Activation of Nurr1 with Amodiaquine Protected Neuron and Alleviated Neuroinflammation after Subarachnoid Hemorrhage in Rats

Huaijun Chen,Hanhai Zeng,Xiongjie Fu,Jingyin Chen,Yang Cao,Chaoran Xu,Jianfeng Zhuang,Lin Wang,Gao Chen,Libin Hu,Hang Zhou,Yucong Peng,Xiaobo Yu,Jianru Li,Guoyang Zhou,Qian Yu,Feng Yan,Robert Ostrowski

doi:10.1155/2021/6669787

Abstract

Background. Nurr1, a member of the nuclear receptor 4A family (NR4A), played a role in neuron protection, anti-inflammation, and antioxidative stress in multidiseases. We explored the role of Nurr1 on subarachnoid hemorrhage (SAH) progression and investigated the feasibility of its agonist (amodiaquine, AQ) as a treatment for SAH. Methods. SAH rat models were constructed by the endovascular perforation technique. AQ was administered intraperitoneally at 2 hours after SAH induction. SAH grade, mortality, weight loss, neurological performance tests, brain water content, western blot, immunofluorescence, Nissl staining, and qPCR were assessed post-SAH. In vitro, hemin was introduced into HT22 cells to develop a model of SAH. Results. Stimulation of Nurr1 with AQ improved the outcomes and attenuated brain edema. Nurr1 was mainly expressed in neuron, and administration of AQ alleviated neuron injury in vivo and enhanced the neuron viability and inhibited neuron apoptosis and necrosis in vitro. Besides, AQ reduced the amount of IL-1β+Iba-1+ cells and inhibited the mRNA level of proinflammatory cytokines (IL-1β and TNF-α) and the M1-like phenotype markers (CD68 and CD86). AQ inhibited the expression of MMP9 in HT22 cells. Furthermore, AQ reduced the expression of nuclear NF-κB and Nurr1 while increased cytoplasmic Nurr1 in vivo and in vitro. Conclusion. Pharmacological activation of Nurr1 with AQ alleviated the neuron injury and neuroinflammation. The mechanism of antineuroinflammation may be associated with the Nurr1/NF-κB/MMP9 pathway in the neuron. The data supported that AQ might be a promising treatment strategy for SAH.

Highlights

Subarachnoid hemorrhage (SAH), a subtype of stroke, mainly caused by the intracranial aneurysm rupture, is characterized by high mortality and morbidity rate [1]
After exposing and dissecting the left external carotid artery (ECA), a 4-0 nylon suture was inserted into ECA, marched along the internal carotid artery (ICA) until feeling the resistance, and pushed into 2-3 mm to perforate the bifurcation between the anterior cerebral artery and middle cerebral artery
After subarachnoid hemorrhage (SAH) models induced 24 h, no significant difference in bleeding volume was observed between the SAH+vehicle and SAH+AQ groups (Figures 1(a) and 1(b))

Summary

Introduction

Subarachnoid hemorrhage (SAH), a subtype of stroke, mainly caused by the intracranial aneurysm rupture, is characterized by high mortality and morbidity rate [1]. Nurr was widely expressed throughout the brain, limited in the midbrain dopaminergic neuron area [9]. It is reasonable to believe that Nurr may play important roles beyond dopaminergic neurons. A member of the nuclear receptor 4A family (NR4A), played a role in neuron protection, anti-inflammation, and antioxidative stress in multidiseases. We explored the role of Nurr on subarachnoid hemorrhage (SAH) progression and investigated the feasibility of its agonist (amodiaquine, AQ) as a treatment for SAH. Hemin was introduced into HT22 cells to develop a model of SAH. Nurr was mainly expressed in neuron, and administration of AQ alleviated neuron injury in vivo and enhanced the neuron viability and inhibited neuron apoptosis and necrosis in vitro. The data supported that AQ might be a promising treatment strategy for SAH

Methods

Results

Conclusion