Stroke is the second leading cause of disability and death worldwide (Campbell et al., 2019), In 2016, there were 13.7 million new stroke cases globally, with 87% being ischemic strokes (Campbell et al., 2019; Barthels and Das, 2020; Saini et al., 2021). The current main treatment options for ischemic stroke focus on restoring blood flow to the affected area through thrombolysis and mechanical thrombectomy (Herpich and Rincon, 2020; Jolugbo and Ariëns, 2021). However, both thrombolysis and thrombectomy have time window limitations and may result in reperfusion injury (Balami et al., 2018; Ospel et al., 2020; Staessens et al., 2021; Ho-Tin-Noé et al., 2023). Therefore, neuroprotective or brain-protective treatments (Lyden, 2021) remain the primary therapeutic choice for AIS (Paul and Candelario-Jalil, 2021; Qiu et al., 2021). Early treatment after the onset of neurological deficits is crucial to minimize neuronal apoptosis (Tuo et al., 2022; Zhao et al., 2022). Neuroinflammation and oxidative stress have long been recognized as key factors contributing to neuronal apoptosis (Radak et al., 2017; Wang et al., 2021, Wang et al., 2021). Following AIS, primary neuronal cell death in the ischemic core is typically mediated by secondary immune/inflammatory responses, characterized by the activation of microglia/macrophages and the production of pro-inflammatory cytokines and ROS (Endres et al., 2022). Currently, a significant amount of research is still focused on the neuroinflammatory response in both MCAO/R animal models and stroke patients, with some studies demonstrating that the attenuation of neuroinflammation has neuroprotective effects in the MCAO/R models (Liu et al., 2020; Przykaza, 2021; Yuan et al., 2021; Zhu et al., 2021; Zeng et al., 2022; Cai et al., 2023). Thus, rescuing ischemic penumbra neurons by inhibiting microglial activation and balancing neuroinflammation remains a promising strategy for the treatment of AIS-induced nerve injury.

TREM2 is a transmembrane receptor of the immunoglobulin superfamily that is mainly expressed in microglial cells in the brain. It plays a critical role in regulating inflammatory responses and the phagocytosis of cell debris in the central nervous system (CNS) (Deczkowska et al., 2020). Activation of TREM2 has been shown to regulate cell proliferation, inhibit the production of inflammatory cytokines, promote cell survival, and enhance the phagocytic activity of microglial cells toward apoptotic neurons (Takahashi et al., 2005; Hsieh et al., 2009). Tremendous evidence suggests that TREM2 is associated with neurodegenerative diseases, traumatic brain injury, and acute cerebrovascular diseases (Takahashi et al., 2007; Krasemann et al., 2017; Filipello et al., 2018; Zhou et al., 2020; Li and Zhang, 2021; Ogonowski et al., 2023). Given the anti-inflammatory and antioxidant properties of TREM2, more studies are exploring its impact on ischemic stroke. The role of TREM2 in the inflammatory response after acute ischemic stroke has become a research focus because it appears to be involved in the regulation of microglial cell function and brain immune response (Kawabori et al., 2015; Kurisu et al., 2019). For example, Wu et al., (2017) have shown that TREM2 inhibits neuronal apoptosis by suppressing the production of pro-inflammatory factors and promoting the generation of anti-inflammatory factors after MCAO/R. Our main objective is to upregulate TREM2 receptors through specific methods to inhibit post-ischemic stroke inflammatory responses and oxidative stress. Therefore, the search for potential agonists of TREM2 is of particular importance. Upregulating the TREM2 receptor with small molecule compounds offers a new therapeutic approach for ischemic stroke.

Our study utilized the TREM2 receptor as the target and employed a high-throughput drug screening method to screen the small molecule compound Baicalin, aiming to increase TREM2 expression. Baicalin, extracted from Scutellaria baicalensis, is known for its bioactive properties, such as anti-inflammatory and antioxidation effects (Wang et al., 2021, Wang et al., 2021). However, the exact mechanism of Baicalin remains unclear. Through our research, we have discovered that Baicalin has the potential to reduce post-ischemic stroke inflammation through TREM2.