# Mitigation of cognitive impairments from radiation therapy

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2023 · —

## Abstract

PROJECT SUMMARY / ABSTRACT
The long-term goal of this proposal is to reduce the adverse late effects of radiation therapy in normal CNS
tissues to ultimately improve the quality of life and extend survival of patients with brain tumors. Radiation therapy
is frequently used in patients with primary or metastatic brain tumors following surgical resection, or in diffused
non-operable brain tumors. However, radiation therapy in the brain often leads to defects in neurocognitive
functions, which limits the level of radiation doses that can be safely administered. Consequently, there is a
critical need to reduce the late effects of radiation therapy in normal brain tissues. The cognitive impairments
point to persistent defects in the hippocampus. Studies in animal models suggest that persistent oxidative stress,
inflammation in the CNS, attrition of the dendritic networks, and reduced production of neurotrophic factors may
contribute to deficits in learning and memory by hindering network connectivity and reducing the production of
new neurons in the hippocampus. Based on these findings, we used a Mn porphyrin-based redox-active drug,
MnBuOE, to suppress oxidative stress and a small molecule flavonoid compound, 7,8-dihydrxyflavone (7,8-
DHF), to mimic the action of neurotrophic factors in cranial irradiation studies with mice. We found both drugs to
increase the production of new neurons important for learning and memory, but each effected a different process
of new neuron production. Whereas MnBuOE promoted the production of immature neurons, 7,8-DHF supported
maturation and long-term survival of newborn neurons. Furthermore, 7,8-DHF treatment also led to preserved
normal cognitive functions, dendritic spine densities, and synaptic proteins levels. The complementary actions
of these two drugs leads us to hypothesize that combined treatment with MnBuOE and 7,8-DHF during
different stages of radiation therapy may provide additive or synergistic effects in preserving normal
cognitive functions. To test the hypothesis and examine the mechanisms underlying preserved cognitive
functions from MnBuOE and 7,8-DHF treatment, we propose to (1) assess the impacts of MnBuOE and 7,8-DHF
treatments on cognitive functions in young adult mice following cranial irradiation; (2) examine the effects of
MnBuOE and 7,8-DHF treatments on cognitive functions in middle-aged mice following cranial irradiation; (3)
investigate the effects of MnBuOE and 7,8-DHF treatments on inhibitory neurons in middle-aged mice following
cranial irradiation; and (4) examine how combined treatments of MnBuOE, 7,8-DHF, and cranial irradiation affect
the growth or survival of glioblastoma. Non-tumor bearing mice will be treated with different combinations of
MnBuOE and 7,8-DHF before and after cranial irradiation. Behavioral, immunohistochemical, biochemical, and
molecular biological approaches will be used to investigate changes in cognitive functions, dendritic structures,
neuroinflammation, an...

## Key facts

- **NIH application ID:** 10695986
- **Project number:** 5I01BX004487-05
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** Ting-Ting Huang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695986

## Citation

> US National Institutes of Health, RePORTER application 10695986, Mitigation of cognitive impairments from radiation therapy (5I01BX004487-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10695986. Licensed CC0.

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