Esketamine Provides Neuroprotection After Intracerebral Hemorrhage in Mice via the NTF3/PI3K/AKT Pathway.
Xiaoyu Niu, Yuanyuan Zheng, Wang Wang, Liwei Zhang, Shaoshuai Wang, Xihua Lu, Junyang Wang, Gaiqing Yang, Ting Zhao, Qiang Li, Nan Li, Junmin Wang, Jian Wang, Changsheng Li
CNS neuroscience & therapeutics December 1, 2024 DOI: 10.1111/cns.70145 via PubMed
Summary
AI-generated from the abstractEsketamine, a drug that blocks NMDA receptors, improved neurological function and promoted nerve repair in mice with intracerebral hemorrhage. RNA sequencing and network pharmacology identified neurotrophin-3 and the PI3K/AKT signaling pathway as key targets. Experiments confirmed that esketamine increased NTF3 protein levels, and blocking the PI3K/AKT pathway with a specific inhibitor reduced the drug's therapeutic effects. The findings suggest esketamine activates the NTF3/PI3K/AKT pathway to aid recovery after brain hemorrhage.
Study at a glance
| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Mice with collagenase-induced intracerebral hemorrhage |
| Intervention | Esketamine |
| Duration | 28 days of adeno-associated virus infection in the mouse striatum |
| Topics | Esketamine |
| Keywords | Ntf3 Pi3k/akt signaling pathway Intracerebral hemorrhage Neuroprotection |
| Citations | 7 |
| Key finding | Esketamine activates the NTF3/PI3K/AKT signaling pathway to improve neurological outcomes and neuroprotection in a mouse model of intracerebral hemorrhage. |
Abstract
Esketamine (ESK), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, modulates neurotransmitter signaling in the central nervous system. However, the specific mechanisms and therapeutic potential of ESK for intracerebral hemorrhage (ICH) remain unclear. This study aimed to investigate whether ESK promotes nerve repair and improves neurological outcomes in an experimental model of ICH. ICH was induced in mice via collagenase injection into the striatum. Body weight, neurological impairment, and behavioral changes were assessed. ESK administration significantly improved several indicators of ICH. Comprehensive RNA transcriptome sequencing and network pharmacology analyses identified neurotrophin-3 (NTF3) and the PI3K/AKT signaling pathway as targets for ESK treatment. Western blotting and immunofluorescence detected the protein expression levels and cellular localization of NTF3. After 28 days of adeno-associated virus infection in the mouse striatum, ESK treatment significantly enhanced neuroprotection, indicating the crucial role of NTF3 in ESK-mediated neuroprotection in ICH mice. Inhibition of the PI3K/AKT pathway using the PI3K-specific inhibitor LY294002 significantly attenuated the therapeutic effects of ESK, suggesting that this pathway is involved in ESK-mediated neurorepair in ICH mice. ESK treatment significantly improved functional outcomes and demonstrated neuroprotective effects in animal models of ICH. NTF3/PI3K/AKT pathway activation by ESK indicates its therapeutic potential in the treatment of ICH.