Momordica charantia Exosome-Like Nanoparticles Exert Neuroprotective Effects Against Ischemic Brain Injury via Inhibiting Matrix Metalloproteinase 9 and Activating the AKT/GSK3β Signaling Pathway

Abstract

Plant exosome-like nanoparticles (ELNs) have shown great potential in treating tumor and inflammatory diseases, but the neuroprotective effect of plant ELNs remains unknown. In the present study, we isolated and characterized novel ELNs from Momordica charantia (MC) and investigated their neuroprotective effects against cerebral ischemia-reperfusion injury. In the present study, MC-ELNs were isolated by ultracentrifugation and characterized. Male Sprague–Dawley rats were subjected to middle cerebral artery occlusion (MCAO) and MC-ELN injection intravenously. The integrity of the blood–brain barrier (BBB) was examined by Evans blue staining and with the expression of matrix metalloproteinase 9 (MMP-9), claudin-5, and ZO-1. Neuronal apoptosis was evaluated by TUNEL and the expression of apoptotic proteins including Bcl2, Bax, and cleaved caspase 3. The major discoveries include: 1) Dil-labeled MC-ELNs were identified in the infarct area; 2) MC-ELN treatment significantly ameliorated BBB disruption, decreased infarct sizes, and reduced neurological deficit scores; 3) MC-ELN treatment obviously downregulated the expression of MMP-9 and upregulated the expression of ZO-1 and claudin-5. Small RNA-sequencing revealed that MC-ELN-derived miRNA5266 reduced MMP-9 expression. Furthermore, MC-ELN treatment significantly upregulated the AKT/GSK3β signaling pathway and attenuated neuronal apoptosis in HT22 cells. Taken together, these findings indicate that MC-ELNs attenuate ischemia-reperfusion–induced damage to the BBB and inhibit neuronal apoptosis probably via the upregulation of the AKT/GSK3β signaling pathway.

Cornin protects against cerebral ischemia/reperfusion injury by preventing autophagy via the PI3K/Akt/mTOR pathway

“…At 24 h post reperfusion, 0.1 ml of 4% Evans blue mixed in 0.9% saline was administered intravenously. A quantitative assay using Evans blue was performed to determine blood–brain barrier (BBB) leakage based on a method described previously [ 23 ].…”

The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases

“…The persistent bleeding from a hemorrhagic stroke causes oxidative stress, neuroinflammation, apoptosis, and BBB disruption [ 56 , 70 ]. In addition, the PI3K/Akt/mTOR pathway can modulate multiple cellular and molecular events including oxidative stress factors, inflammatory responses, programmed cell death, and cell survival, and it protects neurons and the brain from ischemic damages [ 9 , 74 , 75 ]. Hence, this pathway can be considered as one a significant signaling pathway and therapeutic target for neuroprotection against stroke.…”

Plant-Derived Exosome-like Nanoparticles for Biomedical Applications and Regenerative Therapy

“…From these studies, it can be inferred that PDENs control inflammation from the transcriptional levels of mRNA, as some of these studies reported a lowered level of mRNA in various inflammatory markers. PDENs inhibit various intracellular signaling, such as AKT, GSK3β [ 190 ], TCF4, Nrf2 [ 200 ], NF-κB [ 185 ], and AhR [ 187 ], leading to altered transcriptional signaling and modulated downstream protein expressions. De Robertis et al (2020) and Yin et al (2022) reported hindered mRNA level of TNF-α, IL-1β, IL1R1, IL-6, IL-8, MAPK1, ICAM1, TLR8, HMOX1, and NFR1 after PDENs administration [ 195 , 202 ].…”