# Innovative memantine therapy for neuroprotective effects against ischemic stroke and Alzheimer's disease

> **NIH VA I21** · VETERANS HEALTH ADMINISTRATION · 2023 · —

## Abstract

Two of most common neurological diseases among aging veterans are Alzheimer’s disease (AD) and stroke.
Unfortunately, there are limited clinical treatments for either of these diseases. Clinically, AD and stroke are
most likely to strike the same individuals of the aging population. The comorbidity of these two devastating
diseases in the same patients represents a greater challenge for pre-clinical research and clinical treatments.
Noticeably, AD and stroke share some common pathophysiological mechanisms such as NMDA receptor
(NMDAR) hyperactivation-induced excitotoxicity, inflammation, and neurovascular destructions. These two
neurological disorders, however, have been investigated mainly in separate research fields. The interplay of
AD and stroke have rarely been studied, while both are in urgent needs for effective treatments. Memantine
(MEM) is an FDA approved NMDAR antagonist, recommended as a symptomatic treatment for moderate to
severe AD patients. MEM, like other NMDAR antagonists but with unique safety record in clinical applications,
is highly neuroprotective against ischemic stroke. A significant dilemma is that a NMDAR antagonist has to
be administered before or soon (≤3 hours) after the onset of stroke, which is generally impractical in clinical
settings. In this exploratory high potential project, we propose to test the novel hypothesis that early MEM
treatment at mild and moderate AD stages can have dual efficacy of ameliorating AD progression while
priming (preconditioning) the AD brain for enhanced tolerance against ischemic attack that may occur at any
time to >50% AD patients. In a typical AD model of 5xFAD mouse of 4 months old (mild stage group) and 6
months old (moderate stage group), MEM (10 mg/kg/day) will be given in drinking water for 1 month to mimic
chronic AD treatment. Mice will then be subjected to focal ischemic stroke and the protective effect of the
MEM pre-treatment against stroke will be evaluated 3 and 28 days later in comparison to control groups. In
long-term experiments with continued MEM, the AD pathology progression, neurovascular deterioration, key
molecular signals, inflammatory factors, and psychological/cognitive functions will be monitored up to 2
months after stroke. The therapeutic strategy targeting NMDAR hyperactivity and brain preconditioning is
supported by compelling basic and clinical evidence, while the MEM dual effect therapy for AD and stroke
has not been investigated before. Being an FDA approved drug, the anti-AD and anti-stroke MEM treatment
is expected to have a high translational potential readily leading to consequent clinical trials and a game-
change approach for veterans who are susceptible to AD and stroke. It will support more cross-field
investigations for a better understanding of interactive mechanisms and identifying more therapeutic targets
in the comorbidity of these two neurological diseases.

## Key facts

- **NIH application ID:** 10480182
- **Project number:** 1I21RX003865-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Shan P. Yu
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-11-01 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480182

## Citation

> US National Institutes of Health, RePORTER application 10480182, Innovative memantine therapy for neuroprotective effects against ischemic stroke and Alzheimer's disease (1I21RX003865-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10480182. Licensed CC0.

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