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Updated: Jul 17, 2026
A Preclinical Controlled Cortical Impact Model for Traumatic Hemorrhage Contusion and Neuroinflammation
Published on: June 10, 2020
CXCR4 targeting by TPCA‑1 attenuates neuroinflammation in intracerebral hemorrhage through inhibiting NF‑κB and AP‑1
Na Wang1, Li Cao1, Shi-Fang Bei1
1Department of pharmacy, Zhenjiang First People's Hospital, Zhenjiang 212002, China.
Insights
TPCA-1 shows neuroprotective effects against secondary brain injury following intracerebral hemorrhage (ICH). This small molecule targets CXCR4, reducing neuroinflammation and improving neurological outcomes in ICH mouse models.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Intracerebral hemorrhage (ICH) causes secondary brain injury (SBI), leading to poor neurological outcomes.
- Identifying effective small-molecule therapeutics for ICH-induced SBI is crucial.
Purpose of the Study:
- To identify and validate small-molecule agents for neuroprotection against ICH-induced SBI.
- To investigate the therapeutic efficacy and mechanism of TPCA-1 in a mouse ICH model.
Main Methods:
- Bioinformatics analysis to identify ICH-related hub genes and predict candidate compounds using Connectivity Map (CMap).
- Molecular docking to assess binding affinity.
- In vivo evaluation in a mouse ICH model: neurological scoring, cerebral edema assessment, qPCR, Western blot, ELISA.
- Mechanism studies including MST and CETSA assays.
Main Results:
- Bioinformatics identified the chemokine signaling pathway as critical in ICH.
- TPCA-1 demonstrated strong binding affinity for CXCR4 and significantly reduced neurological deficits and cerebral edema in ICH mice.
- TPCA-1 suppressed downstream inflammatory signaling (NF-κB, AP-1) and pro-inflammatory cytokine production.
Conclusions:
- TPCA-1 exerts neuroprotective effects against ICH-induced SBI by targeting CXCR4.
- TPCA-1 alleviates neuroinflammation by inhibiting NF-κB and AP-1 activation.
- TPCA-1 represents a potential therapeutic strategy for managing ICH.
Abstract:
Intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) is a critical contributor to poor neurological outcomes. In this study, we aimed to identify potential small‑molecule therapeutic agents and systematically validate their neuroprotective efficacy. Bioinformatics analysis was performed to screen ICH‑related hub genes, and Connectivity Map (CMap) was used to predict candidate compounds, followed by molecular docking to verify their binding affinity. The therapeutic effect of TPCA‑1 was further evaluated in a mouse ICH model using neurological scoring, cerebral edema assessment, qPCR, Western blot, and ELISA. Bioinformatics analysis indicated that the chemokine signaling pathway is critically involved in ICH pathogenesis. Molecular docking revealed that TPCA‑1 displayed the strongest binding affinity for CXCR4 among all predicted compounds. In vivo, 20 mg/kg TPCA‑1 significantly ameliorated neurological deficits and reduced cerebral edema in ICH mice. Mechanistically, TPCA-1 interacted with CXCR4, as supported by molecular docking, MST, and CETSA assays, and suppressed downstream inflammatory signaling involving NF-κB and AP-1, thereby decreasing the production of pro‑inflammatory cytokines including TNF‑α, IL‑1β, and IL‑6. Importantly, Co-treatment with the CXCR4 inhibitor AMD3100 did not produce additional inhibitory effects. Collectively, TPCA‑1 exerts neuroprotective effects against ICH‑induced SBI by targeting CXCR4, which further inhibits the activation of NF‑κB and AP‑1 and ultimately alleviates neuroinflammation.
