Postischemic Neuroprotection of Aminoethoxydiphenyl Borate Associates Shortening of Peri-Infarct Depolarizations

Abstract

Brain stroke is a highly prevalent pathology and a main cause of disability among older adults. If not promptly treated with recanalization therapies, primary and secondary mechanisms of injury contribute to an increase in the lesion, enhancing neurological deficits. Targeting excitotoxicity and oxidative stress are very promising approaches, but only a few compounds have reached the clinic with relatively good positive outcomes. The exploration of novel targets might overcome the lack of clinical translation of previous efficient preclinical neuroprotective treatments. In this study, we examined the neuroprotective properties of 2-aminoethoxydiphenyl borate (2-APB), a molecule that interferes with intracellular calcium dynamics by the antagonization of several channels and receptors. In a permanent model of cerebral ischemia, we showed that 2-APB reduces the extent of the damage and preserves the functionality of the cortical territory, as evaluated by somatosensory evoked potentials (SSEPs). While in this permanent ischemia model, the neuroprotective effect exerted by the antioxidant scavenger cholesteronitrone F2 was associated with a reduction in reactive oxygen species (ROS) and better neuronal survival in the penumbra, 2-APB did not modify the inflammatory response or decrease the content of ROS and was mostly associated with a shortening of peri-infarct depolarizations, which translated into better cerebral blood perfusion in the penumbra. Our study highlights the potential of 2-APB to target spreading depolarization events and their associated inverse hemodynamic changes, which mainly contribute to extension of the area of lesion in cerebrovascular pathologies.

NS1619 Alleviate Brain-Derived Extracellular Vesicle-Induced Brain Injury by Regulating BKca Channel and Nrf2/HO-1/NF-ĸB Pathway

“…Store-operated Ca 2+ entry (SOCE) mediated by calcium release-activated calcium (CRAC) channels also contributes to increased intracellular calcium and CRAC channel inhibitor improves TBI outcome by inhibiting neuroinflammation [ 46 ]. Another study found that blocking IP3 receptor with 2-APB significantly reduced infarcts in a cerebral ischemia model [ 47 ]. In this study, BDEV can significantly depolarize neurons and endothelial cells and cause cytoplasmic calcium overload in vitro.…”

NS1619 Alleviated Brain Derived Extracellular Vesicles Induced Brain Injury by Regulating the BKCa channel and Nrf2/Ho-1/Nf-kB Pathway

“…Store-operated Ca 2+ entry (SOCE) mediated by calcium release-activated calcium (CRAC) channels also contributes to increased intracellular calcium and CRAC channel inhibitor improves TBI outcome by inhibiting neuroin ammation [44]. Another study found that blocking IP3 receptors with 2-APB signi cantly reduced infarcts in a cerebral ischemia model [45]. In this study, BDEV can signi cantly depolarize neurons and endothelial cells and cause cytoplasmic calcium overload in vitro.…”

Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer

“…Consequently, the pharmacological inhibition of neuronal connexin GJC may offer a strategy for protecting against secondary cell death in such disease contexts. Indeed, several GJC inhibitors, including MFQ, quinine, quinidine, flufenamic acid, 2-APB, and meclofenamic acid, have shown neuroprotective effects by targeting Cx36 22,[41][42][43][44] .…”

“…Consequently, the pharmacological inhibition of neuronal connexin GJC may offer a strategy for protecting against secondary cell death in such disease contexts. Indeed, several GJC inhibitors, including MFQ, quinine, quinidine, flufenamic acid, 2-APB, and meclofenamic acid, have shown neuroprotective effects by targeting Cx36 22,41–44 . Despite its pharmacological promise and its pivotal role in disease-related neuroprotection, the molecular mechanism of Cx36 channel inhibition remains largely elusive.…”