Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases

Issue title: Translational Research and Drug Discovery for Neurodegeneration: Challenges for Latin America

Guest editors: K.S. Jagannatha Rao, Gabrielle B. Britton, Luisa Lilia Rocha Arrieta, Norberto Garcia-Cairasco, Alberto Lazarowski, Adrián Palacios, Antoni Camins Espuny and Ricardo B. Maccioni

Article type: Review Article

Authors: Merelli, Amalia^a | Repetto, Marisa^b | Lazarowski, Alberto^a | Auzmendi, Jerónimo^{a; c; *}

Affiliations: [a] Universidad de Buenos Aires, Facultad de Farmacia y Bioqummica, Departamento de Bioquímica Clínica, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Argentina | [b] Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Analítica y Fisicoquímica, Cátedra de Química General e Inorgánica; Instituto de Bioquímica y Medicina Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (IBIMOL, UBA-CONICET), Argentina | [c] Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina

Correspondence: [*] Correspondence to: Jerónimo Auzmendi, Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Argentina. E-mail: jeronimo.auzmendi@gmail.com.

Abstract: The cerebral hypoxia-ischemia can induce a wide spectrum of biologic responses that include depolarization, excitotoxicity, oxidative stress, inflammation, and apoptosis, and result in neurodegeneration. Several adaptive and survival endogenous mechanisms can also be activated giving an opportunity for the affected cells to remain alive, waiting for helper signals that avoid apoptosis. These signals appear to help cells, depending on intensity, chronicity, and proximity to the central hypoxic area of the affected tissue. These mechanisms are present not only in a large list of brain pathologies affecting commonly older individuals, but also in other pathologies such as refractory epilepsies, encephalopathies, or brain trauma, where neurodegenerative features such as cognitive and/or motor deficits sequelae can be developed. The hypoxia inducible factor 1α (HIF-1α) is a master transcription factor driving a wide spectrum cellular response. HIF-1α may induce erythropoietin (EPO) receptor overexpression, which provides the therapeutic opportunity to administer pharmacological doses of EPO to rescue and/or repair affected brain tissue. Intranasal administration of EPO combined with other antioxidant and anti-inflammatory compounds could become an effective therapeutic alternative, to avoid and/or slow down neurodegenerative deterioration without producing adverse peripheral effects.

Keywords: ABC-transporters, erythropoietin, Fe/Cu, HIF-1α, hypoxia, inflammation, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-201074

Journal: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S109-S126, 2021