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

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.

Hypoxia-Induced Neuroinflammation in Alzheimer’s Disease: Potential Neuroprotective Effects of Centella asiatica

“…Similarly, studies in AD patients using arterial spin-labelling MRI and transcranial Doppler ultrasonography revealed a loss in CBF and impaired CVR as well as altered cerebral metabolic parameters in their brains (Schuff et al, 2009;De Heus et al, 2018), that are associated with decreased oxygen consumption and therefore, indicating a hypoxic environment in the brain. Cerebral hypoxia is a condition that can happen either as global hypoxia or as cerebrovascular accident or ischemic stroke, due to a broad set of clinical pathologies, such as myocardial infarction, cerebral small vessel disease (CSVD), arteriosclerosis, diabetes mellitus or even genetic disorders (Merelli et al, 2020;Bandyopadhyay, 2021). Moreover, some other conditions that lead to a reduced supply of O 2 in the brain include anaemic hypoxia, pulmonary ventilation insufficiency or obstruction defects, obstructive sleep apnoea, neonatal asphyxia, hypobaric altitude hypoxia and carbon monoxide inhalation (Merelli et al, 2020).…”

“…Cerebral hypoxia is a condition that can happen either as global hypoxia or as cerebrovascular accident or ischemic stroke, due to a broad set of clinical pathologies, such as myocardial infarction, cerebral small vessel disease (CSVD), arteriosclerosis, diabetes mellitus or even genetic disorders (Merelli et al, 2020;Bandyopadhyay, 2021). Moreover, some other conditions that lead to a reduced supply of O 2 in the brain include anaemic hypoxia, pulmonary ventilation insufficiency or obstruction defects, obstructive sleep apnoea, neonatal asphyxia, hypobaric altitude hypoxia and carbon monoxide inhalation (Merelli et al, 2020). All of these pathologies can be aggravated by additional factors (for instance, poor lifestyle habits and smoking), leading to neuronal death and eventually cognitive decline (Merelli et al, 2020).…”

“…Moreover, some other conditions that lead to a reduced supply of O 2 in the brain include anaemic hypoxia, pulmonary ventilation insufficiency or obstruction defects, obstructive sleep apnoea, neonatal asphyxia, hypobaric altitude hypoxia and carbon monoxide inhalation ( Merelli et al, 2020 ). All of these pathologies can be aggravated by additional factors (for instance, poor lifestyle habits and smoking), leading to neuronal death and eventually cognitive decline ( Merelli et al, 2020 ).…”

Two-Photon Imaging to Unravel the Pathomechanisms Associated with Epileptic Seizures: A Review

“…Oxidative stress plays an important pathophysiological role in intracellular mechanisms in all of the aforementioned cells and processes [68,81,82]. Most of the involved proteins and molecules in oxidative stress are difficult to assess due to their short lifespan and rapid reactivity with redox state regulating components [83].…”

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

“…Merelli et al [8] review the primary role of hypoxia in the development of inflammation and oxidative stress and discuss the potential for recombinant human erythropoietin in pharmacological doses administered via the route nasal to act as an antiinflammatory and antioxidant anti-apoptotic agent. We are sorry to mention that our beloved colleague S3 Dr. Amalia Merelli died on October 13, 2020 as a result of a breast cancer metastasis while preparing the review.…”