Hippocampal region-specific endogenous neuroprotection as an approach in the search for new neuroprotective strategies in ischemic stroke. Fiction or fact?

Ischemic stroke is the leading cause of death and long-term disability worldwide, and – while major advances in understanding stroke pathophysiology have been made over the past few decades – this has unfortunately not translated into the development of effective therapies (Patel and McMullen, 2017). This leaves the search for such new therapies as a matter of great medical necessity.

To date, attempts to identify neuroprotective targets have involved the study of ischemia-induced molecular cascades, as well as the effort to develop ways of supressing them. But the ischemic cascade is shown to be a complex pathophysiological process of multiple interconnected pathways evolving over time and activated simultaneously or sequentially by a significant reduction in the supply of oxygen and glucose. During the acute-phase stroke, reduced blood flow disrupts ionic homeostasis and increases intracellular calcium-stress reactions (Lipton, 1999). A prolonged increase in levels of calcium impairs glutamate release causing excitotoxic stress, which in turn induces mitochondrial dysfunction and the production of reactive oxygen species (ROS), thereby amplifying the impact of an ischemic episode. In the subacute phase (a few hours to a few days later), apoptotic and inflammatory pathways are activated, leading to neuronal cell death. In addition, disruption of the blood-brain barrier (BBB) leads to an influx of proteins and water into the extracellular space, resulting in edema (Frank et al., 2022; Lipton, 1999; Tymianski, 2011; White et al., 2000).

Although molecular targets for neuroprotection have been identified, to date none of the candidates selected to suppress ischemia-induced cascades have passed rigorous clinical trials (Fisher and Savitz, 2022; Frank et al., 2022; Matei et al., 2020). This state of affairs implies a need for a new approach to the search for potent neuroprotection, hence increased interest in the activation of natural adaptive mechanisms (endogenous neuroprotection) as a promising therapeutic approach (Marmolejo-Martinez-Artesero et al., 2021; Papadakis et al., 2013). The aim here would be to enhance and stimulate the endogenous processes of plasticity and protection of the neuronal system that trigger the brain's intrinsic capacity for self-defense.

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