Neuroprotective and Neurorestorative Effects of Epo and VEGF: Perspectives for New Therapeutic Approaches to Neurological Diseases

Abstract

Background: Erythropoietin (Epo) and vascular endothelial growth factor (VEGF) are two vasoactive molecules with essential trophic effects for brain development. The expression and secretion of both molecules increase in response to neuronal damage and they exert protective and restorative effects, which may also be accompanied by adverse side effects. Objective: We review the most relevant evidence on the neuroprotective and neurorestorative effects of Epo and VEGF in three of the most frequent neurological disorders, namely, stroke, epilepsy and Alzheimer's disease, to develop new therapeutic approaches. Method: Several original scientific manuscripts and reviews that have discussed the evidence in critical way, considering both the beneficial and adverse effects of Epo and VEGF in the selected neurological disorders, were analysed. In addition, throughout this review, we propose several considerations to take into account in the design of therapeutic approaches based on Epo and VEGF signalling. Results: Although the three selected disorders are triggered by different mechanisms, they evolve through similar processes: excitotoxicity, oxidative stress, neuroinflammation, neuronal death, glial reactivity and vascular remodelling. Epo and VEGF exert neuroprotective and neurorestorative effects by acting on these processes due to their pleiotropism. In general, the evidence shows that both Epo and VEGF reduce neuronal death but that at the vascular level, their effects are contradictory. Conclusion: Because the Epo and VEGF signalling pathways are connected in several ways, we conclude that more experimental studies, primarily studies designed to thoroughly assess the functional interactions between Epo and VEGF in the brain under both physiological and pathophysiological conditions, are needed.

Cytokine profile in the peripheral blood and the brain in patients with focal drug-resistant epilepsy

“…В норме VEGF содержится в тканях в незначительном количестве, его экспрессия оказывает сильное влияние на проницаемость сосудов, является мощным ангиогенным белком и принимает участие в процессах неоваскуляризации в патологических ситуациях [26]. Экспрессированный VEGF также способствует мобилизации воспалительных клеток в место повреждения, поддерживая местный воспалительный процесс [9]. Из полученных нами результатов видно, что повышенные уровни белка VEGF обнаруживаются в микрососудах головного мозга при ФРЭ и, скорее всего, могут влиять на основные структурные компоненты плотных контактов.…”

“…На проницаемость ГЭБ значимое влияние оказывают медиаторы воспаления и цитокины [6]. Так, фактор роста эндотелия сосудов А (VEGF-Avascular endothelial growth factor A, далее VEGF) является промотором неоваскуляризации и его увеличение приводит к повышению проницаемости сосудов и нарушению целостности ГЭБ из-за дестабилизации плотных контактов [7,8], мобилизации воспалительных клеток к месту повреждения, поддержанию местного воспалительного процесса и индукции синтеза проангиогенных факторов эндотелиальными клетками [8,9]. VEGF секретируется эндотелиальными и другими клетками в ответ на кислородное голодание.…”

The Effect of Erythropoietin and Its Derivatives on Ischemic Stroke Therapy: A Comprehensive Review

“…It has been widely known that EPO exerts its functions via binding to EPO receptors (EPORs) ( Suresh et al, 2019 ), which activate key signal pathways controlling cell survival, proliferation, differentiation, apoptosis, death, and neuroprotection ( Hernández et al, 2017 ; Suresh et al, 2019 ; Urena-Guerrero et al, 2020 ) ( Figure 2 ). EPORs belong to the class I cytokine receptor superfamily and consist of a WSXWS motif in the extracellular domain of 225 amino acids, a single transmembrane domain of 23 amino acids, and a cytoplasmic domain of 235 amino acids.…”

“…EPORs belong to the class I cytokine receptor superfamily and consist of a WSXWS motif in the extracellular domain of 225 amino acids, a single transmembrane domain of 23 amino acids, and a cytoplasmic domain of 235 amino acids. The cytoplasmic domain, lacking tyrosine kinase activity and associated with Janus kinase (JAK), forms complexes that determine EPORs are homodimeric, heterodimeric, or heterotrimeric ( Liongue et al, 2016 ; Suresh et al, 2019 ; Urena-Guerrero et al, 2020 ). To date, four isoforms of EPORs including the EPOR/EPOR (EPOR), EPOR/β-common receptor (βcR), EphrinB4 receptor (EphB4), and cytokine receptor-like factor 3 (CRLF3) were discovered in animals ( Ostrowski and Heinrich, 2018 ; Suresh et al, 2019 ; Urena-Guerrero et al, 2020 ) Figure 2 .…”

“…In general, EPOR and EPOR/βcR mediate EPO’s protective and regenerative functions in the CNS ( Urena-Guerrero et al, 2020 ). The downstream signaling was first initiated by JAK2 phosphorylation, followed by STAT phosphorylation and activation, and others including PI3K/AKT and ERK1/2 pathways.…”