• A novel CX3CR1 inhibitor AZD8797 facilitates early recovery of rat acute spinal cord injury by inhibiting inflammation and apoptosis.

A novel CX3CR1 inhibitor AZD8797 facilitates early recovery of rat acute spinal cord injury by inhibiting inflammation and apoptosis.

International journal of molecular medicine (2020-04-24)
Guozhao Chen, Zhiping Zhou, Weiping Sha, Liming Wang, Fei Yan, Xiaomei Yang, Xia Qin, Muyao Wu, Di Li, Shoujin Tian, Gang Chen

The present study aimed to evaluate the effect of the CX3CR1 inhibitor AZD8797 in early recovery after acute SCI and elucidate its potential mechanism in blocking inflammation and apoptosis. Adult rats were sacrificed after 3, 7, 10, or 14 days of SCI. The injured spinal tissues were collected for assessing C‑X3‑C motif chemokine ligand 1(CX3CL1)/C‑X3‑C motif chemokine receptor 1 (CX3CR1) expression at each time point via western blotting (WB) and quantitative PCR. The cellular localization of the proteins was detected by immunofluorescence. Another batch of rats (subdivided into sham, injury model, AZD8797 and methylprednisolone groups) were used to evaluate locomotive recovery with a Basso Beattie Bresnahan score. Based on the expression level of CX3CR1, these rats were sacrificed at the most prominent stage of CX3CR1 expression (10 days after SCI), for assessing the serum levels of tumor necrosis factor‑α/interleukin (IL)‑6/IL‑1β and the expression of CX3CL1/CX3CR1/caspase 3/Bcl‑2/Bax in the spinal cord tissues through WB and ELISA. Additionally, apoptosis and necrosis in the injured spinal cord were evaluated by terminal deoxynucleotidyl transferase‑-mediated dUTP nick‑end labeling staining/fluoro‑jade B staining. Expression levels of both CX3CR1 and CX3CL1 reached their peak 10 days after the injury, followed by a dramatic downward trend at 14 days. The enhanced expression of CX3CR1 was detected in astrocytes and microglia of the injured spinal cord. AZD8797 improved locomotive recovery after 10 days of SCI and was as effective as methylprednisolone. The effect of AZD8797 was mediated by suppressing apoptosis, necrosis and inflammatory responses, as assessed by WB/ELISA and morphological examinations. The current study has demonstrated that AZD8797 can effectively block overwhelming inflammation, apoptosis and necrosis after SCI and facilitate early recovery of locomotive function.

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