Pathophysiological clues to therapeutic applications of glutamate mGlu5 receptor antagonists in levodopa-induced dyskinesia

Pourmirbabaei, Shayan; Dolatshahi, Mahsa; Rahmani, Farzaneh

doi:10.1016/j.ejphar.2019.05.004

Cited by 22 publications

(13 citation statements)

References 118 publications

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“…mGluR5 receptors have been reported to be efficiently suppressed by a series of compounds such as phenylpyridine derivatives (2-methyl-6-(phenylethynyl)-pyridine (MPEP), 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), AFQ056/mavoglurant, fenobam, and ADX48621/dipraglurant), which are systemically active [86]. Consistent with this hypothesis, several studies have proven that these antagonists of the mGluR5 receptor exert anti-Parkinsonian effects in different animal models of PD.…”

Section: Key Targets Of Glutamate Receptors In Pd Treatmentmentioning

confidence: 99%

Roles of Glutamate Receptors in Parkinson’s Disease

Zhang

et al. 2019

IJMS

119

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Parkinson’s disease is a progressive neurodegenerative disorder resulting from the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta. It induces a series of functional modifications in the circuitry of the basal ganglia nuclei and leads to severe motor disturbances. The amino acid glutamate, as an excitatory neurotransmitter, plays a key role in the disruption of normal basal ganglia function regulated through the interaction with its receptor proteins. It has been proven that glutamate receptors participate in the modulation of neuronal excitability, transmitter release, and long-term synaptic plasticity, in addition to being related to the altered neurotransmission in Parkinson’s disease. Therefore, they are considered new targets for improving the therapeutic strategies used to treat Parkinson’s disease. In this review, we discuss the biological characteristics of these receptors and demonstrate the receptor-mediated neuroprotection in Parkinson’s disease. Pharmacological manipulation of these receptors during anti-Parkinsonian processes in both experimental studies and clinical trials are also summarized.

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Section: Key Targets Of Glutamate Receptors In Pd Treatmentmentioning

confidence: 99%

Roles of Glutamate Receptors in Parkinson’s Disease

Zhang

et al. 2019

IJMS

119

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“…So far, L-3,4-dihydroxyphenylalanine (L-dopa) remains to be the most effective drug for symptomatic treatment of Parkinson (Smith et al, 2014). However, the adverse effects of long-term L-dopa treatment vary, such as levodopa-induced dyskinesia (LID), which appears in approximately 40% of PD patients after 5 years L-dopa therapy and up to 90% within 10 years (Pourmirbabaei et al, 2019;Sellnow et al, 2019). Furthermore, the uncontrollable LID has been reported to dramatically affect the quality of patients' life and greatly augment the cost of health care for which no satisfying treatment is available (Dodel et al, 2001;Chapuis et al, 2005;Hechtner et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Brain-Region Specific Metabolic Abnormalities in Parkinson’s Disease and Levodopa-Induced Dyskinesia

Yang

Zhang

Wang

et al. 2020

Front. Aging Neurosci.

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Several lines of evidence point to alteration in brain metabolic homeostasis in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), yet the metabolic mechanism in different brain regions underlying PD and LID remains largely unknown. The present study aimed to uncover the metabolic pathways across anatomical regions in the brain of PD and LID. Using an NMR-based metabolomic approach, we generated the metabolomics profiling data from six different brain regions of PD rats and following the onset of LIDs. The diversity of metabolite patterns across the brain and its relation to PD and LID were further investigated through principal component analysis (PCA) and multivariate general linear model. Compared with control rats, dopamine loss in PD rats produced a marked and persistent metabolic disturbance in neurotransmitter metabolism and energy pathway, resulting in a metabolic imbalance among different brain regions. In LID rats, levodopa replacement did not restore the midbrain-striatum metabolic crosstalk and metabolic disturbance throughout the brain was involved in levodopa related involuntary movements. Most notably, the midbrain and right cortex were identified as the primary regions of metabolic abnormalities in PD and LID rats. Neurochemical differences in metabolic phenotypes were mainly defined by various neurotransmitters including glutamate, glutamine and aspartate. Accordingly, we found that the PD and LID rats exhibited lower levels of synaptophysin (SYP), a marker for synaptic plasticity, compared with control rats. These findings provide key insights into the metabolic mechanism underlying PD and LID by defining brain-region specific metabolic phenotype, with implications for developing targeted therapies.

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“…3‐[(2‐methyl‐1,3‐thiazol‐4‐yl)ethynyl] pyridine and 2‐methyl‐6‐(phenylethynyl)‐pyridine were the first mGlu5 receptor antagonists reported to be able to reduce dyskinesia in animal models. In these models, therapeutic effects have also been shown for other mGlu5 receptor antagonists such as AFQ056/mavoglurant and ADX48621/dipraglurant, 85 however, benefits have not been confirmed in clinical trials 86 …”

Section: Scientific Advancesmentioning

confidence: 99%

Continuous Dopaminergic Stimulation as a Treatment for Parkinson's Disease: Current Status and Future Opportunities

2020

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Levodopa‐induced motor complications remain an important source of disability for many patients with Parkinson's disease. Substantial laboratory evidence indicates that motor complications relate to the nonphysiological restoration of brain dopamine with intermittent doses of standard oral levodopa. Dopamine levels are normally maintained at a relatively constant level, even following a dose of levodopa. However, in the Parkinsonian state, where dopamine terminals have degenerated with a loss of their buffering capacity, intermittent doses of levodopa lead to dramatic peak and trough fluctuations in striatal dopamine levels. This results in pulsatile stimulation of dopamine receptors, molecular changes in striatal neurons, physiological changes in pallidal neurons, and ultimately the development of motor complications. These observations led to the hypothesis that continuous delivery of levodopa might be associated with a reduced risk of motor complications. This concept is known as continuous dopamine stimulation (CDS). Preliminary studies in animal models and patients with Parkinson's disease supported this hypothesis, suggesting a reduced risk of both motor fluctuations and dyskinesias. The present review considers the scientific advances and the more definitive clinical trials testing this concept that have taken place during the past decade and considers ongoing experimental studies and future opportunities. © 2020 International Parkinson and Movement Disorder Society

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Pathophysiological clues to therapeutic applications of glutamate mGlu5 receptor antagonists in levodopa-induced dyskinesia

Cited by 22 publications

References 118 publications

Roles of Glutamate Receptors in Parkinson’s Disease

Roles of Glutamate Receptors in Parkinson’s Disease

Brain-Region Specific Metabolic Abnormalities in Parkinson’s Disease and Levodopa-Induced Dyskinesia

Continuous Dopaminergic Stimulation as a Treatment for Parkinson's Disease: Current Status and Future Opportunities

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