Neuropilin-1 promotes mitochondrial structural repair and functional recovery in rats with cerebral ischemia

Abstract

Objectives Available literature documents that ischemic stroke can disrupt the morphology and function of mitochondria and that the latter in other disease models can be preserved by neuropilin-1 (NRP-1) via oxidative stress suppression. However, whether NRP-1 can repair mitochondrial structure and promote functional recovery after cerebral ischemia is still unknown. This study tackled this very issue and explored the underlying mechanism. Methods Adeno-associated viral (AAV)-NRP-1 was stereotaxically inoculated into the cortex and ipsilateral striatum posterior of adult male Sprague-Dawley (SD) rats before a 90-min transient middle cerebral artery occlusion (tMCAO) and subsequent reperfusion. Lentivirus (LV)-NRP-1 was transfected into rat primary cortical neuronal cultures before a 2-h oxygen-glucose deprivation and reoxygenation (OGD/R) injury to neurons. The expression and function of NRP-1 and its specific protective mechanism were investigated by Western Blot, immunofluorescence staining, flow cytometry, magnetic resonance imaging, transmission electron microscopy, etc. The binding was detected by molecular docking and molecular dynamics simulation. Results Both in vitro and in vivo models of cerebral ischemia/reperfusion (I/R) injury presented a sharp increase in NRP-1 expression. The expression of AAV-NRP-1 markedly ameliorated the cerebral I/R-induced damage to the motor function and restored the mitochondrial morphology. The expression of LV-NRP-1 alleviated mitochondrial oxidative stress and bioenergetic deficits. AAV-NRP-1 and LV-NRP-1 treatments increased the wingless integration (Wnt)-associated signals and β-catenin nuclear localization. The protective effects of NRP-1 were reversed by the administration of XAV-939. Conclusions NRP-1 can produce neuroprotective effects against I/R injury to the brain by activating the Wnt/β-catenin signaling pathway and promoting mitochondrial structural repair and functional recovery, which may serve as a promising candidate target in treating ischemic stroke.

Dual-Modality Nanoprobe for Noninvasive Detection of Microthrombus after Cerebral Ischemia/Reperfusion

“…To induce the CI/R mice from transient middle cerebral artery occlusion (tMCAO) model, a method previously described in the literature was followed. , The mice were anesthetized with 1% isoflurane in air to enable spontaneous breathing. A filament (Ruiwode, China) was carefully inserted into the common carotid artery (CCA) and advanced toward the middle cerebral artery (MCA) through the internal carotid artery (ICA).…”

The Nervous System Development Regulator Neuropilin-1 as a Potential Prognostic Marker and Therapeutic Target in Brain Cancer

“…In in vitro and in vivo rat models of cerebral ischemia, a sharp increase in NRP1 expression is observed in the neural tissue. Expression of adeno-associated viral (AAV)-NRP1 markedly ameliorates ischemia-induced impairment of motor function, rescues changes in mitochondrial morphology, and improves mitochondrial oxidative stress and bioenergetic deficits [32]. Expression of NRP1 in the spinal cord is increased in a mouse model of amyotrophic lateral sclerosis [33].…”

Cornerstone Cellular Pathways for Metabolic Disorders and Diabetes Mellitus: Non-Coding RNAs, Wnt Signaling, and AMPK

“…The pathways of programmed cell death during DM are closely linked to cellular energy pathways and oxidative stress (Figure 2). Apoptosis yields cell death during metabolic disease through a series of stages [106,159,[274][275][276]. The initial stage involves the externalization of membrane phosphatidylserine (PS) residues on cell surfaces that can attract inflammatory cells, such as microglia, to dispose of injured cells during the initial phase of apoptosis [106,131,[277][278][279][280][281].…”

“…In particular, microglia are important for removing damaged cells during membrane PS externalization and apoptosis [106,131,145,277,278,298,308,[324][325][326][327]]. Yet, microglia can lead to the generation of oxidative stress through the production of ROS [8,165,167,246,250,[328][329][330][331], which can require modulation by non-coding RNAs [251,[332][333][334][335][336], Wnt signaling [27,28,106,115,276,[337][338][339], and trophic factor pathways with erythropoietin (EPO) [27,[340][341][342][343][344][345][346]. In other scenarios, microglial cells can be helpful for protection during amyotrophic lateral sclerosis [347], remove brain amyloid [348,349], and preserve cholesterol homeostasis with autophagy …”

“…Wnt signaling and WISP1 are vital pathways during metabolic disorders and DM for the oversight of oxidative stress, programmed cell death, and non-coding RNA function (Figure 2). Wnt proteins, which are cysteine-rich glycosylated proteins, are part of the wingless pathway that can modulate cell development and survival during aging, cardiovascular disorders, tumorigenesis, organogenesis, neurodegeneration, vascular disease, inflammation, and DM [25,28,48,76,92,115,131,150,184,276,296,297,305,307,338,339,[457][458][459][460][461][462][463][464][465][466][467]. Wnt proteins that can involve Wnt1 oversee programmed cell death [105,219,278,299,339,362,387,[467][468][469][470][471][472], pancreatic β-cell development and growth [473], skeletal function [152,305,307], trophic factor protec...…”