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Sökning: WFRF:(Bézard Erwan) > (2020-2023)

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1.
  • Bezard, Erwan, et al. (författare)
  • mu Opioid Receptor Agonism for L-DOPA-Induced Dyskinesia in Parkinson's Disease
  • 2020
  • Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 40:35, s. 6812-6819
  • Tidskriftsartikel (refereegranskat)abstract
    • Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine precursor L-DOPA, but its prolonged usage causes dyskinesias referred to as L-DOPA-induced dyskinesia (LID). Several studies in animal models of PD have suggested that dyskinesias are associated with a heightened opioid cotransmitter tone, observations that have led to the notion of a LID-related hyperactive opioid transmission that should be corrected by mu opioid receptor antagonists. Reports that both antagonists and agonists of the mu opioid receptor may alleviate LID severity in primate models of PD and LID, together with the failure of nonspecific antagonist to improve LID in pilot clinical trials in patients, raises doubt about the reliability of the available data on the opioid system in PD and LID. After in vitro characterization of the functional activity at the mu opioid receptor, we selected prototypical agonists, antagonists, and partial agonists at the mu opioid receptor. We then showed that both oral and discrete intracerebral administration of a mu receptor agonist, but not of an antagonist as long thought, ameliorated LIDs in the gold-standard bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinelesioned female macaque model of PD and LID. The results call for a reappraisal of opioid pharmacology in the basal ganglia as well as for the development of brain nucleus-targeted mu opioid receptor agonists.
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2.
  • Fridjonsdottir, Elva, et al. (författare)
  • Mass spectrometry imaging identifies abnormally elevated brain L-DOPA levels and extrastriatal monoaminergic dysregulation in L-DOPA-induced dyskinesia
  • 2021
  • Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:2
  • Tidskriftsartikel (refereegranskat)abstract
    • L-DOPA treatment for Parkinson's disease frequently leads to dyskinesias, the pathophysiology of which is poorly understood. We used MALDI-MSI to map the distribution of L-DOPA and monoaminergic pathways in brains of dyskinetic and nondyskinetic primates. We report elevated levels of L-DOPA, and its metabolite 3-O-methyldopa, in all measured brain regions of dyskinetic animals and increases in dopamine and metabolites in all regions analyzed except the striatum. In dyskinesia, dopamine levels correlated well with L-DOPA levels in extrastriatal regions, such as hippocampus, amygdala, bed nucleus of the stria terminalis, and cortical areas, but not in the striatum. Our results demonstrate that L-DOPA-induced dyskinesia is linked to a dysregulation of L-DOPA metabolism throughout the brain. The inability of extrastriatal brain areas to regulate the formation of dopamine during L-DOPA treatment introduces the potential of dopamine or even L-DOPA itself to modulate neuronal signaling widely across the brain, resulting in unwanted side effects.
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3.
  • Hulme, Heather, et al. (författare)
  • Basal ganglia neuropeptides show abnormal processing associated with L-DOPA-induced dyskinesia
  • 2022
  • Ingår i: NPJ PARKINSONS DISEASE. - : Springer Nature. - 2373-8057. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • L-DOPA administration is the primary treatment for Parkinson's disease (PD) but long-term administration is usually accompanied by hyperkinetic side-effects called L-DOPA-induced dyskinesia (LID). Signaling neuropeptides of the basal ganglia are affected in LID and changes in the expression of neuropeptide precursors have been described, but the final products formed from these precursors have not been well defined and regionally mapped. We therefore used mass spectrometry imaging to visualize and quantify neuropeptides in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposed parkinsonian and LID Macaca mulatta brain samples. We found that dyskinesia severity correlated with the levels of some abnormally processed peptides - notably, des-tyrosine dynorphins, substance P (1-7), and substance P (1-9) - in multiple brain regions. Levels of the active neuropeptides; dynorphin B, dynorphin A (1-8), alpha-neoendorphin, substance P (1-11), and neurokinin A, in the globus pallidus and substantia nigra correlated with putaminal levels of L-DOPA. Our results demonstrate that the abundance of selected active neuropeptides is associated with L-DOPA concentrations in the putamen, emphasizing their sensitivity to L-DOPA. Additionally, levels of truncated neuropeptides (which generally exhibit reduced or altered receptor affinity) correlate with dyskinesia severity, particularly for peptides associated with the direct pathway (i.e., dynorphins and tachykinins). The increases in tone of the tachykinin, enkephalin, and dynorphin neuropeptides in LID result in abnormal processing of neuropeptides with different biological activity and may constitute a functional compensatory mechanism for balancing the increased L-DOPA levels across the whole basal ganglia.
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4.
  • Hulme, Heather, et al. (författare)
  • Simultaneous mass spectrometry imaging of multiple neuropeptides in the brain and alterations induced by experimental parkinsonism and L-DOPA therapy
  • 2020
  • Ingår i: Neurobiology of Disease. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0969-9961 .- 1095-953X. ; 137
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuropeptides are important signalling molecules in the brain and alterations in their expression levels have been linked to neurological disorders such as Parkinson's disease. It is challenging to map neuropeptide changes across and within brain regions because of their low in vivo concentrations and complex post-translational processing. Consequently, the role of neuropeptides in Parkinson's disease is not well understood. Thus, we have developed and evaluated a method to image multiple neuropeptides simultaneously in both rat and primate brain tissue sections by matrix-assisted laser desorption/ionisation mass spectrometry imaging at high lateral resolution. Using a unilateral 6-hydroxydopamine rat model of Parkinson's disease, we imaged changes in enkephalins, dynorphins, tachykinins and neurotensin associated with the dopaminergic denervation and L-DOPA treatment in multiple brain regions. L-DOPA administration significantly affected neuropeptides in the globus pallidus, while neuropeptides in the caudate-putamen were mostly affected by dopamine depletion. Using high lateral resolution imaging, we observed an increase of neurotensin in the dorsal sub-region of the globus pallidus after dopamine depletion. This study highlights the capacity of mass spectrometry imaging to elucidate the dynamics of neuropeptide signalling during Parkinson's disease and its treatment.
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5.
  • Kaya, Ibrahim, et al. (författare)
  • On-Tissue Chemical Derivatization for Comprehensive Mapping of Brain Carboxyl and Aldehyde Metabolites by MALDI-MS Imaging
  • 2023
  • Ingår i: Journal of the American Society for Mass Spectrometry. - : American Chemical Society (ACS). - 1044-0305 .- 1879-1123. ; 34:5, s. 836-846
  • Tidskriftsartikel (refereegranskat)abstract
    • The visualization of small metabolites by MALDI mass spectrometry imaging in brain tissue sections is challenging due to low detection sensitivity and high background interference. We present an on-tissue chemical derivatization MALDI mass spectrometry imaging approach for the comprehensive mapping of carboxyls and aldehydes in brain tissue sections. In this approach, the AMPP (1-(4-(aminomethyl)phenyl)pyridin-1-ium chloride) derivatization reagent is used for the covalent charge-tagging of molecules containing carboxylic acid (in the presence of peptide coupling reagents) and aldehydes. This includes free fatty acids and the associated metabolites, fatty aldehydes, dipeptides, neurotoxic reactive aldehydes, amino acids, neurotransmitters and associated metabolites, as well as tricarboxylic acid cycle metabolites. We performed sensitive ultrahigh mass resolution MALDI-MS detection and imaging of various carboxyl-and aldehyde containing endogenous metabolites simultaneously in rodent brain tissue sections. We verified the AMPP-derivatized metabolites by tandem MS for structural elucidation. This approach allowed us to image numerous aldehydes and carboxyls, including certain metabolites which had been undetectable in brain tissue sections. We also demonstrated the application of on-tissue derivatization to carboxyls and aldehydes in coronal brain tissue sections of a nonhuman primate Parkinson's disease model. Our methodology provides a powerful tool for the sensitive, simultaneous spatial molecular imaging of numerous aldehydes and carboxylic acids during pathological states, including neurodegeneration, in brain tissue.
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6.
  • Kaya, Ibrahim, et al. (författare)
  • Spatial lipidomics reveals brain region-specific changes of sulfatides in an experimental MPTP Parkinson's disease primate model
  • 2023
  • Ingår i: NPJ PARKINSONS DISEASE. - : Springer Nature. - 2373-8057. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to the neurotoxin MPP+ in the brain causes permanent Parkinson's disease-like symptoms by destroying dopaminergic neurons in the pars compacta of the substantia nigra in humans and non-human primates. However, the complete molecular pathology underlying MPTP-induced parkinsonism remains poorly understood. We used dual polarity matrix-assisted laser desorption/ionization mass spectrometry imaging to thoroughly image numerous glycerophospholipids and sphingolipids in coronal brain tissue sections of MPTP-lesioned and control non-human primate brains (Macaca mulatta). The results revealed specific distributions of several sulfatide lipid molecules based on chain-length, number of double bonds, and importantly, hydroxylation stage. More specifically, certain long-chain hydroxylated sulfatides with polyunsaturated chains in the molecular structure were depleted within motor-related brain regions in the MPTP-lesioned animals, e.g., external and internal segments of globus pallidus and substantia nigra pars reticulata. In contrast, certain long-chain non-hydroxylated sulfatides were found to be elevated within the same brain regions. These findings demonstrate region-specific dysregulation of sulfatide metabolism within the MPTP-lesioned macaque brain. The depletion of long-chain hydroxylated sulfatides in the MPTP-induced pathology indicates oxidative stress and oligodendrocyte/myelin damage within the pathologically relevant brain regions. Hence, the presented findings improve our current understanding of the molecular pathology of MPTP-induced parkinsonism within primate brains, and provide a basis for further research regarding the role of dysregulated sulfatide metabolism in PD.
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7.
  • Marmion, David J., et al. (författare)
  • Viral-based rodent and nonhuman primate models of multiple system atrophy : Fidelity to the human disease
  • 2021
  • Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 148
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple system atrophy (MSA) is a rare and extremely debilitating progressive neurodegenerative disease characterized by variable combinations of parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal dysfunction. MSA is a unique synucleinopathy, in which alpha synuclein-rich aggregates are present in the cytoplasm of oligodendroglia. The precise origin of the alpha synuclein (aSyn) found in the glial cytoplasmic inclusions (GCIs) as well the mechanisms of neurodegeneration in MSA remain unclear. Despite this fact, cell and animal models of MSA rely on oligodendroglial overexpression of aSyn. In the present study, we utilized a novel oligotrophic AAV, Olig001, to overexpress aSyn specifically in striatal oligodendrocytes of rats and nonhuman primates in an effort to further characterize our novel viral vector-mediated MSA animal models. Using two cohorts of animals with 10-fold differences in Olig001 vector titers, we show a dose-dependent formation of MSA-like pathology in rats. High titer of Olig001-aSyn in these animals were required to produce the formation of pS129+ and proteinase K resistant aSyn-rich GCIs, demyelination, and neurodegeneration. Using this knowledge, we injected high titer Olig001 in the putamen of cynomolgus macaques. After six months, histological analysis showed that oligodendroglial overexpression of aSyn resulted in the formation of hallmark GCIs throughout the putamen, demyelination, a 44% reduction of striatal neurons and a 12% loss of nigral neurons. Furthermore, a robust inflammatory response similar to MSA was produced in Olig001-aSyn NHPs, including microglial activation, astrogliosis, and a robust infiltration of T cells into the CNS. Taken together, oligodendroglial-specific viral vector-mediated overexpression of aSyn in rats and nonhuman primates faithfully reproduces many of the pathological disease hallmarks found in MSA. Future studies utilizing these large animal models of MSA would prove extremely valuable as a pre-clinical platform to test novel therapeutics that are so desperately needed for MSA.
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8.
  • Outeiro, Tiago F., et al. (författare)
  • From iPS Cells to Rodents and Nonhuman Primates : Filling Gaps in Modeling Parkinson's Disease
  • 2021
  • Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:4, s. 832-841
  • Tidskriftsartikel (refereegranskat)abstract
    • Parkinson's disease (PD) is primarily known as a movement disorder because of typical clinical manifestations associated with the loss of dopaminergic neurons in the substantia nigra. However, it is now widely recognized that PD is a much more complex condition, with multiple and severe nonmotor features implicating additional brain areas and organs in the disease process. Pathologically, typical forms of PD are characterized by the accumulation of α-synuclein-rich protein inclusions known as Lewy bodies and Lewy neurites, although other types of protein inclusions are also often present in the brain. Familial forms of PD have provided a wealth of information about molecular pathways leading to neurodegeneration, but only to add to the complexity of the problem and uncover new knowledge gaps. Therefore, modeling PD in the laboratory has become increasingly challenging. Here, we discuss knowledge gaps and challenges in the use of laboratory models for the study of a disease that is clinically heterogeneous and multifactorial. We propose that the combined use of patient-derived cells and animal models, along with current technological tools, will not only expand our molecular and pathophysiological understanding of PD, but also assist in the identification of therapeutic strategies targeting relevant pathogenic pathways.
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