Hyperhomocysteinemia is a common metabolic disorder that causes significant increase in the total level of plasma homocysteine. In spite of the FDA-mandated fortification of food with folic acid, as an attempt to lower homocysteine level, the incidence of hyperhomocysteinemia in the elderly population is still quite large. This is mainly due to lowered nutritional absorption and decreased metabolic function with advanced age. Epidemiological studies have established that hyperhomocysteinemia is a risk factor for neurological diseases. However, the direct impact of hyperhomocysteinemia on the outcome of neurological diseases is still not known. Our findings now show that ischemic insult under hyperhomocysteinemic condition leads to concurrent activation of a novel signaling pathway involving GluN2A-NMDAR activation that in conjunction with the canonical pathway exacerbates ischemic brain injury. The long-term goal of our research is to develop therapeutic interventions for reducing the adverse effect of hyperhomocysteinemia on cerebral ischemia and related neurodegenerative disorders. The objective of this particular application is to delineate whether GluN2A-NMDAR mediated neuroinflammation plays a central role in the exacerbation of ischemic brain damage under hyperhomocysteinemic condition. The central hypothesis is that under hyperhomocysteinemic condition, GluN2A-NMDAR-mediated excessive release of the pro-inflammatory mediators MCP-1 and PGE2 from neurons results in augmentation of post-ischemic microglial activation and peripheral immune cell infiltration. The proposed studies will use (1) primary neuronal cultures to delineate the signaling cascade, downstream of homocysteine-GluN2A-NMDAR stimulation, involved in the increased expression and release of MCP-1 and PGE2 from neurons; (2) hyperhomocysteinemic rat and mice, as well as a series of conditional knockout mice to evaluate the role GluN2A-NMDAR in post-ischemic augmentation of inflammatory response in hyperhomocysteinemic animals; and (3) magnetic resonance imaging (MRI) and a battery of behavioral tests to evaluate the long-term efficacy of post-ischemic inhibition of GluN2A-NMDAR signaling pathway in reducing brain damage in hyperhomocysteinemic animals. The proposed research is significant since it will fill a knowledge gap that is critical for future designing of novel therapeutic targets to mitigate the severity of stroke outcome under hyperhomocysteinemic condition.

Public Health Relevance

The proposed studies will evaluate whether pre-disposition to mild hyperhomocysteinemic conditions could accelerate and enhance the neuro-inflammatory response in the brain following an ischemic insult, resulting in exacerbation of brain damage. The research is relevant to public health because the findings can help in the development of potentially novel therapeutic agents for intervention in cerebral ischemia and other age related neurodegenerative disorders in hyperhomocysteinemic individuals. The project is also relevant to NINDS mission that pertains to advance our fundamental knowledge about the signaling pathways that are activated in hyperhomocysteinemic individuals during ischemia and the application of the knowledge to reduce the extent of disability and mortality in this population.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Bosetti, Francesca
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University of New Mexico Health Sciences Center
Schools of Medicine
United States
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Poddar, Ranjana; Chen, Alexandria; Winter, Lucas et al. (2017) Role of AMPA receptors in homocysteine-NMDA receptor-induced crosstalk between ERK and p38 MAPK. J Neurochem 142:560-573
Poddar, Ranjana; Rajagopal, Sathyanarayanan; Winter, Lucas et al. (2017) A peptide mimetic of tyrosine phosphatase STEP as a potential therapeutic agent for treatment of cerebral ischemic stroke. J Cereb Blood Flow Metab :271678X17747193
Poddar, Ranjana; Rajagopal, Sathyanarayanan; Shuttleworth, C William et al. (2016) Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of the Brain-enriched Tyrosine Phosphatase STEP: MOLECULAR BASIS FOR ZN2+-INDUCED ERK MAPK ACTIVATION. J Biol Chem 291:813-25
Rajagopal, Sathyanarayanan; Deb, Ishani; Poddar, Ranjana et al. (2016) Aging is associated with dimerization and inactivation of the brain-enriched tyrosine phosphatase STEP. Neurobiol Aging 41:25-38