Peng Lu*, Ye Zhang, Huanjiang Niu and Yirong Wang Pages 4270 - 4277 ( 8 )
Background: ALMS1-IT1, a recently identified lncRNA, has been proven to play a crucial role in regulating tumor progression and predicting the survival time of tumor patients. Data analysis from the Human Body Map (HBM) revealed that ALMS1-IT1 is expressed mainly in brain tissues.
Methods: In this study, the role of ALMS1-IT in regulating neuro-inflammation and functional recovery was investigated after ischemic cerebral damage. To this end, the rat model of transient middle cerebral artery occlusion (tMCAO) was constructed, the cell model of oxygen-glucose deprivation (OGD) was established using BV2 microglial cells, and the aberrant expression of ALMS1-IT1 was assessed in brain tissues. After ALMS1- IT1 knockdown through intrathecal injection of Lv-shALMS1-IT1, neuro-inflammatory response and functional tests including a modified neurological severity score (mNSS) and a foot-fault test were assessed.
Results: The level of ALMS1-IT1 was promptly enhanced at 12 hours (h) following MCAO, peaking at 48 h, and remaining high at day 14 compared to the sham group. Pro-inflammatory cytokines (IL-1β, IL-6, and TNF- α) were increased after MCAO, whereas ALMS1-IT1 inhibition suppressed the expression of IL-1β, IL-6 and TNF-α in MCAO rats. The results from mNSS and foot-fault test showed that ALMS1-IT1 knockdown significantly improved spatial learning and sensorimotor function of MCAO rats. Mechanistically, ALMS1-IT1 knockdown suppressed the activation of NF-κB signaling in vitro and in vivo, as evidenced by decreased p65 expression and p65 nuclear translocation. ALMS1-IT1 overexpression facilitated pro-inflammatory cytokines expression in microglia, whereas the effect was blocked by treatment with JSH-23 (a specific NF-κB inhibitor).
Conclusion: These data demonstrated that ALMS1-IT1 inhibition improved neurological function of MCAO rats, at least in part by repressing NF-κB-dependent neuro-inflammation.
Ischemic cerebral injury, neuro-inflammation, MCAO, NF-κB, ALMS1-IT1, mNSS.
Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310016, Department of Hematology, Sir Run Run Shaw Hospital,Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310016, Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310016, Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310016