Project II - Lipton Program Director/Principal Investigator (Last, First, Middle): Llpton, Stuart A. PROJECT SUMMARY (See instructions): Since NMDA-type glutamate receptors play an important role in both normal and abnormal function of the CNS, it is important to develop a drug that has minimal effects on normal NMDAR function, such as synaptic transmission and plasticity, but has significant effects during pathological conditions of excessive stimulation. This Team of Investigators was the first to show that Memantine, a charged adamantane drug that is a low affinity NMDAR antagonist, is clinically tolerated because of its unique mechanism of action in the NMDAR channel, termed Uncompetitive, Fast Off-rate {UFO;Lipton, 2007). This work greatly contributed to the FDA approval of Memantine for Alzheimer's disease. In the past five years, we developed drugs with improved efficacy over Memantine, termed NitroMemantine drugs. The new drugs take advantage of additional sites on the NMDAR for S-nitrosylation (transfer ofthe NO group to critical Cys residues), which we discovered decrease excessive receptor activity, in combination with the channel blocking effect of Memantine. We found that NitroMemantine compounds decrease hypoxic-ischemic disease in the newborn and adult to a greater extent than Memantine. These drugs avoid systemic side effects of NO by targeting the NO group to the NMDAR via attachment to the Memantine moiety (as shown in Project I). Of importance, redox-active adduct of NitroMemantine (the nitro group) is an alkyl nitrate and therefore lacks the toxicity of true nitric oxide (NO) since it has one less electron than NO'and consequently has different chemical reactivity. Our studies with novel/safe NMDAR antagonists have important implications for the treatment of various forms of mental retardation and developmental disabilities due to overstimulation of extrasynaptic glutamate receptors that injure synapses, as we recently published. Here, we propose to develop these novel NMDAR antagonists in vitro and in vivo in animal models to treat cognitive dysfunction in Down syndrome by carrying out the following specific aims. 1) To characterize the contribution of synaptic vs. extrasynaptic NMDAR activity in p-amyloid (AB)?mediated neuronal damage related to Down syndrome. 2) To restore synaptic vs. extrasynaptic 'balance'in the hippocampal autapse in vitro model using the novel NMDAR antagonist NitroMemantine vs. Memantine in order to prevent B-amyloid (AB)?mediated neuronal damage. For these experiments, we will use induced pluripotent stem cell (iPSC)-derived and fetal brain-derived neurons from Down syndrome patients. 3) To treat the cognitive deficits associated with Down syndrome in vivo in the Ts65Dn mouse model by normalizing the balance between synaptic and extrasynaptic activity with NitroMemantine treatment.

Public Health Relevance

This grant aims to develop novel, clinically-tolerated NMDA receptor antagonists called NitroMemantines in order to prevent cognitive deficits seen in Down syndrome (DS). Neurons in DS manifest synaptic damage, in part exemplified by a loss of thin dendritic spines. We show here that our novel NMDA receptor antagonists can prevent this dendritic spine loss, which occurs in part because of AB oligomers, and thus can protect synapses and improve cognitive deficits in DS.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-N (51))
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Okamoto, Shu-ichi; Lipton, Stuart A (2015) S-Nitrosylation in neurogenesis and neuronal development. Biochim Biophys Acta 1850:1588-93
Zhu, Saiyong; Ambasudhan, Rajesh; Sun, Woong et al. (2014) Small molecules enable OCT4-mediated direct reprogramming into expandable human neural stem cells. Cell Res 24:126-9
Jeon, Gye Sun; Nakamura, Tomohiro; Lee, Jeong-Seon et al. (2014) Potential effect of S-nitrosylated protein disulfide isomerase on mutant SOD1 aggregation and neuronal cell death in amyotrophic lateral sclerosis. Mol Neurobiol 49:796-807
Chan, Shing Fai; Sances, Sam; Brill, Laurence M et al. (2014) ATM-dependent phosphorylation of MEF2D promotes neuronal survival after DNA damage. J Neurosci 34:4640-53
Choi, Min Sik; Nakamura, Tomohiro; Cho, Seung-Je et al. (2014) Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in parkinson's disease models. J Neurosci 34:15123-31
Okamoto, Shu-Ichi; Nakamura, Tomohiro; Cieplak, Piotr et al. (2014) S-nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death. Cell Rep 8:217-28
Molokanova, Elena; Akhtar, Mohd Waseem; Sanz-Blasco, Sara et al. (2014) Differential effects of synaptic and extrasynaptic NMDA receptors on A?-induced nitric oxide production in cerebrocortical neurons. J Neurosci 34:5023-8
Marco, Sonia; Giralt, Albert; Petrovic, Milos M et al. (2013) Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models. Nat Med 19:1030-8
Sunico, Carmen R; Nakamura, Tomohiro; Rockenstein, Edward et al. (2013) S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson's disease. Mol Neurodegener 8:29
Talantova, Maria; Sanz-Blasco, Sara; Zhang, Xiaofei et al. (2013) A? induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A 110:E2518-27

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