D-serine adjuvant treatment alleviates behavioural and motor symptoms in Parkinson's disease

Abstract

Parkinson's disease (PD) manifestations include motor symptoms and behavioural deficits that resemble schizophrenia negative symptoms. The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) represents a novel pharmacological target in PD. D-serine (DSR) allosterically modulates in-vivo NMDAR-mediated neurotransmission and has been shown to improve negative and antipsychotic drug-induced parkinsonian symptoms in schizophrenia patients. This pilot study assessed DSR effects in ten PD patients who completed a 6-wk double-blind, placebo-controlled, crossover adjuvant treatment trial with 30 mg/kg.d DSR. Primary outcome analyses consisted of separate repeated-measures multivariate analyses of variance for Unified Parkinson's Disease Rating Scale (UPDRS), Simpson-Angus Scale for Extrapyramidal Symptoms (SAS), Abnormal Involuntary Movement Scale (AIMS), and Positive and Negative Syndrome Scale (PANSS) scores. DSR treatment was well tolerated and resulted in increased DSR serum levels (p=0.001) and significantly reduced UPDRS (p=0.02), SAS (p=0.009) and PANSS (0.05) total scores. These preliminary findings suggest that DSR treatment may be beneficial in PD. Larger-sized studies with optimized DSR dosages are warranted.

Behavioral and cognitive effects of the N-methyl-d-aspartate receptor co-agonist d-serine in healthy humans: Initial findings

“…Increases of similar magnitude have been reported following administration of single DSR doses in healthy humans (Tsai et al, 2008) and schizophrenia patients and are likely to result in increased CSF concentration and synaptic availability of DSR. Nevertheless, despite the robust serum levels increase, as in previous clinical trials that have assessed a~2 g/d DSR regimen (Gelfin et al, 2012;Tsai and Lin, 2010), no side effects have been registered with this compound in the present investigation.…”

“…sodium benzoate (Lane et al, 2013;Lin et al, 2014), inhibitors represents a major drug development target. Moreover, NMDAR-GLY site agonism has also been proposed as an innovative pharmacological mechanism for dementia (Huang et al, 2012), movement disorders (Heresco-Levy et al, 2013a;Gelfin et al, 2012), obsessive compulsive disorder (Hoffman-La Roche, 2013;Greenberg et al, 2009) and depression .…”

Has an Angel Shown the Way? Etiological and Therapeutic Implications of the PCP/NMDA Model of Schizophrenia

“…In such studies, highly significant, large effect size improvement in antipsychotic-induced motor symptoms was observed (figure 3). Although glycine-site agonists have been tested most for schizophrenia, the ability to manipulate NMDA receptors may be relevant to conditions others than schizophrenia, such as Parkinson's disease, 58 where motor symptoms are primary.…”

Glycine Transporter-1 Inhibition Promotes Striatal Axon Sprouting via NMDA Receptors in Dopamine Neurons

“…These effects may, however, rather occur through actions on other receptors than NMDA receptors (Calabresi et al, 2010). In a recent pilot study, Parkinson's patients treated with D-serine, which binds to the NMDA receptor glycine site, showed improvement as assessed by the Unified Parkinson's Disease Rating Scale and the Positive and Negative Symptoms Scale after 6 weeks of treatment (Gelfin et al, 2012), suggesting that GlyT1 inhibitors may be beneficial as adjuvant treatment in Parkinson's disease (Heresco-Levy et al, 2013).…”