Doxycycline and its derivative, COL‐3, decrease dyskinesia induced by <scp>l</scp>‐DOPA in hemiparkinsonian rats

Bortolanza, Mariza; Nascimento, Glauce Crivelaro do; Raisman‐Vozari, Rita; Del‐Bel, Elaine

doi:10.1111/bph.15439

Cited by 26 publications

(31 citation statements)

References 72 publications

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“…DOX was also found to decrease the expression of several inflammation markers in microglial cultures activated with the bacterial inflammogen lipopolysaccharide (LPS) [8], which indicates that DOX's neuroprotective effects may be due in part to its ability to limit inflammation-related events [9,10]. The anti-inflammatory properties of DOX may also explain why this tetracycline provided relief against L-DOPA-induced dyskinesia in a PD rat model [11]. Interestingly, DOX was also found capable of preventing amyloid aggregation of α Synuclein (αS) and tau, two seeding-prone proteins involved in PD [12,13] and Alzheimer's disease [14] pathologies, respectively, suggesting that this tetracycline has the potential of a multimodal neuroprotective drug.…”

Section: Introductionmentioning

confidence: 98%

The Chemically-Modified Tetracycline COL-3 and Its Parent Compound Doxycycline Prevent Microglial Inflammatory Responses by Reducing Glucose-Mediated Oxidative Stress

Ferreira

Pereira

Francis

et al. 2021

Cells

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We used mouse microglial cells in culture activated by lipopolysaccharide (LPS) or α-synuclein amyloid aggregates (αSa) to study the anti-inflammatory effects of COL-3, a tetracycline derivative without antimicrobial activity. Under LPS or αSa stimulation, COL-3 (10, 20 µM) efficiently repressed the induction of the microglial activation marker protein Iba-1 and the stimulated-release of the pro-inflammatory cytokine TNF-α. COL-3′s inhibitory effects on TNF-α were reproduced by the tetracycline antibiotic doxycycline (DOX; 50 µM), the glucocorticoid dexamethasone, and apocynin (APO), an inhibitor of the superoxide-producing enzyme NADPH oxidase. This last observation suggested that COL-3 and DOX might also operate themselves by restraining oxidative stress-mediated signaling events. Quantitative measurement of intracellular reactive oxygen species (ROS) levels revealed that COL-3 and DOX were indeed as effective as APO in reducing oxidative stress and TNF-α release in activated microglia. ROS inhibition with COL-3 or DOX occurred together with a reduction of microglial glucose accumulation and NADPH synthesis. This suggested that COL-3 and DOX might reduce microglial oxidative burst activity by limiting the glucose-dependent synthesis of NADPH, the requisite substrate for NADPH oxidase. Coherent with this possibility, the glycolysis inhibitor 2-deoxy-D-glucose reproduced the immunosuppressive action of COL-3 and DOX in activated microglia. Overall, we propose that COL-3 and its parent compound DOX exert anti-inflammatory effects in microglial cells by inhibiting glucose-dependent ROS production. These effects might be strengthened by the intrinsic antioxidant properties of DOX and COL-3 in a self-reinforcing manner.

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Section: Introductionmentioning

confidence: 98%

The Chemically-Modified Tetracycline COL-3 and Its Parent Compound Doxycycline Prevent Microglial Inflammatory Responses by Reducing Glucose-Mediated Oxidative Stress

Ferreira

Pereira

Francis

et al. 2021

Cells

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“…Changes in these parameters may alter the kinetics of L-DOPA entering the damaged brain area, and therefore, promote the occurrence of motor complications (Westin et al, 2006). Second, activated astrocytes produce excessive proinflammatory factors (e.g., IL-1β, TNF-α, COX-2, and iNOS), which are associated with LID (Bortolanza et al, 2015(Bortolanza et al, , 2021Dos Santos Pereira et al, 2021). Third, astrocytes are chemically excitable cells that express numerous receptors (including glutamate receptors),induce synapse formation, and secrete gliotransmitters, which allows modulation of synaptic plasticity and neural excitability (Blanco-Suarez et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Histological Correlates of Neuroanatomical Changes in a Rat Model of Levodopa-Induced Dyskinesia Based on Voxel-Based Morphometry

Zhang

Chen

et al. 2021

Front. Aging Neurosci.

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Long-term therapy with levodopa (L-DOPA) in patients with Parkinson’s disease (PD) often triggers motor complications termed as L-DOPA-induced dyskinesia (LID). However, few studies have explored the pathogenesis of LID from the perspective of neuroanatomy. This study aimed to investigate macroscopic structural changes in a rat model of LID and the underlying histological mechanisms. First, we established the hemiparkinsonism rat model through stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle, followed by administration of saline (PD) or L-DOPA to induce LID. Magnetic resonance imaging (MRI) and behavioral evaluations were performed at different time points. Histological analysis was conducted to assess the correlations between MRI signal changes and cellular contributors. Voxel-based morphometry (VBM) analysis revealed progressive bilateral volume reduction in the cortical and subcortical areas in PD rats compared with the sham rats. These changes were partially reversed by chronic L-DOPA administration; moreover, there was a significant volume increase mainly in the dorsolateral striatum, substantia nigra, and piriform cortex of the lesioned side compared with that of PD rats. At the striatal cellular level, glial fibrillary acidic protein-positive (GFAP+) astrocytes were significantly increased in the lesioned dorsolateral striatum of PD rats compared with the intact side and the sham group. Prolonged L-DOPA treatment further increased GFAP levels. Neither 6-OHDA damage nor L-DOPA treatment influenced the striatal expression of vascular endothelial growth factor (VEGF). Additionally, there was a considerable increase in synapse-associated proteins (SYP, PSD95, and SAP97) in the lesioned striatum of LID rats relative to the PD rats. Golgi-Cox staining analysis of the dendritic spine morphology revealed an increased density of dendritic spines after chronic L-DOPA treatment. Taken together, our findings suggest that striatal volume changes in LID rats involve astrocyte activation, enrichment of synaptic ultrastructure and signaling proteins in the ipsilateral striatum. Meanwhile, the data highlight the enormous potential of structural MRI, especially VBM analysis, in determining the morphological phenotype of rodent models of LID.

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“…Pre-clinical studies with anti-inflammatory compounds such as corticosterone [56], cannabidiol [57,58], nitric oxide synthase inhibitors [59][60][61][62], thalidomide [63], or doxycycline [64] reduced the severity of dyskinesia in animals and were associated with a reduction in neuroinflammatory markers. Our results support future therapies based on modulating neuroinflammation.…”

Section: Metabolic Pathwaymentioning

confidence: 99%

Metabolic Profile in Plasma AND CSF of LEVODOPA-induced Dyskinesia in Parkinson’s Disease: Focus on Neuroinflammation

et al. 2021

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The existence of few biomarkers and the lack of a better understanding of the pathophysiology of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) require new approaches, as the metabolomic analysis, for discoveries. We aimed to identify a metabolic profile associated with LID in patients with PD in an original cohort and to confirm the results in an external cohort (BioFIND). In the original cohort, plasma and CSF were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. LC-MS/MS and metabolomics data analysis were used to perform untargeted metabolomics. Untargeted metabolomics data from the BioFIND cohort were analyzed. We identified a metabolic profile associated with LID in PD, composed of multiple metabolic pathways. In particular, the dysregulation of the glycosphingolipid metabolic pathway was more related to LID and was strongly associated with the severity of dyskinetic movements. Furthermore, bile acid biosynthesis metabolites simultaneously found in plasma and CSF have distinguished patients with LID from other participants. Data from the BioFIND cohort confirmed dysregulation in plasma metabolites from the bile acid biosynthesis pathway. There is a distinct metabolic profile associated with LID in PD, both in plasma and CSF, which may be associated with the dysregulation of lipid metabolism and neuroinflammation.

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Doxycycline and its derivative, COL‐3, decrease dyskinesia induced by l‐DOPA in hemiparkinsonian rats

Cited by 26 publications

References 72 publications

The Chemically-Modified Tetracycline COL-3 and Its Parent Compound Doxycycline Prevent Microglial Inflammatory Responses by Reducing Glucose-Mediated Oxidative Stress

The Chemically-Modified Tetracycline COL-3 and Its Parent Compound Doxycycline Prevent Microglial Inflammatory Responses by Reducing Glucose-Mediated Oxidative Stress

Histological Correlates of Neuroanatomical Changes in a Rat Model of Levodopa-Induced Dyskinesia Based on Voxel-Based Morphometry

Metabolic Profile in Plasma AND CSF of LEVODOPA-induced Dyskinesia in Parkinson’s Disease: Focus on Neuroinflammation

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