# Microglial K+ Channels in Ischemic Stroke

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $334,406

## Abstract

Ischemic stroke elicits a strong neuroinflammatory response characterized by massive microglia activation.
However, microglia do not only cause damage by releasing pro-inflammatory cytokines and reactive oxygen
species, they can also exert beneficial functions. Similar to macrophages, microglia can assume a classically
activated (M1-like) or alternatively activated (M2-like) phenotype. While M2-like microglia are presumably
neuroprotective and anti-inflammatory and have been described to peak relatively early in rodent models of
ischemic stroke, M1-polarized microglia begin to appear later in the infarct area, especially in the border zone,
and expand neuronal injury. An effective anti-inflammatory treatment for stroke should therefore not be a
general immunosuppressant but instead suppress microglia in a subtype specific manner by preferentially
targeting pro-inflammatory microglia. Our group has a long history of studying K+ channels in the immune
system and previously developed small molecule inhibitors for the voltage-gated KV1.3 and the Ca2+-activated
KCa3.1 channel as immunomodulators. We recently obtained exciting new data showing that M1 and M2
microglia significantly differ in their K+ channel expression profiles and here propose to test whether KV1.3
blockers can preferentially inhibit M1-like microglia functions and preserve beneficial M2-like functions.
We propose to test this therapeutic hypothesis with three interrelated Specific Aims: Under Aim-1 we
will investigate the expression profile and the functional role of K+ channels in cultured M1 and M2 microglia
and macrophages. In Aim-2 we will study microglia in a more “natural environment” and use organotypic slices
exposed to hypoxia/aglycemia or acute slices from Cx3cr1GFP/+ mice subjected to reversible middle cerebral
artery occlusion (MCAO) to determine K+ channel expression and function using whole-cell patch-clamp,
immunohistochemistry, qPCR and flow cytometry. As part of these experiments we will characterize the time
courses of K+ channel and M1 and M2 marker expression and correlate them with brain cytokine profiles and
pathology. Parallel immunohistochemical experiments will be performed on brain sections from stroke patients
to evaluate K+ channel expression in the context of M1 and M2 markers in humans. Finally, in Aim-3 we are
proposing to test our hypothesis that selective targeting of M1-like microglia with KV1.3 blockers is beneficial in
ischemic stroke by evaluating the effect of KV1.3 knockout and pharmacological blockade with our KV1.3
blocker PAP-1 in MCAO. These experiments will include studies where PAP-1 administration will match the
time-course of the presence of KV1.3 on microglia in the infarct. Overall, we expect that KV1.3 blockade will
spare beneficial microglia functions such as phagocytosis of debris and production of neurotrophic factors and
preferentially target detrimental pro-inflammatory microglia functions. This strategy could be very beneficial ...

## Key facts

- **NIH application ID:** 9886291
- **Project number:** 5R01NS100294-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** HEIKE WULFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $334,406
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886291

## Citation

> US National Institutes of Health, RePORTER application 9886291, Microglial K+ Channels in Ischemic Stroke (5R01NS100294-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9886291. Licensed CC0.

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