-OHDA), served as the experimental framework. Motor function was evaluated using the cylinder test, and inflammasome inhibition was determined by assessing the expression of NLRP3, caspase-1, and the pro-inflammatory cytokine IL-1β in both the SNpc and STR through ELISA analysis. Furthermore, the evaluation of oxidative stress was facilitated by quantifying malondialdehyde (MDA) levels in the same regions.
RESULTS
BCP treatment demonstrated significant improvements in motor dysfunction, as assessed by the cylinder test (p=0.0011) and exhibited a neuroprotective effect on dopaminergic neurons within the SNpc (p=0.0017), as well as nerve fibers in the STR (p=0.0399). In terms of its ability to inhibit the inflammasome, BCP led to decreased expression levels of NLRP3 (p=0.0401 in STR and p = 0.0139 in SNpc), caspase-1 (p=0.0004 in STR), and MDA (p=0.0085 in STR and p=0.0414 in SNpc).
CONCLUSION
These results point to BCP's potential in mitigating the motor deficit, inhibiting NLRP3 inflammasome activation, and attenuating lipid peroxidation induced by 6-OHDA.
Topics: Humans; Caspases; Disease Models, Animal; Dopaminergic Neurons; Inflammasomes; Mice, Inbred C57BL; Neuroinflammatory Diseases; Neuroprotection; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidopamine; Parkinson Disease; Mice; Animals
PubMed: 37924806
DOI: 10.1016/j.parkreldis.2023.105906 -
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