Poppy Kristina Sasmita, Raden Mohamad Javier, Steven Aviano Shenelo, Andra Danika, Andreas Dexter Geson, Bernadus Bernardino Bramantyo
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. © The Author(s) 2025.
Anatomy Department, Atma Jaya Catholic University of Indonesia, Jakarta, 14440, Indonesia; Department of Cardiology and Vascular Medicine, Universitas Indonesia Hospital, Depok, 16424, Indonesia; Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Bulaksumur, Caturtunggal, Sleman, 55281, Indonesia; Faculty of Medicine, Universitas Brawijaya, Malang, 65145, Indonesia; Cardiology Research Office, Department of Cardiology and Vascular Medicine, Dr. Sardjito General Hospital, Yogyakarta, 55284, Indonesia
