Abstract
Dysfunction of NMDA receptor (NMDAR)-mediated transmission is supposed to contribute to the motor and non-motor symptoms of Parkinson’s Disease (PD), and to L-DOPA-induced dyskinesia. Besides the main agonist L-glutamate, two other amino acids in the atypical D-configuration, D-serine and D-aspartate, activate NMDARs. In the present work, we investigated the effect of dopamine depletion on D-amino acids metabolism in the brain of MPTP-lesioned Macaca mulatta, and in the serum and cerebrospinal fluid of PD patients. We found that MPTP treatment increases D-aspartate and D-serine in the monkey putamen while L-DOPA rescues both D-amino acids levels. Conversely, dopaminergic denervation is associated with selective D-serine reduction in the substantia nigra. Such decrease suggests that the beneficial effect of D-serine adjuvant therapy previously reported in PD patients may derive from the normalization of endogenous D-serine levels and consequent improvement of nigrostriatal hypoglutamatergic transmission at glycine binding site. We also found reduced D-serine concentration in the cerebrospinal fluid of L-DOPA-free PD patients. These results further confirm the existence of deep interaction between dopaminergic and glutamatergic neurotransmission in PD and disclose a possible direct influence of D-amino acids variations in the changes of NMDAR transmission occurring under dopamine denervation and L-DOPA therapy.
Highlights
Dysfunction of NMDA receptor (NMDAR)-mediated transmission is supposed to contribute to the motor and non-motor symptoms of Parkinson’s Disease (PD), and to L-DOPA-induced dyskinesia
We first analyzed the content of DA and its metabolite, 3,4-Dihydroxyphenylacetic acid (DOPAC), in the putamen of Macaca mulatta treated with MPTP or MPTP + L-DOPA
Structural, functional and synaptic modifications occurring at NMDARs in PD represent a topic of intense investigation since these receptors are postulated to play a primary role in the progression and treatment of this neurodegenerative disease[13,44,45,46]
Summary
Dysfunction of NMDA receptor (NMDAR)-mediated transmission is supposed to contribute to the motor and non-motor symptoms of Parkinson’s Disease (PD), and to L-DOPA-induced dyskinesia. Besides the main agonist L-glutamate, two other amino acids in the atypical D-configuration, D-serine and D-aspartate, activate NMDARs. In the present work, we investigated the effect of dopamine depletion on D-amino acids metabolism in the brain of MPTP-lesioned Macaca mulatta, and in the serum and cerebrospinal fluid of PD patients. We found reduced D-serine concentration in the cerebrospinal fluid of L-DOPA-free PD patients These results further confirm the existence of deep interaction between dopaminergic and glutamatergic neurotransmission in PD and disclose a possible direct influence of D-amino acids variations in the changes of NMDAR transmission occurring under dopamine denervation and L-DOPA therapy. In this regard, preclinical observations showed altered D-Ser concentrations in the brain of MPTP- and 6-OHDA-lesioned rodents[25,26,27]. In order to assess the translational relevance of preclinical studies in parkinsonian monkeys, we analyzed the concentration of these NMDAR-related modulators in the serum and cerebrospinal fluid (CSF) of PD patients
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