NS1619 Alleviate Brain-Derived Extracellular Vesicle-Induced Brain Injury by Regulating BKca Channel and...

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Traumatic brain injury (TBI) leads to secondary brain injury, partly mediated by brain-induced extracellular vesicles (BDEV).
• The precise mechanisms by which BDEV contribute to TBI pathology and potential therapeutic interventions remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanisms underlying BDEV-induced brain injury.
• To investigate the potential of the BKca channel opener NS1619 in attenuating BDEV-mediated TBI.

Main Methods:

• In vivo studies using TBI models with BDEV and lactadherin administration.
• In vitro assessments of neuronal, endothelial, and microglial cells (HT-22, bEnd3, BV-2) using fluorescent staining, CCK-8, LDH assay, and enzyme activity measurements.
• Evaluation of oxidative stress markers (DHE, 4-HNE) and mitochondrial function (JC-1 staining).
• Analysis of the Nrf2/HO-1/NF-κB signaling pathway and in vivo administration of NS1619 to TBI mice.

Main Results:

• BDEV exacerbated TBI symptoms, including blood-brain barrier disruption, edema, neuronal damage, apoptosis, oxidative stress, and neuroinflammation.
• NS1619 treatment reversed BDEV-induced cellular damage in vitro, normalizing membrane potential, calcium levels, and enhancing cell viability.
• NS1619 mitigated oxidative stress, protected mitochondrial function, and modulated the Nrf2/HO-1/NF-κB pathway.
• In vivo, NS1619 administration improved TBI outcomes, reduced neuroinflammation, and activated the Nrf2/HO-1 pathway.

Conclusions:

• BDEV aggravates brain injury through mechanisms involving membrane potential disruption, calcium overload, oxidative stress, and neuroinflammation.
• The BKca channel opener NS1619 demonstrates significant neuroprotective effects against BDEV-induced pathology in vitro and in vivo.
• NS1619's therapeutic potential lies in its ability to modulate the BKca channel and the Nrf2/HO-1/NF-κB pathway, offering a promising strategy for TBI treatment.