# Novel therapeutic approaches for traumatic brain injury induced cognitive deficits

> **NIH NIH R01** · SAINT LOUIS UNIVERSITY · 2022 · $331,406

## Abstract

Deficits in participation-level performance of specific cognitive tasks are one of the primary cognitive
impairments reported after a mild TBI.3 There are no FDA-approved preventive or curative interventions.
Mitochondrial dysfunction4-10 and neuroinflammation11-15 in the central nervous system (CNS) are postulated as
underlying causes of cognitive impairment. Our preliminary data suggests that dysregulation of adenosine
metabolism and loss of signaling at the A3 adenosine receptor (AR) subtype (A3AR) is key to these processes.
Extracellular adenosine is regulated by ectonucleotidases and adenosine kinase and preliminary results in a
mouse model of mild-TBI (close head weight drop)2,16 revealed that TBI altered the expression of these
enzymes in the prefrontal cortex (PFC) and hippocampus. This was associated with time dependent
development of memory and learning deficits [Novel Object/Place Recognition (NOPRT) and T-maze tests].
Supplementing adenosine signaling with highly selective, orally bioavailable, CNS penetrant A3AR agonists
given therapeutically significantly attenuated TBI-induced memory and learning deficits 4 weeks after injury
without any confounding influence on locomotor activity. Moreover, pilot data now links A3AR agonism to the
inhibition of TBI-induced oxidative/nitrative stress (nitroxidative stress), neuroinflammation and activation of
nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. Our findings are very exciting since A3AR
agonists (e.g., IB-MECA) are already in advanced clinical trials for other indications with a good safety
profile.17,18 Two Specific Aims will test our hypothesis: dysregulation of adenosinergic signaling in the brain
contributes to TBI-induced cognitive impairment; restoring adenosinergic signaling with highly selective A3AR
agonists is an effective strategy for therapeutic intervention. A multidisciplinary approach is used in male and
female mice. Pharmacological and genetic studies as well as time course and dose responses with selective
A3AR agonists are proposed. Studies will also include A3AR antagonists and A3AR knockout mice to confirm
selectivity of response. In Aim 1, we will examine whether a decrease in adenosine signaling at the A3AR
contributes to TBI-induced cognitive deficits. In Aim 2, we will 1) examine whether restoring A3AR signaling
with A3AR agonists ameliorates TBI-induced cognitive deficits, 2) validate A3AR as a target for therapeutic
intervention with selective A3AR agonists and 3) investigate their mechanism of action by examining their
impact on the mitochondrial dysfunction and neuroinflammatory processes that are intimately linked to the
development of cognitive deficits. Our multidisciplinary research plan is anticipated to provide evidence for the
applicability of highly selective A3AR agonists to preserve cognitive function following TBI while investigating
their underlying protective mechanism(s).

## Key facts

- **NIH application ID:** 10307126
- **Project number:** 5R01NS111120-03
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** SUSAN A FARR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $331,406
- **Award type:** 5
- **Project period:** 2019-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307126

## Citation

> US National Institutes of Health, RePORTER application 10307126, Novel therapeutic approaches for traumatic brain injury induced cognitive deficits (5R01NS111120-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10307126. Licensed CC0.

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