# Preconditioning brain white matter against ischemia

> **NIH NS R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2026 · $575,751

## Abstract

PROJECT SUMMARY
A growth in the aging population together with improved stroke care has resulted in an increase in survivors and
a rise in recurrent ischemic events, presenting major challenges for overburdened healthcare economics for
these patients. Consequently, approaches to induce tolerance in the brain against ischemia have gained new
momentum in clinical and experimental studies. However, mechanisms of ischemic preconditioning (IPC) have
been primarily studied in gray matter (GM), despite white matter (WM) injury and axon dysfunction being critical
components of clinical deficits observed in stroke patients. Moreover, most in vivo models of IPC performed in
rodents consist of short episodes of hypoxia/ischemia and are not applicable to translate into clinical settings as
therapeutics. Therefore, there is an unmet need to establish clinically applicable pharmacological approaches to
preconditioning the brain against ischemia. Our preliminary results show that CX-4945 (Silmitasertib), an FDA-
approved Casein Kinase 2 (CK2) inhibitor, preconditions WM, promotes axon function recovery and improves
behavioral outcomes after an in vitro or in vivo ischemic injury. Although aging reduces neuronal IPC, CX-4945
comparably preconditions young and aging WM by preserving mitochondrial motility. Because the threshold to
precondition is reported to be higher in females, the main goal of this current proposal is to understand the
mechanisms of preconditioning conferred by CK2 inhibition in young and aging male and female WM.
We have reported that CK2 signals via the CDK5 and AKT pathways to mediate ischemic WM injury. Thus, CK2
inhibition correlates with the preservation of oligodendrocytes, axon structure and function, and conservation of
mitochondrial dynamics in young and aging WM. Our preliminary data show that a brief period of CK2 inhibition
with CX-4945 effectively preconditions axon function by maintaining mitochondrial motility. Furthermore,
preconditioning with CX

## Key facts

- **NIH application ID:** 11318941
- **Project number:** 5R01NS132492-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Selva  Baltan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NS
- **Fiscal year:** 2026
- **Award amount:** $575,751
- **Award type:** 5
- **Project period:** 2023-04-15T00:00:00 → 2028-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11318941

## Citation

> US National Institutes of Health, RePORTER application 11318941, Preconditioning brain white matter against ischemia (5R01NS132492-04). Retrieved via AI Analytics 2026-06-30 from https://api.ai-analytics.org/grant/nih/11318941. Licensed CC0.

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