Antagonism of NMDA receptors as a potential treatment for Down syndrome: A pilot randomized controlled trial

Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Translational Psychiatry (Impact Factor: 5.62). 07/2012; 2(7):e141. DOI: 10.1038/tp.2012.66
Source: PubMed


Down syndrome (DS) is the most common genetic cause of intellectual disability. The N-methyl-D-aspartate (NMDA) receptor uncompetitive antagonist, memantine hydrochloride (memantine), has been shown to improve learning/memory and rescue one form of hippocampus synaptic plasticity dysfunction in the best-studied mouse model of DS available, the Ts65Dn mouse. Given the status of memantine as a treatment for Alzheimer's disease (AD) approved by the Food and Drug Administration, the preclinical evidence of potential efficacy in Ts65Dn mice, and the favorable safety profile of memantine, we designed a study to investigate whether the findings in the mouse model could be translated to individuals with DS. In this pilot, proof-of-principle study we hypothesized that memantine therapy would improve test scores of young adults with DS on measures of episodic and spatial memory, which are generally considered to be hippocampus dependent. Accordingly, in this randomized, double-blind, placebo-controlled trial, we compared the effect of 16-week treatment with either memantine or placebo on cognitive and adaptive functions of 40 young adults with DS using a carefully selected set of neuropsychological outcome measures. Safety and tolerability were also monitored. Although no significant differences were observed between the memantine and placebo groups on the two primary outcome measures, we found a significant improvement in the memantine group in one of the secondary measures associated with the primary hypothesis. Only infrequent and mild adverse events were noted.

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    • "Epigallocatechin gallate, a green tea polyphenol, that modulates DYRK1A functioning is proved to be helpful in enhancement of cognitive performance in DS patients[103]. The N-methyl-D-aspartate (NMDA) receptor uncompetitive antagonist, memantine hydrochloride (memantine), is able to improve learning/ memory and save one type of hippocampus synaptic plasticity dysfunction in the best-studied mouse model of DS[104]. The use of folinic acid or antioxidants in DS patients is not supported by scientific evidence and do not improve the cognitive performance in such patients. "
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    ABSTRACT: Children and adolescents with DS are exposed to significant physical, sexual and emotional developmental changes. They also often have some psychiatric problems as externalizing disorders, depression, anxiety and/or obsessive-compulsive disorder. They also suffer from behavior and psychosocial problems in the process of their growth, such as expressing their feelings, learning problems as their shortage of language and cognition. Children with DS are amenable for good education and they can enter a special education school for special education, so that training of their fine motor, gross motor and intellectual abilities is helpful to improve their development. They can be encouraged to improve body functions and accentuating gaining more functional proficiencies that facilitate improving participation in age-suitable activities. Early detection and proper treatment of emotional, psychiatric or developmental disorders ensure good prognosis.
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    • "Indeed, the Tc1 mice show protein abnormalities potentially relevant to oxidative stress, and NMDA and GABA receptor signaling. Drugs targeting each of these processes have been or are being used in clinical trials with people with DS (52–54). So far, antioxidants and the NMDA receptor antagonist, memantine, have shown no or very limited benefit. "
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    ABSTRACT: The Tc1 mouse model of Down syndrome (DS) is functionally trisomic for approximately 120 human chromosome 21 (HSA21) classical protein coding genes. Tc1 mice display features relevant to the DS phenotype, including abnormalities in learning and memory and synaptic plasticity. To determine the molecular basis for the phenotypic features, levels of 90 phosphorylation-specific and phosphorylation-independent proteins were measured by Reverse Phase Protein Arrays in hippocampus and cortex, and 64 in cerebellum, of Tc1 mice and littermate controls. Abnormal levels of proteins involved in MAP kinase, mTOR, GSK3B and neuregulin signaling were identified in trisomic mice. In addition, altered correlations among levels of NMDA receptor subunits and the HSA21 proteins APP and TIAM1, and between immediate early gene (IEG) proteins and the HSA21 protein SOD1 were found in hippocampus of Tc1 mice, suggesting altered stoichiometry among these sets of functionally interacting proteins. Protein abnormalities in Tc1 mice were compared with results of a similar analysis of Ts65Dn mice, a DS mouse model that is trisomic for orthologs of 50 genes trisomic in the Tc1 plus an additional 38 HSA21 orthologs. While there are similarities, abnormalities unique to the Tc1 include increased levels of the S100B calcium binding protein, mTOR proteins RAPTOR and P70S6, the AMP-kinase catalytic subunit AMPKA, the IEG proteins CFOS and ARC, and the neuregulin 1 receptor ERBB4. These data identify novel perturbations, relevant to neurological function and to some seen in Alzheimer's Disease, that may occur in the DS brain, potentially contributing to phenotypic features and influencing drug responses.
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    ABSTRACT: Running may affect the mood, behavior and neurochemistry of running animals. In the present study, we investigated whether voluntary daily running, sustained over several months, might improve cognition and motor function and modify the brain levels of selected proteins (SOD1, DYRK1A, MAP2, APP and synaptophysin) in Ts65Dn mice, a mouse model for Down syndrome (DS). Ts65Dn and age-matched wild-type mice, all females, had free access to a running wheel either from the time of weaning (post-weaning cohort) or from around 7 months of age (adult cohort). Sedentary female mice were housed in similar cages, without running wheels. Behavioral testing and evaluation of motor performance showed that running improved cognitive function and motor skills in Ts65Dn mice. However, while a dramatic improvement in the locomotor functions and learning of motor skills was observed in Ts65Dn mice from both post-weaning and adult cohorts, improved spatial memory was seen only in Ts65Dn mice that had free access to the wheel from weaning. The total levels of APP and MAP2ab were reduced and the levels of SOD1 were increased in the runners from the post-weaning cohort, while only the levels of MAP2ab and α-cleaved C-terminal fragments of APP were reduced in the adult group in comparison with sedentary trisomic mice. Hence, our study demonstrates that Ts65Dn females benefit from sustained voluntary physical exercise, more prominently if running starts early in life, providing further support to the idea that a properly designed physical exercise program could be a valuable adjuvant to future pharmacotherapy for DS.
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