# A Cholesterol metabolite functions as an endogenous neuroprotectant through blockade of ASIC

> **NIH NIH SC3** · MOREHOUSE SCHOOL OF MEDICINE · 2020 · $106,500

## Abstract

Project Summary/Abstract
 Oxysterols, the oxygenated derivatives of cholesterol, have been identified for several
decades, however, their roles in the physiology and pathological processes, particularly in
nervous system, are largely unknown. Our previous study showed that the major cholesterol
metabolite, cholestane-3β, 5α, 6β-triol (Triol), functions as an important endogenous
neuroprotectant. Here, we hypothesize that blockade of acid-sensing ion channel (ASIC) 1a
serves as a novel mechanism underlying its neuroprotective effect, based on the following
arguments and preliminary data: (1) The concentration of Triol increases after ischemic
preconditioning (IPC), which contributes to IPC mediated neuroprotection; (2) The activation of
calcium permeable ASIC1a exacerbates ischemic injury, and that pharmacological blockade or
knockout of ASIC1a produces a significant protection; (3) In brain ischemia, blockade of ASIC1a
has a therapeutic time window of ~5h, which is close to that of Triol (> 4h); (4) Our preliminary
data clearly demonstrated that Triol significantly inhibits ASIC1a currents as well as its surface
expression, at a concentration that occurs during ischemic preconditioning; (5) The preliminary
data suggest that the inhibition of ASIC is specific to Triol, as its precursor cholesterol has no
effect on ASIC currents. To rigorously test the hypothesis that Triol functions as an endogenous
neuroprotectant through blockade of ASIC1a, the following specific aims will be examined:
Aim 1. Determine the effect of Triol on ASIC current and calcium entry.
Aim 2. Determine the inhibitory effect of Triol on ASIC1a surface expression.
Aim 3. Determine whether the neuroprotection caused by Triol is mediated through inhibition of
ASIC1a.
Aim 4. Study the structure-activity relationship, and identify the amino acids that mediate the
inhibitory effect of Triol on ASIC1a.

## Key facts

- **NIH application ID:** 9849299
- **Project number:** 5SC3GM122593-03
- **Recipient organization:** MOREHOUSE SCHOOL OF MEDICINE
- **Principal Investigator:** TIANDONG LENG
- **Activity code:** SC3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $106,500
- **Award type:** 5
- **Project period:** 2018-02-06 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849299

## Citation

> US National Institutes of Health, RePORTER application 9849299, A Cholesterol metabolite functions as an endogenous neuroprotectant through blockade of ASIC (5SC3GM122593-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9849299. Licensed CC0.

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