The long-term neuroprotective effects of calcium (Ca²⁺) modulation in ischemic stroke: a systematic review from animal models

Abstract

Background: Ischemic stroke is a leading cause of disability, with calcium (Ca²⁺) dysregulation contributing to neuronal injury and impaired recovery. While early clinical trials targeting calcium signaling showed limited success, growing preclinical evidence supports the potential of calcium modulation for long-term neuroprotection. This systematic review evaluates the long-term effects of calcium modulation in animal models of ischemic stroke.
Methods: A comprehensive search across PubMed, Scopus, Web of Science, and the Cochrane Library up to June 2025 identified studies investigating calcium-targeted interventions (e.g., calcium channel blockers, chelators, antioxidants) with ≥ 30 days of follow-up. Risk of bias was assessed using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I).
Results: Nine studies met the inclusion criteria. Interventions like L-type calcium channel blockers, magnesium sulfate, and ischemic preconditioning consistently reduced infarct volume (e.g., 22.4 ± 0.5% with preconditioning vs. 51.6 ± 2.1% with knockout) and improved neurobehavioral outcomes [e.g., epigallocatechin gallate (EGCG)-treated rats scored 2.17 ± 0.05 vs. 3.63 ± 0.06 in controls]. Molecular pathways involved included phosphoinositide 3-kinase (PI3K)/AKT, stromal interaction molecule 1 (STIM1)/ORAI1, and calcium-sensor proteins such as NCKX2.
Discussion: Calcium modulation holds strong promise for neuroprotection in ischemic stroke models. Although clinical gaps remain, these findings support the development of calcium-targeted therapies for stroke recovery, especially when combined with multimodal strategies.

Keywords

calcium dysregulation / calcium modulation / ischemic stroke / neuroprotection / stroke recovery

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