Neuroprotection by Exogenous and Endogenous Neuregulin-1 in Mouse Models of Focal Ischemic Stroke

Abstract

Identifying novel neuroprotectants that can halt or reverse the neurological effects of stroke is of interest to both clinicians and scientists. We and others previously showed the pre-clinical neuroprotective efficacy of neuregulin-1 (NRG-1) in rats following focal brain ischemia. In this study, we examined neuroprotection by exogenous and endogenous NRG-1 using a mouse model of ischemic stroke. C57BL6 mice were subjected to middle cerebral artery occlusion (MCAO) followed by reperfusion. NRG-1 or vehicle was infused intra-arterially (i.a.) or intravenously (i.v.) after MCAO and before the onset of reperfusion. NRG-1 treatment (16 μg/kg; i.a.) reduced cerebral cortical infarct volume by 72% in mice when delivered post-ischemia. NRG-1 also inhibited neuronal injury as measured by Fluoro Jade B labeling and rescued NeuN immunoreactivity in neurons. Neuroprotection by NRG-1 was also observed in mice when administered i.v. (100 μg/kg) in both male and female mice. We investigated whether endogenous NRG-1 was neuroprotective using male and female heterozygous NRG-1 knockout mice (NRG-1+/−) compared with wild-type mice (WT) littermates. NRG-1+/− and WT mice were subjected to MCAO for 45 min, and infarct size was measured 24 h following MCAO. NRG-1+/− mice displayed a sixfold increase in cortical infarct size compared with WT mice. These results demonstrate that NRG-1 treatment mitigates neuronal damage following cerebral ischemia. We further showed that reduced endogenous NRG-1 results in exacerbated neuronal injury in vivo. These findings suggest that NRG-1 represents a promising therapy to treat stroke in human patients.

The Endocrine Disruptor Bisphenol A (BPA) Affects the Enteric Neurons Immunoreactive to Neuregulin 1 (NRG1) in the Enteric Nervous System of the Porcine Large Intestine

“…The decrease in total number of neurons noted in the present study under the impact of BPA also confirms neurotoxic properties of this substance. Taking into account the neurotoxicity of BPA, on the one hand, and the positive influence of NRG1 on neuronal cells and its neuroprotective effects on the other [8], it can be assumed that changes noted in the present study are connected with neuroprotective and adaptive reactions under the impact of BPA.…”

“…As regards the nervous system, the majority of previous studies concern distribution and functions of NRG1 in the central nervous system. This substance has been found in the brain of various animal species, including, among others, human [6], rat [7], mouse [8] and goose [9]. Based on previous studies, it is known that NRG1 in the central nervous system is involved in hypothalamic control of sexual maturation in rats [10], participates in mechanisms connected with oligodendrocytes survivability and differentiation in mice [11] and also regulates the higher nervous functions in rats (including memory and learning) [12].…”

Spatial Analysis of Neural Cell Proteomic Profiles following Ischemic Stroke in Mice using High-Plex Digital Spatial Profiling

“…Fluoro Jade B (FJB; Cat#AG310, Millipore, Billerica, MA) labeling was performed in an adapted accordance to Noll et al 2019 to ensure infarct presence and record infarct size and location (Noll et al 2019). Sections were post-fixed with 10% formalin for 10 minutes and then washed twice with PBS for 5 minutes.…”

“…Gene and protein profile expressions have often been analyzed after ischemic stroke to elucidate these mechanisms during various timepoints (Surles-Zeigler et al 2018, Xu et al 2005, Xu et al 2004, Rodriguez-Mercado et al 2012, Simmons et al 2016, Wang et al 2015, Noll et al 2019, but have been limited by technological challenges. Technology limitations have included the requirement that tissue to be analyzed in sections, such as the entire ipsilateral and contralateral hemispheres.…”

Impact of High Salt Diet on Cerebral Vascular Function and Stroke in Tff3−/−/C57BL/6N Knockout and WT (C57BL/6N) Control Mice

“…Genetically modified mice are frequently used stroke models for studying the molecular pathophysiology of stroke [15,16,17,18]. The Tff3 −/− / C57BL/6N ( Tff3 ) knockout mice model represents a promising new model for studying vascular function, atherosclerotic lesions, and the synthesis of proinflammatory cytokines due to altered lipid metabolism [19,20].…”