# Repurposing of KCa3.1 Inhibitor Senicapoc for Stroke: A Pre-clinical Study

> **NIH NIH R61** · UNIVERSITY OF WASHINGTON · 2022 · $391,514

## Abstract

The concept of drug repurposing refers to the evaluation and use of existing drugs, as well as failed, abandoned,
or not yet pursued clinical development candidates, for new clinical indications. This idea has gained increasing
traction in recent years including for CNS disorders such as stroke. Microglia (MG), the resident immune cells of
the CNS, and infiltrating macrophages (MP) are critical in ischemic brain injury. Modulating the MG/MP
phenotype is a promising avenue for developing novel therapeutics for stroke. KCa3.1 is a calcium activated
potassium channel that is highly expressed in reactive MG/MP. Prior studies using either genetic deletion or
pharmacologic ablation of KCa3.1 have demonstrated that it contributes to neuroinflammation and exacerbation
of post-stroke injury. Senicapoc is a KCa3.1-specific inhibitor that has been used in human clinical trials for non-
neurological indications. The drug has a proven safety record and there is substantial pharmacokinetic (PK),
pharmacodynamic (PD) and cell type specific expression data completed and available on this agent. The goals
of the R61 phase of this proposal are: (1) Quantify senicapoc's PK profile specifically in the setting of stroke
(mouse transient middle cerebral artery occlusion/reperfusion model) and identify an optimal dosing and
temporal administration paradigm for ischemic brain injury, (2) Determine the efficacy of senicapoc in reducing
stroke-induced brain injury in young adult wild-type mice using cutting-edge neuroimaging technology as well as
sensory-motor, neurobehavioral and cognitive longitudinal assessments and (3) Determine senicapoc's PD
profile and quantify the drug's CNS target engagement using state-of-the-art neuroimmunology biomarkers. PK
assessments will include quantifying total and free levels of senicapoc in brain and plasma using HPLC/mass
spectroscopy. In addition we will quantify levels of pro-inflammatory cytokines and chemokines using
immunoassays. Efficacy assessments will include multiparametric 14 T MRI to quantify infarct volume (DWI/T2),
cerebral edema (T2/FLAIR) and white matter integrity (DTI/tractography). Sensory-motor, neurobehavioral and
cognitive measures will include both observational and dynamic assessments. For PD studies, we will examine
the effect of senicapoc on stroke-induced changes in the neuroimmune response in vivo using MG/MP-targeted
TSPO-radioligand and positron emission spectroscopy (PET) as well as ex vivo studies using flow cytometry
and immunofluorescent microscopy. For the R33 phase of the project, we will determine if senicapoc's efficacy
and PD profiles in stroke are altered: (i) in mice by age and/or sex and (ii) in spontaneously hypertensive, co-
morbid rats. Overall, these studies will provide a comprehensive assessment of the ability of senicapoc to
influence stroke-induced changes in the CNS and provide a scientific foundation for future clinical trials assessing
both drug (senicapoc) and target (KCa3.1).

## Key facts

- **NIH application ID:** 10463846
- **Project number:** 5R61NS123195-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** JONATHAN R WEINSTEIN
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,514
- **Award type:** 5
- **Project period:** 2021-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463846

## Citation

> US National Institutes of Health, RePORTER application 10463846, Repurposing of KCa3.1 Inhibitor Senicapoc for Stroke: A Pre-clinical Study (5R61NS123195-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10463846. Licensed CC0.

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