Glial Cells as Therapeutic Approaches in Brain Ischemia-Reperfusion Injury

Abstract

Ischemic stroke is the second cause of mortality and the first cause of long-term disability constituting a serious socioeconomic burden worldwide. Approved treatments include thrombectomy and rtPA intravenous administration, which, despite their efficacy in some cases, are not suitable for a great proportion of patients. Glial cell-related therapies are progressively overcoming inefficient neuron-centered approaches in the preclinical phase. Exploiting the ability of microglia to naturally switch between detrimental and protective phenotypes represents a promising therapeutic treatment, in a similar way to what happens with astrocytes. However, the duality present in many of the roles of these cells upon ischemia poses a notorious difficulty in disentangling the precise pathways to target. Still, promoting M2/A2 microglia/astrocyte protective phenotypes and inhibiting M1/A1 neurotoxic profiles is globally rendering promising results in different in vivo models of stroke. On the other hand, described oligodendrogenesis after brain ischemia seems to be strictly beneficial, although these cells are the less studied players in the stroke paradigm and negative effects could be described for oligodendrocytes in the next years. Here, we review recent advances in understanding the precise role of mentioned glial cell types in the main pathological events of ischemic stroke, including inflammation, blood brain barrier integrity, excitotoxicity, reactive oxygen species management, metabolic support, and neurogenesis, among others, with a special attention to tested therapeutic approaches.

Dysregulation of mTOR Signaling after Brain Ischemia

“…As a result, there is a decrease in the supply of nutrients (glucose), oxygen, and growth factors to neurons. These conditions lead to neuronal injury or death, bringing about serious neurological dysfunction, the severity of which depends on the size of the area affected in the brain and the duration of the occlusion [ 95 ].…”

“…The area severely affected by hypoperfusion, named the ischemic core, presents a high rate of neuronal death by necrosis ( Figure 5 ). The less affected region surrounding the core is called the penumbra and is characterized by apoptosis, which can be rescued ( Figure 5 ) [ 95 ]. Given these considerations, one of the most important targets in neuro-regenerative approaches after ischemia is the penumbra region.…”

“…Most studies addressing cerebral ischemia have focused on attempts to reduce neuronal death to ameliorate damage. Unfortunately, the promising results obtained in animal models using neuroprotective agents have not been reproduced in humans [ 95 ].…”

“…One well-known mechanism of astrocyte-driven neuroprotection is the capacity of these cells to reduce excitotoxicity by decreasing excessive extracellular glutamate released by damaged neurons. This decrease is achieved through the activation and overexpression of various astrocytic glutamate transporters, such as glutamate transporter-1 (GLT-1) [ 95 ]. In addition, astrocytes are involved in the management of oxidative stress [ 140 ].…”

“…Like microglia (see Section 2.2.2 ), astrocytes can acquire an A1 (pro-inflammatory) or A2 (anti-inflammatory or neuroprotector) phenotype. Reactive astrocytes reduce the detrimental accumulation of reactive oxygen species (ROS) during ischemia, thereby reflecting their potential role as anti-oxidative players under pathological conditions [ 95 , 141 , 142 ]. While there is extensive information about the role of astrocytes after cerebral ischemia, few studies have described the participation of mTOR activity in this context.…”