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

Fernández-Serra R, Martínez-Alonso E, Alcázar A, Chioua M, Marco-Contelles J, Martínez-Murillo R, Ramos M, Guinea GV, González-Nieto D. Int J Mol Sci. 2022 Jul 4;23(13):7449. doi: 10.3390/ijms23137449.PMID: 35806455
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.
Funding: This research was funded by the Ministerio de Economía y Competitividad Grants MAT2016-79832-R (to G.V.G. and D.G.-N.) and SAF2015-65586-R (to J.M.-C.), ISCIII and FEDER grant RD21/0006/0019 (to A.A.), Ministerio de Ciencia e Innovación grant PID2020-116403RB-I00 funded by MCIN/AEI/10.13039/501100011033 (to D.G.-N.) and funds from the regional government of Madrid: Neurocentro-B2017/BMD-3760 (to G.V.G., R.M.-M. and D.G.-N.) and IND2018/BMD-9804 (to G.V.G.).