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- Hulme, Heather E., et al.
(författare)
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Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection
- 2017
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S. Typhimurium infection. To further understand host-pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S. Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S. Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169(+) sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4(+) CD25(+) T cells and an increased number of B220(+) CD19(+) B cells. The reduction in CD4(+) CD25(+) T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome.
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- Bezard, Erwan, et al.
(författare)
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mu Opioid Receptor Agonism for L-DOPA-Induced Dyskinesia in Parkinson's Disease
- 2020
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 40:35, s. 6812-6819
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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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- Hulme, Heather, et al.
(författare)
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Basal ganglia neuropeptides show abnormal processing associated with L-DOPA-induced dyskinesia
- 2022
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Ingår i: npj Parkinson's Disease. - : Springer Nature. - 2373-8057. ; 8:1
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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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- Hulme, Heather, et al.
(författare)
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Mass spectrometry imaging of multiple basal ganglia neuropeptides shows abnormal neuropeptide processing associated with L-DOPA-induced dyskinesia in a primate model of Parkinson’s disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)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). Signalling neuropeptides of the basal ganglia are affected in LID and alterations in the expression of neuropeptide precursors have been described, but the final products of the precursors are not well defined and regionally mapped. Thus, we used matrix-assisted laser desorption/ionization 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 the abundance of some abnormally processed peptides—des-tyrosine dynorphins, substance P (1-7) and substance P (1-9)—correlated with dyskinesia severity in multiple brain regions. Other dynorphins, α-neoendorphin and neurokinin A correlated with regional L-DOPA or dopamine levels in the internal and external globus pallidus. Our results demonstrate that the abundance of selected active neuropeptides is associated with local L-DOPA and dopamine concentrations, but the severity of LID is associated with loss of N-terminal tyrosine from dynorphin peptides and C-terminal truncation of substance P peptides, modifications that generally reduce the neuropeptides’ activity.
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- Hulme, Heather, et al.
(författare)
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Simultaneous mass spectrometry imaging of multiple neuropeptides in the brain and alterations induced by experimental parkinsonism and L-DOPA therapy
- 2020
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Ingår i: Neurobiology of Disease. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0969-9961 .- 1095-953X. ; 137
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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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- Vallianatou, Theodosia, et al.
(författare)
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Integration of Mass Spectrometry Imaging and Machine Learning Visualizes Region-Specific Age-Induced and Drug-Target Metabolic Perturbations in the Brain
- 2021
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 12:10, s. 1811-1823
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Tidskriftsartikel (refereegranskat)abstract
- Detailed metabolic imaging of specific brain regions in early aging may expose pathophysiological mechanisms and indicate effective neuropharmacological targets in the onset of cognitive decline. Comprehensive imaging of brain aging and drug-target effects is restricted using conventional methodology. We simultaneously visualized multiple metabolic alterations induced by normal aging in specific regions of mouse brains by integrating Fourier-transform ion cyclotron resonance mass spectrometry imaging and combined supervised and unsupervised machine learning models. We examined the interplay between aging and the response to tacrine-induced acetylcholinesterase inhibition, a well-characterized therapeutic treatment against dementia. The dipeptide carnosine (β-alanyl-l-histidine) and the vitamin α-tocopherol were significantly elevated by aging in different brain regions. l-Carnitine and acetylcholine metabolism were found to be major pathways affected by aging and tacrine administration in a brain region-specific manner, indicating altered mitochondrial function and neurotransmission. The highly interconnected hippocampus and retrosplenial cortex displayed different age-induced alterations in lipids and acylcarnitines, reflecting diverse region-specific metabolic effects. The subregional differences observed in the hippocampal formation of several lipid metabolites demonstrate the unique potential of the technique compared to standard mass spectrometry approaches. An age-induced increase of endogenous antioxidants, such as α-tocopherol, in the hippocampus was detected, suggesting an augmentation of neuroprotective mechanisms in early aging. Our comprehensive imaging approach visualized heterogeneous age-induced metabolic perturbations in mitochondrial function, neurotransmission, and lipid signaling, not always attenuated by acetylcholinesterase inhibition.
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