D-SPARK is a Phase 2 clinical trial evaluating D-serine, an endogenous N-methyl-D-aspartate receptor (NMDAR) co-agonist, as a potential disease-modifying treatment for Parkinson's disease. The trial is sponsored by Haukeland University Hospital and aims to determine whether D-serine can slow or modify the progression of PD through modulation of glutamatergic neurotransmission.
The rationale for D-serine in PD stems from growing evidence that NMDAR hypofunction contributes to dopaminergic neuronal loss, while proper NMDAR signaling is essential for synaptic plasticity and neuronal survival in the substantia nigra. By enhancing NMDAR activation through D-serine supplementation, the trial seeks to protect remaining dopaminergic neurons and potentially improve motor and non-motor symptoms.
| Parameter |
Details |
| Phase |
Phase 2 |
| NCT Number |
NCT07312110 |
| Status |
Recruiting |
| Intervention |
D-serine |
| Sponsor |
Haukeland University Hospital |
| Study Design |
Randomized, double-blind, placebo-controlled |
- Evaluate the safety and tolerability of D-serine in Parkinson's disease patients
- Assess disease modification potential through motor and non-motor symptom progression
- Determine optimal dosing regimen for neuroprotective effects
- Diagnosis of Parkinson's disease (UK Brain Bank criteria)
- Age 40-80 years
- Disease duration 1-10 years
- Stable dopaminergic medication for at least 4 weeks
- MMSE score ≥ 24
- Significant cognitive impairment (MMSE < 24)
- Psychiatric disorders requiring current treatment
- History of seizures or epilepsy
- Significant renal or hepatic impairment
- Current use of NMDAR antagonists
D-serine is the primary endogenous co-agonist of the N-methyl-D-aspartate receptor, acting at the glycine modulatory site (GlyB). Unlike glycine, D-serine has higher brain bioavailability and is synthesized predominantly in astrocytes, making it the primary regulator of NMDAR function in the central nervous system.
The NMDAR requires two distinct co-agonists for activation:
- Glutamate (the primary neurotransmitter)
- D-serine or glycine (the co-agonist)
Under physiological conditions, D-serine occupancy at the GlyB site is approximately 60-80%, leaving room for pharmacologic enhancement.
D-serine-mediated NMDAR activation exerts neuroprotection through several interconnected pathways:
Synaptic Plasticity Enhancement
- NMDAR activation promotes long-term potentiation (LTP) in dopaminergic neurons
- Enhances dendritic spine density in the substantia nigra
- Improves synaptic connectivity and function
Anti-Apoptotic Signaling
- Activates PI3K/Akt survival pathways
- Inhibits caspase-3 activation
- Prevents mitochondrial dysfunction
Anti-Inflammatory Effects
- Modulates microglial activation states
- Reduces pro-inflammatory cytokine release
- Decreases neuroinflammation-mediated neuronal loss
Calcium Homeostasis
- Regulates Ca2+ influx through NMDAR
- Promotes appropriate calcium signaling for neuronal survival
- Prevents excitotoxic damage while maintaining physiological function
In PD, multiple factors contribute to NMDAR dysfunction:
- Dopaminergic denervation reduces D-serine release from substantia nigra neurons
- Glial dysfunction impairs D-serine synthesis and recycling
- Oxidative stress alters NMDAR subunit composition and function
These changes result in NMDAR hypofunction, which may accelerate dopaminergic neuron death through impaired plasticity and reduced trophic support. D-serine supplementation aims to correct this hypofunction and restore protective NMDAR signaling.
Preclinical studies in various PD animal models have demonstrated:
- MPTP-induced parkinsonism: D-serine administration protected dopaminergic neurons from MPTP toxicity
- 6-OHDA model: D-serine improved behavioral outcomes and reduced lesion volume
- α-synuclein transgenic models: D-serine attenuated neurodegeneration and motor deficits
- D-serine levels are reduced in the substantia nigra of PD patients
- NMDAR subunits show altered expression in PD brains
- GlyB site agonists show promise in neuroprotective paradigms
¶ Randomization and Blinding
Patients will be randomized 1:1 to receive either:
- D-serine (dose TBD)
- Matching placebo
Double-blind design ensures neither patients nor investigators know the allocation.
- Oral D-serine administration
- Dose titration to target dose over 4 weeks
- Maintenance treatment for 52 weeks
- Follow-up period post-treatment
- Change in MDS-UPDRS Part III (motor) score
- Safety and tolerability assessment
- Motor symptom progression (MDS-UPDRS Total)
- Non-motor symptoms (NMS Scale, MoCA)
- Quality of life measures (PDQ-39)
- Biomarker assessments