# Molecular basis of hyperhomocysteinemia induced brain injury in ischemic stroke

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $592,165

## Abstract

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.

## Key facts

- **NIH application ID:** 9973002
- **Project number:** 2R01NS083914-06
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Ranjana Poddar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $592,165
- **Award type:** 2
- **Project period:** 2014-05-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973002

## Citation

> US National Institutes of Health, RePORTER application 9973002, Molecular basis of hyperhomocysteinemia induced brain injury in ischemic stroke (2R01NS083914-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9973002. Licensed CC0.

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