# Therapeutic implications of purinergic receptor P2X4 in ischemic stroke

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $414,687

## Abstract

Abstract/Summary
Cerebrovascular diseases including ischemic stroke contribute to Alzheimer disease (AD) neuropathological
changes, including brain atrophy and accumulation of abnormal proteins such as amyloid beta (Aβ). In the
geriatric population, the incidence of dementia significantly increases after stroke. Nevertheless, the molecular
links between stroke and dementia are not clearly understood but could be related to neuroinflammation.
Neuroinflammation plays a key role in the pathogenesis of AD, the most prevalent form of dementia. Among
the innate immune cells, brain resident microglia and infiltrated monocytes –– collectively called brain
macrophages –– are the primary players in neuroinflammation. Activated brain macrophages exhibit diverse
phenotypes and complex interactions during AD pathology. P2X4R, the most calcium-permeable and robust
P2XR subtype present on brain macrophages, is activated by extracellular ATP. Acute activation of P2X4R on
macrophages leads to inflammasome formation and thus may contribute to progressive neuroinflammation
during AD progression. We previously showed that P2X4R expression and activity in myeloid cells increases
swiftly and exacerbates injury after ischemic stroke. Either pharmacological inhibition or genetic deletion of
P2X4R showed acute neuroprotective effects after stroke in young adult mice. P2X4R blockade reduces
microglial activation and CNS infiltration of peripheral monocytes after stroke. Infiltrated monocytes from
P2X4R KO mice show increased clearance of dead tissue after stroke. These data support the hypothesis that
P2X4R activation of both circulating monocytes and microglia exacerbate neuroinflammation and inhibit post-
stroke recovery. We will use our mouse model of myeloid cell-specific P2X4R deficiency in conjunction with
3xTG AD model to evaluate P2X4R and/or its downstream targets for the treatment of AD and AD-related
dementia. In the following two aims, we want to know: 1) If P2X4R expression increases in the 3xTG AD
mouse model and if its absence reduces brain damage; and 2) If deletion of P2X4R on myeloid cells improves
the cognitive deficiencies that occur in AD mice with or without stroke. Regardless of the results, these simple
aims will be able to identify if P2X4R plays a role in AD progression.

## Key facts

- **NIH application ID:** 10711456
- **Project number:** 3R01NS125405-02S1
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Rajkumar Verma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $414,687
- **Award type:** 3
- **Project period:** 2022-06-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10711456

## Citation

> US National Institutes of Health, RePORTER application 10711456, Therapeutic implications of purinergic receptor P2X4 in ischemic stroke (3R01NS125405-02S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10711456. Licensed CC0.

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