Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells

Author:

Meng Qingqi1ORCID,Chen Zhiteng2ORCID,Gao Qingyuan2ORCID,Hu Liqiong3,Li Qilong2,Li Shutai2,Cui Lili4,Feng Zhencheng1,Zhang Xingliang56ORCID,Cui Shiyun7ORCID,Zhang Haifeng28ORCID

Affiliation:

1. Department of Orthopedics, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China

2. Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China

3. Department of Intensive Care Unit, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China

4. Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China

5. Institute of Pediatrics, Department of Pediatric Surgery, Shenzhen Children’s Hospital, Shenzhen 518038, China

6. Department of Pediatrics, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China

7. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China

8. Laboratory & Medical Research Center, Sun Yat-sen University, Guangzhou 510275, China

Abstract

Background. Neurodegenerative diseases, such as Alzheimer’s disease, and traumatic brain and spinal cord injury (SCI) are prevalent in clinical practice. Inhibition of hyperactive inflammation and proliferation of endogenous neural stem cells (NSCs) is a promising treatment strategy for SCI. Our previous studies demonstrated the beneficial effects of rosiglitazone (Rosi) on SCI, but its roles in inflammation inhibition and proliferation of NSCs are unknown. Methods. SCI in a rat model was established, and the effects of Rosi on motor functions were assessed. The effects of Rosi on NSC proliferation and the underlying mechanisms were explored in details. Results. We showed that Rosi ameliorated impairment of moto functions in SCI rats, inhibited inflammation, and promoted proliferation of NSCs in vivo. Rosi increased ATP production through enhancing glycolysis but not oxidative phosphorylation. Rosi reduced mitophagy by downregulating PTEN-induced putative kinase 1 (PINK1) transcription to promote NSC proliferation, which was effectively reversed by an overexpression of PINK1 in vitro. Through KEGG analysis and experimental validations, we discovered that Rosi reduced the expression of forkhead box protein O1 (FOXO1) which was a critical transcription factor of PINK1. Three FOXO1 consensus sequences (FCSs) were found in the first intron of the PINK1 gene, which could be potentially binding to FOXO1. The proximal FCS (chr 5: 156680169–156680185) from the translation start site exerted a more significant influence on PINK1 transcription than the other two FCSs. The overexpression of FOXO1 entirely relieved the inhibition of PINK1 transcription in the presence of Rosi. Conclusions. Besides inflammation inhibition, Rosi suppressed mitophagy by reducing FOXO1 to decrease the transcription of PINK1, which played a pivotal role in accelerating the NSC proliferation.

Funder

Natural Science Foundation of Guangdong Province

Publisher

Hindawi Limited

Subject

Cell Biology,Aging,General Medicine,Biochemistry

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