Small-molecule fusion peptide TAT-KIR improving neurofunctional recovery by regulating astrocytes activation in mice after traumatic brain injury

张厚莹 程立雪 冯韵然 王心怡 吴晗溪 曹为众 杨舒涵 孙浩然 舒章 马凯歌 胡晓宣

doi:10.16098/j.issn.0529-1356.2026.04.001

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Acta Anatomica Sinica ›› 2026, Vol. 57 ›› Issue (4) : 391-399. DOI: 10.16098/j.issn.0529-1356.2026.04.001

Small-molecule fusion peptide TAT-KIR improving neurofunctional recovery by regulating astrocytes activation in mice after traumatic brain injury

ZHANG Hou-ying¹, CHENG Li-xue¹, FENG Yun-ran^1,2, WANG Xin-yi¹, WU Han-xi¹, CAO Wei-zhong¹, YANG Shu-han¹, SUN Hao-ran¹, SHU Zhang¹, MA Kai-ge^1*, HU Xiao-xuan^1,3 *

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Abstract

ObjectiveTo investigate the therapeutic potential of the small-molecule fusion peptide trans-activator of transcription（TAT）-kinase inhibitory region（KIR）of cytokine signaling 3（SOCS3） protein in mice by modulating astrocyte activation after traumatic brain injury (TBI). Methods Male C57BL/6 mice (2-month-old) were randomly divided into three groups, sham group (sham), TBI group (TBI), and TAT-KIR group (TAT-KIR), and each group had 15 mice. The TBI group received traumatic brain injury using Feeney’s free-fall method, the TAT-KIR group was injected with TAT-KIR in situ right after TBI, the sham group underwent craniotomy without impact. Western blotting was used to assess the activation of JAK2/STAT3 pathway at day 1 post-TBI. Immunofluorescence staining was employed to evaluate the astrocyte activation and the neuron loss at day 1, 3, 7, and 14 post-TBI, and Sholl analysis was used to analyze the morphology of astrocytes. Meanwhile, neurological severity score (NSS) and beam walking tests were used to evaluate motor function. At day 3 and 7 post-TBI, Real-time PCR was performed to measure the mRNA expression levels of C3, H2-D1, Serping1, H2-T23 (A1-astrocyte) and transglutaminase 1(Tgm-1), cardiotrophin-like cytokine factor 1（Clcf1）, S100 calcium-binding protein A10(S100a10), CD109 (A2-astrocyte), and the cytokines secreted by activated astrocytes. ELISA was used to detecte the amount of glutamate in injured cortex. Results In the TAT-KIR treated group, TBI-induced activation of the JAK2/STAT3 signaling pathway and astrogliosis were suppressed. The branches of activated astrocytes decreased. The mRNA level of C3, H2-D1, Serping1, H2-T23 were downregulated, while the mRNA level of Tgm-1, Clcf1, CD109, S100a10 were upregulated. At the same time, the synaptogenic factors, including Gpc4, Sparcl1, Thbs1, Thbs2, and the neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT3), nerve growth gactor (NGF) were significantly upregulated. The expression of glutamate transporters, including glutamate transporter 1（GLT-1）and glutamate/aspartate transporter（GLAST）increased, while the amount of extracellular glutamate decreased. The neuron loss of TBI mice gradually reduced with the time. NSS scores decreased and the distance of beam walking significantly increased. Conclusion Administration of TAT-KIR during the acute phase of TBI reduced astrocyte activation, upregulated the proportion of A2 astrocyte, and subsequently accelerated neurological function recovery in TBI mice.

Key words

Traumatic brain injury

/ Trans-activator of transcription-kinase inhibitory region of suppressor of cytokine signaling 3 protein / Astrocyte / Neurological function restoration / Feeney’s free fall / Immunofluorescence / Mouse

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ZHANG Hou-ying, CHENG Li-xue, FENG Yun-ran, WANG Xin-yi, WU Han-xi, CAO Wei-zhong, YANG Shu-han, SUN Hao-ran, SHU Zhang, MA Kai-ge, HU Xiao-xuan. Small-molecule fusion peptide TAT-KIR improving neurofunctional recovery by regulating astrocytes activation in mice after traumatic brain injury[J]. Acta Anatomica Sinica. 2026, 57(4): 391-399 https://doi.org/10.16098/j.issn.0529-1356.2026.04.001

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