| 1. |
- Bezard, Erwan, et al.
(author)
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mu Opioid Receptor Agonism for L-DOPA-Induced Dyskinesia in Parkinson's Disease
- 2020
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In: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 40:35, s. 6812-6819
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Journal article (peer-reviewed)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. |
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| 3. |
- Fridjonsdottir, Elva
(author)
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Imaging neurochemical changes associated with Parkinson´s disease and L-DOPA-induced dyskinesia using mass spectrometry
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Parkinson’s disease (PD), caused by a loss of midbrain dopamine neurons, is the second most common neurodegenerative disease worldwide after Alzheimer’s disease. The primary treatment choice for PD is L-DOPA, the precursor for dopamine, which only affects symptoms and does not inhibit disease progression. Most patients develop motor complications during long-term L-DOPA treatment called L-DOPA-induced dyskinesia (LID), which are abnormal involuntary movements. LID has been associated with biochemical alterations in a number of signalling systems in the basal ganglia, including the dopaminergic, serotonergic, cholinergic and opioidergic systems, among others. Defining region-specific alterations of these signalling molecules and comprehensive metabolic pathways in the brain will help to improve our understanding of their involvement in LID. In the work upon which this thesis is based, we exploited the advantages of mass spectrometry imaging (MSI) to perform on-tissue mapping of a large number of molecules in a single experiment for investigating biochemical changes associated with LID. A novel matrix-assisted laser desorption/ionisation (MALDI) MSI on-tissue chemical derivatisation approach was developed that enabled imaging of primary amine and phenolic hydroxyl group containing neurotransmitters and their comprehensive metabolic pathways. In addition, a tissue clean-up protocol which improved the limit of detection of multiple neuropeptides involved in basal ganglia signalling was established. These methods were applied to neurotoxin-based animal models of PD and LID, including the gold-standard model, namely the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered non-human primate model. LID was found to be associated with extremely high levels of L-DOPA throughout the brain, but no significant increase in striatal dopamine was observed, contradicting the widely accepted hypothesis that LID is induced by elevated striatal dopamine levels. Furthermore, LID was associated with increased levels of signalling neuropeptides throughout the basal ganglia, where abnormally processed neuropeptides correlated with LID severity. Untargeted multivariate analysis revealed that LID was associated with increased abundance of the vasculature marker heme B in the striatum, suggesting angiogenesis and increased blood flow to this region. Moreover, important methyl donors, including S-adenosylmethionine, betaine and α-glycerophosphocholine were affected by MPTP exposure and LID. In conclusion, the studies included in this thesis provide methods for investigating multiple signalling molecules in single tissue sections and novel and comprehensive insights into the biochemical changes that occur in LID.
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| 4. |
- Fridjonsdottir, Elva, et al.
(author)
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Mass spectrometry imaging identifies abnormally elevated brain L-DOPA levels and extrastriatal monoaminergic dysregulation in L-DOPA-induced dyskinesia
- 2021
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:2
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Journal article (peer-reviewed)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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| 5. |
- Fridjonsdottir, Elva, et al.
(author)
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Mass spectrometry imaging reveals brain-region specific changes in metabolism and acetylcholine levels in experimental Parkinson’s disease and L-DOPA-induced dyskinesia
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Other publication (other academic/artistic)abstract
- There is evidence that cholinergic alterations are linked to various motor and non-motor symptoms of Parkinson’s disease. We therefore used mass spectrometry imaging to investigate regional changes in acetylcholine abundance in the brain of a non-human primate model of Parkinson’s disease (PD) and L-DOPA-induced dyskinesia (LID). We also present an experimental design for performing untargeted analysis using MALDI-MSI with multiple experiments incorporating quality control samples to monitor experimental variability. We observed that MPTP treatment (i) led to reductions in putaminal acetylcholine levels that persisted after L-DOPA treatment and (ii) appeared to induce a shift of choline metabolism from α-glycerophosphocholine towards betaine. LID animals exhibited reduced levels of various metabolites important for brain homeostasis including S-adenosylmethionine, glutathione, adenosine monophosphate, and acylcarnitines. The vasculature marker heme B was upregulated in the putamen of LID animals, suggesting increased blood-flow in the dyskinetic putamen. These results provide new insights into pathological choline-related metabolic changes in PD and LID.
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| 6. |
- Fridjonsdottir, Elva, et al.
(author)
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Region-Specific and Age-Dependent Multitarget Effects of Acetylcholinesterase Inhibitor Tacrine on Comprehensive Neurotransmitter Systems
- 2022
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In: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 17:1, s. 147-158
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Journal article (peer-reviewed)abstract
- Regional brain distribution and metabolism of neurotransmitters and their response to drug treatment are fundamentally important for understanding the central effects of neuroactive substances. We used matrix-assisted laser desorption/ionization mass spectrometry imaging in combination with multivariate analysis to visualize in anatomical detail metabolic effects of aging and tacrine-mediated acetylcholinesterase inhibition on comprehensive neurotransmitter systems in multiple mouse brain regions of 12-week-old and 14-month-old mice. We detected age-related increases in 3,4-dihydroxyphenylacetaldehyde and histamine, indicating oxidative stress and aging deficits in astrocytes. Tacrine had a significant impact on the metabolism of neurotransmitters in both age groups; predominantly, there was an increased norepinephrine turnover throughout the brain and decreased 3-methoxy tyramine, a marker for dopamine release, in the striatum. The striatal levels of histamine were only elevated after tacrine administration in the older animals. Our results demonstrated that tacrine is a multitarget and region-specific neuroactive agent, inducing age-specific responses. Although well-studied, the complete mechanisms of the action of tacrine are not fully understood, and the current findings reveal features that may help explain its treatment-related effectiveness and central side effects.
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| 7. |
- Hulme, Heather, et al.
(author)
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Basal ganglia neuropeptides show abnormal processing associated with L-DOPA-induced dyskinesia
- 2022
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In: NPJ PARKINSONS DISEASE. - : Springer Nature. - 2373-8057. ; 8:1
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Journal article (peer-reviewed)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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| 8. |
- Hulme, Heather, et al.
(author)
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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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Other publication (other academic/artistic)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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| 9. |
- Hulme, Heather, et al.
(author)
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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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In: Neurobiology of Disease. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0969-9961 .- 1095-953X. ; 137
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Journal article (peer-reviewed)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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| 10. |
- Mantas, Ioannis, et al.
(author)
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TAAR1-Dependent and-Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition
- 2021
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 90:1, s. 16-27
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Journal article (peer-reviewed)abstract
- BACKGROUND: Monoamine oxidase inhibitors (MAOIs) exert therapeutic actions by elevating extracellular levels of monoamines in the brain. Irreversible MAOIs cause serious hypertensive crises owing to peripheral accumulation of tyramine, but the role of tyramine in the central effects of MAOIs remains elusive, an issue addressed herein. To achieve robust inhibition of MAOA/B, the clinically used antidepressant tranylcypromine (TCP) was employed. METHODS: Behavioral, histological, mass spectrometry imaging, and biosensor-mediated measures of glutamate were conducted with MAOIs in wild-type and TAAR1-knockout (KO) mice. RESULTS: Both antidepressant and locomotion responses to TCP were enhanced in TAAR1-KO mice. A recently developed fluoromethylpyridinium-based mass spectrometry imaging method revealed robust accumulation of striatal tyramine on TCP administration. Furthermore, tyramine accumulation was higher in TAAR1-KO versus wild type mice, suggesting a negative feedback mechanism for TAAR1 in sensing tyramine levels. Combined histoenzymological and immunohistological studies revealed hitherto unknown TAAR1 localization in brain areas projecting to the substantia nigra/ventral tegmental area. Using an enzyme-based biosensor technology, we found that both TCP and tyramine reduced glutamate release in the substantia nigra in wild-type but not in TAAR1-KO mice. Moreover, glutamate measures in freely moving animals treated with TCP demonstrated that TAAR1 prevents glutamate accumulation in the substantia nigra during hyperlocomotive states. CONCLUSIONS: These observations suggest that tyramine, in interaction with glutamate, is involved in centrally mediated behavioral, transcriptional, and neurochemical effects of MAOIs.
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| 11. |
- Shariatgorji, Mohammadreza, et al.
(author)
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Comprehensive mapping of neurotransmitter networks by MALDI-MS imaging
- 2019
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In: Nature Methods. - : NATURE PUBLISHING GROUP. - 1548-7091 .- 1548-7105. ; 16:10, s. 1021-1028
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Journal article (peer-reviewed)abstract
- We present a mass spectrometry imaging (MSI) approach for the comprehensive mapping of neurotransmitter networks in specific brain regions. Our fluoromethylpyridinium-based reactive matrices facilitate the covalent charge-tagging of molecules containing phenolic hydroxyl and/or primary or secondary amine groups, including dopaminergic and serotonergic neurotransmitters and their associated metabolites. These matrices improved the matrix-assisted laser desorption/ionization (MALDI)-MSI detection limit toward low-abundance neurotransmitters and facilitated the simultaneous imaging of neurotransmitters in fine structures of the brain at a lateral resolution of 10 mu m. We demonstrate strategies for the identification of unknown molecular species using the innate chemoselectivity of the reactive matrices and the unique isotopic pattern of a brominated reactive matrix. We illustrate the capabilities of the developed method on Parkinsonian brain samples from human post-mortem tissue and animal models. The direct imaging of neurotransmitter systems provides a method for exploring how various neurological diseases affect specific brain regions through neurotransmitter modulation.
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| 12. |
- Shariatgorji, Reza, et al.
(author)
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Spatial visualization of comprehensive brain neurotransmitter systems and neuroactive substances by selective in situ chemical derivatization mass spectrometry imaging
- 2021
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In: Nature Protocols. - : Springer Nature. - 1754-2189 .- 1750-2799. ; 16:7, s. 3298-3321
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Journal article (peer-reviewed)abstract
- Molecule-specific techniques such as MALDI and desorption electrospray ionization mass spectrometry imaging enable direct and simultaneous mapping of biomolecules in tissue sections in a single experiment. However, neurotransmitter imaging in the complex environment of biological samples remains challenging. Our covalent charge-tagging approach using on-tissue chemical derivatization of primary and secondary amines and phenolic hydroxyls enables comprehensive mapping of neurotransmitter networks. Here, we present robust and easy-to-use chemical derivatization protocols that facilitate quantitative and simultaneous molecular imaging of complete neurotransmitter systems and drugs in diverse biological tissue sections with high lateral resolution. This is currently not possible with any other imaging technique. The protocol, using fluoromethylpyridinium and pyrylium reagents, describes all steps from tissue preparation (-1 h), chemical derivatization (1-2 h), data collection (timing depends on the number of samples and lateral resolution) and data analysis and interpretation. The specificity of the chemical reaction can also help users identify unknown chemical identities. Our protocol can reveal the cellular locations in which signaling molecules act and thus shed light on the complex responses that occur after the administration of drugs or during the course of a disease.
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| 13. |
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| 14. |
- Vallianatou, Theodosia, et al.
(author)
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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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In: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 12:10, s. 1811-1823
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Journal article (peer-reviewed)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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| 15. |
- Vallianatou, Theodosia, et al.
(author)
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Molecular imaging identifies age-related attenuation of acetylcholine in retrosplenial cortex in response to acetylcholinesterase inhibition
- 2019
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In: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 44, s. 2091-2098
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Journal article (peer-reviewed)abstract
- The neurotransmitter of the cholinergic system, acetylcholine plays a major role in the brain's cognitive function and is involved in neurodegenerative disorders. Here, we present age-related alterations of acetylcholine levels after administration of the acetylcholinesterase inhibitor drug tacrine in normal mice. Using a quantitative, robust and molecular-specific mass spectrometry imaging method we found that tacrine administration significantly raised acetylcholine levels in most areas of sectioned mice brains, inter alia the striatum, hippocampus and cortical areas. However, acetylcholine levels in retrosplenial cortex were significantly lower in 14-month-old than in 12-week-old animals following its administration, indicating that normal aging affects the cholinergic system's responsivity. This small brain region is interconnected with an array of brain networks and is involved in numerous cognitive tasks. Simultaneous visualization of distributions of tacrine and its hydroxylated metabolites in the brain revealed a significant decrease in levels of the metabolites in the 14-month-old mice. The results highlight strengths of the imaging technique to simultaneously investigate multiple molecular species and the drug-target effects in specific regions of the brain. The proposed approach has high potential in studies of neuropathological conditions and responses to neuroactive treatments.
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| 16. |
- Zhang, Xiaoqun, et al.
(author)
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Deficits in Motor Performance, Neurotransmitters and Synaptic Plasticity in Elderly and Experimental Parkinsonian Mice Lacking GPR37
- 2020
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In: Frontiers in Aging Neuroscience. - : FRONTIERS MEDIA SA. - 1663-4365. ; 12
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Journal article (peer-reviewed)abstract
- Parkinson's disease (PD) etiology is attributed to aging and the progressive neurodegeneration of dopamine (DA) neurons of substantia nigra pars compacta (SNc). GPR37 is an orphan G-protein Coupled Receptor (GPCR) that is linked to the juvenile form of PD. In addition, misfolded GPR37 has been found in Lewy bodies. However, properly folded GPR37 found at the cell membrane appears to exert neuroprotection. In the present study we investigated the role of GPR37 in motor deficits due to aging or toxin-induced experimental parkinsonism. Elderly GPR37 knock out (KO) mice displayed hypolocomotion and worse fine movement performance compared to their WT counterparts. Striatal slice electrophysiology reveiled that GPR37 KO mice show profound decrease in long term potentiation (LTP) formation which is accompanied by an alteration in glutamate receptor subunit content. GPR37 KO animals exposed to intrastriatal 6-hydroxydopamine (6-OHDA) show poorer score in the behavioral cylinder test and more loss of the DA transporter (DAT) in striatum. The GPR37 KO striata exhibit a significant increase in GABA which is aggravated after DA depletion. Our data indicate that GPR37 KO mice have DA neuron deficit, enhanced striatal GABA levels and deficient corticostriatal LTP. They also respond stronger to 6-OHDA-induced neurotoxicity. Taken together, the data indicate that properly functional GPR37 may counteract aging processes and parkinsonism.
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