# Neurotrophic strategy to mitigate chemotherapy-related brain injury

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $476,970

## Abstract

ABSTRACT
Cancer-related cognitive impairment (CRCI), often referred as “chemobrain”, is prevalent up to
75% of all breast cancer survivors. These impairments cause significant distress and reduce the
quality for life for survivors. Despite growing realization of the long-term clinical problem of CRCI
in millions of cancer survivors, there is a conspicuous absence of clinical recourse available.
Therefore, regenerative strategies to restore cognition and normal brain function in the cancer
patients and survivors are clearly needed. Our past clinical and pre-clinical studies have
established that doxorubicin, which is commonly used in breast cancer, can lead to a significant
decline in the blood (human) and brain (rodent) levels of brain derived neurotrophic factor (BDNF).
BDNF is abundantly expressed in the prefrontal cortex and hippocampus and plays important
roles in neuronal repair and survival, dendritic and axonal growth, long-term potentiation, and
neural stem cell maintenance. In our human studies, pathological reductions of BDNF were linked
to higher risk of cognitive toxicity. Similarly, we have shown that chronic chemotherapy
significantly impaired performance on the hippocampus and cortex-dependent cognitive tasks in
the rodents. These deficits were linked with reduced neurogenesis, elevated neuroinflammation,
and significant damage to the newly born and mature neuronal architecture, dendrites, spines,
and synaptic integrity. To mitigate these deficits, our preliminary rodent studies involving mice
receiving doxorubicin with riluzole, an orally active glutamate-modulating medication, has
prevented the reduction of hippocampus BDNF levels. Thus, we hypothesize that: i)
chemotherapy-induced reduction of BDNF leads to the long-term neurodegenerative
consequences culminating into cognitive impairments and, ii) augmentation of BDNF in vivo will
restore cognitive function in brains exposed to chemotherapy and will provide neuroprotection
against CRCI. We will test our hypothesis with three specific aims. In Aim 1, we will systematically
examine brain and plasma BDNF levels to link its trajectory with CRCI and neurobiological
underpinnings in a mouse model of breast cancer chemotherapy. In Aim 2, we will determine the
neuroprotective impact of enhancing BDNF in vivo to reverse CRCI. In Aim 3, we will evaluate
the neuroprotective effect of BDNF-enhancing riluzole to ameliorate CRCI. This study will link the
neurobiological underpinnings of chemotherapy and neuroprotective effects of BDNF against
CRCI. If demonstrated to be successful, our translationally feasible pharmacological
approach will provide basis for future studies to repurpose riluzole as a therapeutic option
for mitigating CRCI.

## Key facts

- **NIH application ID:** 10922862
- **Project number:** 5R01CA276212-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Munjal M Acharya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $476,970
- **Award type:** 5
- **Project period:** 2023-09-06 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922862

## Citation

> US National Institutes of Health, RePORTER application 10922862, Neurotrophic strategy to mitigate chemotherapy-related brain injury (5R01CA276212-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10922862. Licensed CC0.

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