# Mechanisms of Dantrolene Neuroprotection in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $332,767

## Abstract

Abstract
 Coronavirus disease 2019 (COVID-19), a pandemic affecting millions of patients around
the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with no
effective drug treatments. Both infection and transfection of virus in host cells require
abnormally elevated Ca2+ concentrations in cytosol and endosome via overactivation of
ryanodine receptors (RyRs) Ca2+ channel located on the membrane of the endoplasmic
reticulum (ER). Dantrolene, an antagonist of RyRs, has been demonstrated to inhibit SARS-
CoV-2-mediated host cell toxicity and damage. In the presence of RyRs overactivation and
excessive and abnormal elevation of cytosolic and endosome Ca2+ concentrations, the spike
proteins (S1, S2) of the virus play important roles in binding, fusion, and virus replication in the
host cell, eventually leading to cell damage or death. Our long-term goal is to examine the
efficacy and mechanisms of dantrolene to treat AD. The overall objective of this study is to
investigate the effects and underlying mechanisms of dantrolene to protect against host cell
damage or death induced by SARS-CoV-2 spike proteins-mediated overactivation of RyRs and
associated Ca2+ dysregulation. Our central hypothesis supported by preliminary data is that
dantrolene inhibits SARS-CoV-2 spike proteins-mediated cell damage by inhibiting the
overactivation of RyRs and by restoring intracellular Ca2+ homeostasis in AD cells. We
will test this hypothesis with the following specific aims. Specific Aim 1 (SA1). To determine
the effects of dantrolene on SARS-CoV-2 spike (S) proteins-mediated Ca2+ dysregulation
and cell damage by apoptosis in AD cells using induced pluripotent stem cells (iPSC), from
skin fibroblasts of patients with either sporadic (SAD) or familial (FAD), and human
neuroblastoma cells (SH-SY5Y), with knocked-in AD presenilin 1 mutation (M146L). Specific
Aim 2 (SA2). To determine the effects and mechanisms of dantrolene on SARS-CoV-2
spike (S) proteins-mediated pathological pathways leading to host cell damage. We will
examine the effects of S proteins on mitochondria oxygen consumption, ATP production,
reactive oxygen species (ROS) production, ER stress, and cytokine release. We will correlate
the results between SA1 and SA2. We expect that dantrolene will inhibit S proteins-mediated
overactivation of RyRs and associated disruption of intracellular Ca2+ homeostasis and cell
death by apoptosis.

## Key facts

- **NIH application ID:** 10227272
- **Project number:** 3R01AG061447-03S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** HUAFENG WEI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $332,767
- **Award type:** 3
- **Project period:** 2019-03-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10227272

## Citation

> US National Institutes of Health, RePORTER application 10227272, Mechanisms of Dantrolene Neuroprotection in Alzheimer's Disease (3R01AG061447-03S1). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10227272. Licensed CC0.

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