Summary of included studies and main findings.
| Study ID | Study design | Participants | Summary of findings |
|---|---|---|---|
| Cuomo et al., 2022 [1] | Experimental in vivo study | Male Sprague-Dawley rats subjected to middle cerebral artery occlusion (MCAO) treated with ischemic preconditioning (IPC) | IPC increased the expression of NCKX2, K+-dependent Na+/Ca2+ exchanger, following MCAO, mediated by the p-AKT signaling pathway. NCKX2 knockout yielded lower neuroprotective capacity, indicated by the greater infarct size (51.6 ± 2.1% with NCKX2 knockout + preconditioning vs. 22.4 ± 0.5% with preconditioning). |
| Dhyani et al., 2023 [2] | In vitro study | HMC3 microglial cell line, subjected to a hypoxic gradient and treated with an L-type calcium channel blocker (CCB) | L-type CCB improved the hypoxic conditions, similar to reoxygenation, indicated by the alleviation of cytosolic calcium level and preservation of cell viability within one hour of treatment, in cell lines with a hypoxic gradient. CCB administration also inhibited immune response by decreasing oxidative stress markers, namely HIF1A and OXR1. |
| Park et al., 2024 [3] | Experimental in vivo study | Male Sprague-Dawley rats subjected to MCAO treated with epigallocatechin gallate (EGCG; 50 mg/kg) | MCAO resulted in diminished neurobehavioral functions and increased infarct size as well as decreased hippocalcin expression, a neuronal calcium sensor protein. Administration of EGCG improved neurological deficits (2.17 ± 0.05 in EGCG vs. 3.63 ± 0.06 in controls), prevented cell death and intracellular calcium overload in glutamate-exposed neurons, and alleviated the decreased hippocalcin expression (0.52 ± 0.05 in EGCG vs. 0.11 ± 0.02 in controls). Additionally, EGCG reduced caspase-3 (1.43 ± 0.02 vs. 1.69 ± 0.02) and cleaved caspase-3 (5.32 ± 0.21 vs. 6.15 ± 0.35) expression levels associated with glutamate exposure. |
| Secondo et al., 2019 [4] | Experimental in vivo study | Sprague-Dawley rats MCAO treated with IPC | IPC stimulated store-operated calcium entry (SOCE) and Ca2+ release, which then inhibited the downregulation of stromal interaction molecule 1 (STIM1) and a structural component of the CRAC calcium channel (ORAI1) associated with oxygen and glucose deprivation. In contrast, STIM1 and ORAI1 silencing resulted in endoplasmic reticulum stress, marked by the increased activity of 78-kDa glucose-regulated protein (GRP78) and caspase-3. |
| Tang et al., 2015 [5] | Experimental in vivo and in vitro study | Male C57BL/6 mice subjected to permanent MCAO and treated with pertussis toxin (PTx) | PTx exhibited maximal reduction of infarct size when a 40–60% reduction of relative CBF was observed following permanent MCAO (2.12 ± 1.58 mm3 vs. 12.3 ± 3.8 mm3, p < 0.01). PTx also inhibited calcium influx into the neurons, which resulted in increased neuronal survival (1.1 ± 0.12, p < 0.01) or apoptosis prevention by reducing caspase-3-positive cell density (1.36 ± 0.05 vs. 1.89 ± 0.2, p < 0.01) and salvage of ischemic penumbra. |
| Wang et al., 2025 [6] | Experimental in vivo study | Male ICR mice subjected to MCAO and treated with the traditional Chinese medicine borneol | The nanoformulation of the traditional Chinese medicine borneol restored intracellular Ca2+ level and redox homeostasis, improved CBF (increased to 93.9 ± 2.4% after 24 hours), alleviated cerebral histopathology, and prevented apoptosis mediated by PI3K/Akt/Bcl-2/Bax/Cyto-C/Caspase-3,9 signaling pathway 3 hours after its administration, following MCAO. Its efficacy on oxidative stress was indicated by superoxide level reduction, both in the middle (by 56.1%) and high (77.4%) doses. Additionally, this formulation also inhibited astrocyte overactivation, microglia polarization towards pro-inflammatory phenotype, and NF-κB/TNF-α/IL-6 signaling pathway. Borneol treatment also alleviated the neurobehavioral score, similar to that of Edaravone, a commonly used pharmacological agent for ischemic stroke. |
| Zhang et al., 2023 [7] | Experimental in vivo and in vitro study | Male C57BL/6J mice subjected to transient MCAO (tMCAO) and treated with small interfering ribonucleic acid (siRNA) and STIM1 knockout | tMCAO induced the deterioration of autophagic flux in the neurons through STIM1 protein level increase (1.83 ± 0.13 vs. sham 1.00 ± 0.02, p < 0.05) by stimulating SOCE and inhibiting AKT/mTOR pathway. STIM1 downregulation through siRNA administration inhibited autophagic activity, and additionally, STIM1 knockdown specimens exhibited greater improvement of neurological deficits following tMCAO. To evaluate the role of the AKT/mTOR pathway, STIM1-knockout mice were treated with AKT/mTOR inhibitor, AZD5363, which exacerbated infarct volume (39.33 ± 4.04% vs. Cap 22.33 ± 5.51%, p < 0.05) and brain edema (23.58 ± 2.43% vs. Cap 15.06 ± 1.53%, p < 0.05). |
| Zhang et al., 2025 [8] | Experimental in vivo and in vitro study | Sprague-Dawley rats subjected to MCAO and treated with intra-arterial hypothermia infusion solution containing magnesium sulfate (MgSO4; IA-SCMI) | IA-SCMI conferred better infarct reduction and the greatest CBF following MCAO compared to intra-arterial selective cooling saline infusion (IA-SCSI). In vitro analysis revealed that MgSO4 and hypothermia resulted in greater cell viability after oxygen and glucose deprivation through inhibition of calcium overload and reactive oxygen species (ROS) production. Additionally, MgSO4 and hypothermia alone exhibited benefits on cell viability. |
| Zhao et al., 2022 [9] | Experimental in vivo study | Adult Sprague-Dawley rats subjected to MCAO and ischemia/reperfusion, treated with moderate ethanol-preconditioning (EtOH-PC) | EtOH-PC 24 hours prior to I/R conferred neuroprotection and increased the calcium-sensitive potassium (BKCa) channels both in the penumbra and infarct core. EtOH-PC also inhibited apoptosis, reduced infarct size, and improved neurological function. |
CBF: cerebral blood flow; HIF1A: hypoxia-inducible factor 1-alpha; OXR1: oxidation resistance 1; IA-SCMI: intra-arterial selective cooling magnesium infusion.