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)
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Sanford-Burnham Medical Research Institute
La Jolla
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Akhtar, Mohd Waseem; Sanz-Blasco, Sara; Dolatabadi, Nima et al. (2016) Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation. Nat Commun 7:10242
Nakamura, Tomohiro; Lipton, Stuart A (2016) Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases. Trends Pharmacol Sci 37:73-84
Nakanishi, Nobuki; Kang, Yeon-Joo; Tu, Shichun et al. (2016) Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model. J Mol Neurosci 58:59-65
Sanz-Blasco, Sara; Piña-Crespo, Juan C; Zhang, Xiaofei et al. (2016) Levetiracetam inhibits oligomeric Aβ-induced glutamate release from human astrocytes. Neuroreport 27:705-9
Nakamura, Tomohiro; Lipton, Stuart A (2016) Nitrosative Stress in the Nervous System: Guidelines for Designing Experimental Strategies to Study Protein S-Nitrosylation. Neurochem Res 41:510-4
Sunico, Carmen R; Sultan, Abdullah; Nakamura, Tomohiro et al. (2016) Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons. Proc Natl Acad Sci U S A 113:E7564-E7571
Nakamura, Tomohiro; Prikhodko, Olga A; Pirie, Elaine et al. (2015) Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. Neurobiol Dis 84:99-108
Satoh, Takumi; Stalder, Romain; McKercher, Scott R et al. (2015) Nrf2 and HSF-1 Pathway Activation via Hydroquinone-Based Proelectrophilic Small Molecules is Regulated by Electrochemical Oxidation Potential. ASN Neuro 7:
Galluzzi, L; Bravo-San Pedro, J M; Vitale, I et al. (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 22:58-73
Zhang, Dongxian; Lee, Brian; Nutter, Anthony et al. (2015) Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid. J Neurochem 133:898-908

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