Neuropsychiatric Disease and Treatment (Aug 2021)
Inhibition of NOD1 Attenuates Neonatal Hypoxia-Ischemia Induced Long-Term Cognitive Impairments in Mice Through Modulation of Autophagy-Related Proteins
Abstract
Fang Liu,1 Mingyu Shao,1 Feng Xu,2 Fang Rong3 1Department of Child Health Care, Zibo Central Hospital, Zibo, 255000, Shandong, People’s Republic of China; 2Department of Pediatrics, Zibo Central Hospital, Zibo, 255000, Shandong, People’s Republic of China; 3The Community Clinic of Overseas Chinese Town, Zibo Central Hospital, North Gate of Zhongrun Overseas Chinese Town, Zibo, 255000, Shandong, People’s Republic of ChinaCorrespondence: Fang RongThe Community Clinic of Overseas Chinese Town, Zibo Central Hospital, North Gate of Zhongrun Overseas Chinese Town, Zhangdian District, Zibo, 255000, Shandong, People’s Republic of ChinaTel +86-18678186178Email [email protected]: Autophagy is implicated in neonatal hypoxia-ischemia (HI) induced cognitive impairment. The nucleotide-oligomerizing domain-1 (NOD1), a protein involved in inflammatory responses, has been shown to activate autophagy to promote progression of other diseases. We aimed to investigate whether and how NOD1 is involved in HI-induced brain injury using an HI mouse model.Methods: We induced HI in neonatal mice and examined levels of NOD1 and genes associated with autophagy. We then inhibited NOD1 by intracerebroventricular injection of si-NOD1 following HI induction and tested the effects on autophagy, inflammatory responses and long-term behavioral outcomes through Morris water maze and open field tests.Results: We found that HI induction significantly elevated mRNA levels of NOD1 (3.54 folds change) and autophagy-related genes including Atg5 (3.89 folds change) and Beclin-1 (3.34 folds change). NOD1 inhibition following HI induction suppressed autophagy signaling as well as HI induced proinflammatory cytokine production. Importantly, NOD1 inhibition after HI improved long-term cognitive function, without impacting exploratory and locomotor activities.Conclusion: We show here that NOD1 is involved in the pathogenesis of HI-induced brain injury through modulation of autophagy-related proteins and inflammatory responses. Our findings suggest that NOD1 may be a potent target for developing therapeutic strategies for treating HI-induced brain injury.Keywords: neonatal, hypoxia-ischemia, cognitive impairment, NOD1, autophagy
