COVID-19-Related Brain Injury: The Potential Role of Ferroptosis

Abstract

The COVID-19 pandemic has caused devastating loss of life and a healthcare crisis worldwide. SARS-CoV-2 is the causative pathogen of COVID-19 and is transmitted mainly through the respiratory tract, where the virus infects host cells by binding to the ACE2 receptor. SARS-CoV-2 infection is associated with acute pneumonia, but neuropsychiatric symptoms and different brain injuries are also present. The possible routes by which SARS-CoV-2 invades the brain are unclear, as are the mechanisms underlying brain injuries with the resultant neuropsychiatric symptoms in patients with COVID-19. Ferroptosis is a unique iron-dependent form of non-apoptotic cell death, characterized by lipid peroxidation with high levels of glutathione consumption. Ferroptosis plays a primary role in various acute and chronic brain diseases, but to date, ferroptosis in COVID-19-related brain injuries has not been explored. This review discusses the mechanisms of ferroptosis and recent evidence suggesting a potential pathogenic role for ferroptosis in COVID-19-related brain injury. Furthermore, the possible routes through which SARS-CoV-2 could invade the brain are also discussed. Discoveries in these areas will open possibilities for treatment strategies to prevent or reduce brain-related complications of COVID-19.

Revisiting Regulated Cell Death Responses in Viral Infections

“…Previous studies have also reported that ferroptosis may also play a potential role in the development of COVID-19-related brain injuries as Fe is one of the most abundant metals found in the brain and is needed for normal physiological processes of the brain. The brain is also sensitive to oxidative stress generated by ROS and lipid peroxidation due to its high level of PUFAs as the cell membranes of the neurons contain high amounts of PUFAs, thus being susceptible to ROS-mediated oxidation caused by a cytokine storm, a key feature of SARS-CoV-2 infection in COVID-19 [237,238]. Ferroptosis may also occur due to the dysregulation of Fe homeostasis in COVID-19 patients.…”

Regulated necrosis in COVID-19: A double-edged sword

“…ROS, reactive nitrogen species, and reactive sulfur species ( 116 , 120 , 121 ) produced during pathological conditions can cause oxidative damage and ischemia-reperfusion injury to different organs, such as the lungs, liver, kidney, heart, intestine, and brain ( 122 – 124 ). To a great extent, ferroptosis is associated with hyperinsulinemia, hypercoagulable state, hemorrhagic stroke injury, shock, and MODS ( 123 , 125 , 126 ).…”

Aspectos fisiopatológicos envolvidos na sintomatologia da COVID-19 e suas consequências: uma revisão bibliográfica de literatura

“…Em relação ao sistema nervoso central, o coronavírus ataca o cérebro através de três caminhos diferentes, sendo eles: líquido cefalorraquidiano, nervos periféricos e vasos sanguíneos, se houver rompimento da barreira hematoencefálica. Tal lesão na barreira pode ocorrer pelo excesso de citocinas e, consequentemente, pelo recrutamento de células inflamatórias para o local (Zhang et al, 2022). Foram descritos inúmeros sintomas neuropsiquiátricos e, segundo Zhang et al (2022), eles são decorrentes de lesões diretas nas células cerebrais, causadas pela invasão do SARS-CoV-2 nos receptores ECA2 e de microderrames ou micro-hemorragias no tecido nervoso que, por sua vez, surgem devido à liberação de trombina pelas células endoteliais do cérebro ao sofrerem agressões.…”

“…Tal lesão na barreira pode ocorrer pelo excesso de citocinas e, consequentemente, pelo recrutamento de células inflamatórias para o local (Zhang et al, 2022). Foram descritos inúmeros sintomas neuropsiquiátricos e, segundo Zhang et al (2022), eles são decorrentes de lesões diretas nas células cerebrais, causadas pela invasão do SARS-CoV-2 nos receptores ECA2 e de microderrames ou micro-hemorragias no tecido nervoso que, por sua vez, surgem devido à liberação de trombina pelas células endoteliais do cérebro ao sofrerem agressões. A trombina pertence a uma das etapas fundamentais da coagulação e posterior formação de trombos.…”

“…Muitas pessoas também relataram distúrbios no olfato e no paladar, ocorrendo pela invasão do vírus ao bulbo olfatório, danificando as células nervosas presentes naquela região. Além dos sintomas, o SARS-CoV-2 foi responsável por várias doenças no sistema nervoso central, como, por exemplo: AVC isquêmico, hemorragia intracerebral, encefalite, transtorno de estresse pós-traumático, distúrbio extrapiramidal e do movimento (Zhang et al, 2022). Segundo Huynh, et al, (2022), entre 4 a 20% dos indivíduos contaminados pelo novo coronavírus apresentaram alguma queixa cutânea com manifestações durante as quatro primeiras semanas.…”