Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain

Abstract

Hypoxic-Ischemic Encephalopathy (HIE) in the brain is the leading cause of morbidity and mortality in neonates and can lead to irreparable tissue damage and cognition. Thus, investigating key mediators of the HI response to identify points of therapeutic intervention has significant clinical potential. Brain repair after HI requires highly coordinated injury responses mediated by cell-derived extracellular vesicles (EVs). Studies show that stem cell-derived EVs attenuate the injury response in ischemic models by releasing neuroprotective, neurogenic, and anti-inflammatory factors. In contrast to 2D cell cultures, we successfully isolated and characterized EVs from whole brain rat tissue (BEV) to study the therapeutic potential of endogenous EVs. We showed that BEVs decrease cytotoxicity in an ex vivo oxygen glucose deprivation (OGD) brain slice model of HI in a dose- and time-dependent manner. The minimum therapeutic dosage was determined to be 25 μg BEVs with a therapeutic application time window of 4–24 h post-injury. At this therapeutic dosage, BEV treatment increased anti-inflammatory cytokine expression. The morphology of microglia was also observed to shift from an amoeboid, inflammatory phenotype to a restorative, anti-inflammatory phenotype between 24–48 h of BEV exposure after OGD injury, indicating a shift in phenotype following BEV treatment. These results demonstrate the use of OWH brain slices to facilitate understanding of BEV activity and therapeutic potential in complex brain pathologies for treating neurological injury in neonates.

Lipidomics reveal the cognitive improvement effects of Acer truncatum Bunge seed oil on hypoxic–ischemic encephalopathy rats

“…43 The conversion of ALA C18:3 ω-3 to EPA C20:5 ω-3 and DHA C22:6 ω-3 is a crucial metabolic pathway, with DHA playing a vital role as a nutritional component in reducing adverse impacts on neurological development. [44][45][46] Furthermore, OA C18:1 ω-9, a neuroactive molecule, has been utilized in neuropathic pain treatment after neurotrauma, 47 while EA C22:1 ω-9 supplementation has been demonstrated to enhance memory in rats with cognitive impairment. 48 EA C22:1 ω-9 and OA C18:1 ω-9 chains can be elongated and converted into NA C24:1 ω-9 in the brain, as supported by previous research.…”

Exosomes as a therapeutic tool to promote neurorestoration and cognitive function in neurological conditions: Achieve two ends with a single effort

“…Hypoxic encephalopathy triggers a kind of CNS dysfunction with high mortality and morbidity in neonates and even life‐lasting paralysis 131 . Brain‐derived extracellular vesicles (BEVs) ameliorate the neurotoxicity in oxygen–glucose deprivation (OGD) brain slices based on a dose‐time dependent procedure 132 . Human amniotic fluid‐derived exosomes significantly augment the expression level of hypoxia‐inducible factor 1 α (HIF‐1α) and vascular endothelial growth factor (VEGF) that coincide with a decrease in the escape latency time and increase in the target quadrant occupancy of MWM test 133 …”

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EVISF) reveals sex‐dependent changes in microglial EV proteome in response to Aβ pathology

“…Over the past decade, advanced protocols for isolating sEVs from the extracellular space of postmortem brain tissue were developed to understand region‐specific changes associated with pathology (Banigan et al., 2013 , Cohn et al., 2021 , Gallart‐Palau et al., 2016 , Huang et al., 2020 , Hurwitz et al., 2018 , Muraoka et al., 2020 , Nguyen et al., 2022 , Perez‐Gonzalez et al., 2012 , Pérez‐González et al., 2017 , Vella et al., 2017 ). Implementation of these methods demonstrated that levels of sEVs are differentially modulated by various AD risk factors (e.g., APOE4, Down syndrome, APP) as a function of age and disease severity (Gauthier et al., 2017 , Hartley et al., 2015 , Mathews & Levy, 2019 , Peng et al., 2019 , Perez‐Gonzalez et al., 2012 , Wisniewski et al., 1985 ).…”