Abstract
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.
Highlights
Parkinson’s disease (PD) is a common age-related neurodegenerative disorder due to the loss of dopaminergic neurons in the substantia nigra par compacta (SNpc) thereby leading to the dopamine depletion in the striatum (Huang et al, 2019)
Forelimb function test was conducted at days 3, 8, 13, 18 after L-dopa/benserazide treatment, results showed that the percent of left forelimb use of total wall contacts of rats in normal rats (Con) group is around 50%, while the percent of left forelimb use was significantly reduced in PD rats with a partial lesion of the nigrostriatal pathway
We found that: (1) dopamine loss in PD rats produces a marked and persistent metabolic disturbance in neurotransmitter metabolism and energy pathway, resulting in a metabolic imbalance among different brain regions; (2) L-dopa replacement did not restore the midbrain-striatum metabolic crosstalk and metabolic disturbance throughout the brain was involved in levodopa related involuntary movements; and (3) further multivariate general linear model identified that a significant perturbation of Glu-Gln-γ-aminobutyric acid (GABA) cycle in midbrain and right cortex of both PD and levodopa-induced dyskinesia (LID) rats, accompanied by reduced synaptic plasticity
Summary
Parkinson’s disease (PD) is a common age-related neurodegenerative disorder due to the loss of dopaminergic neurons in the substantia nigra par compacta (SNpc) thereby leading to the dopamine depletion in the striatum (Huang et al, 2019). 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). In light of this urgent medical need for rapidly aging populations, there is an urgent need to identify the mechanism underlying PD and LID
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