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
United States
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Mann, Aman P; Scodeller, Pablo; Hussain, Sazid et al. (2018) Publisher Correction: Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer's disease. Nat Commun 9:1070
Nagar, Saumya; Noveral, Sarah M; Trudler, Dorit et al. (2017) MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress. Proc Natl Acad Sci U S A 114:E4048-E4056
Mann, Aman P; Scodeller, Pablo; Hussain, Sazid et al. (2017) Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer's disease. Nat Commun 8:1403
Tu, Shichun; Akhtar, Mohd Waseem; Escorihuela, Rosa Maria et al. (2017) NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism. Nat Commun 8:1488
Satoh, Takumi; Lipton, Stuart (2017) Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate. F1000Res 6:2138
Nakamura, Tomohiro; Lipton, Stuart A (2017) 'SNO'-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders. Trends Endocrinol Metab 28:879-892
Chen, Shanyan; Cui, Jiankun; Jiang, Tao et al. (2017) Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke. J Cereb Blood Flow Metab 37:188-200
Nagar, Saumya; Trudler, Dorit; McKercher, Scott R et al. (2017) Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency. Invest Ophthalmol Vis Sci 58:3741-3749
Nakamura, Tomohiro; Lipton, Stuart A (2016) Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases. Trends Pharmacol Sci 37:73-84
Macrez, Richard; Stys, Peter K; Vivien, Denis et al. (2016) Mechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities. Lancet Neurol 15:1089-102

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