4.5 Central nervous system impairment in COVID-19
The symptoms of SARS-CoV-2 infection usually appeared in the human respiratory system, while coronavirus infection has been associated with neurological manifestations. Upon nasal infection, coronavirus invades the central nervous system (CNS) through the olfactory bulb, causing inflammation and demyelination(Bohmwald et al. , 2018). For example, a retrospective case series of 214 patients has been analyzed that 25% patients have CNS manifestation: headache (13%), dizziness (17%), impaired consciousness (8%) and so on, while they did not perform clearly electroencephalography (EEG) or cerebrospinal fluid (CSF) analysis(Mao et al. , 2020). Another retrospective study has confirmed the occurrence of CNS following COVID-19(Chen et al. , 2020). As a matter of fact, the evidence on the CNS involvement of COVID-19 is scarce but still worthy of more attentions, because the infection of SARS-CoV-2 may partially explain why some patients develop respiratory failure. The entry of SARS-CoV-2 into human host cells is mainly mediated by the cellular receptor ACE2, thus the CNS manifestation may be associated with the expression of ACE2 in brain. In K18-hACE2 (hACE2 expression was driven by K18 promoter) mice, the brain was a major target organ for SARS infection(McCray et al. , 2007). The virus entered the brain primary via the olfactory bulb resulting in rapid, transneuronal spread to other areas of the brain and finally induced the death of experimental animal(Netland et al. , 2008). Although it is limited to explore the occurrence of CNS following COVID-19, there are lots of evidences that have proved the function of ACE2 in brain injury or stroke. Accordingly, ACE2-deficient mice showed increased oxidative stress in the brain and autonomic dysfunctions compared to controls(Xia et al. , 2011). However, in a stroke model triggered by middle cerebral artery occlusion ACE2 overexpression in the brain resulted in a decreased stroke volume and improved neurological scores in mice(Chen et al. , 2014; Zheng et al. , 2014). Moreover, the human RAAS transgenic mice showed enhanced cerebral damage in experimental ischemia models which again could be prevented by additional transgenic expression of ACE2 in neurons(Zhenget al. , 2014). Further experiments have demonstrated an intracellular expression of ACE2 based on immunohistochemistry in different areas of the brain(Doobay et al. , 2007) and Ang (1-7) expression in primary neuronal cell culture from hypothalamic-brain stem areas(Gironacci et al. , 2013). Interestingly, it has been reported that in this brain region Ang (1-7) can be formed independent of Ang Ⅱ processing(Pereira et al. , 2013). Using MAS antagonists, the authors revealed that ACE2 exerts its beneficial effects in ischemic brain injury by shifting the balance between Ang Ⅱ and Ang (1-7) in favor of the latter, thereby reducing local reactive oxygen species production(Regenhardt et al. , 2013). Numerous reports showed that ACE2/Ang (1-7)/Mas axis has beneficial effects in brain injury(Bennionet al. , 2015; Bennion et al. , 2018; Jiang et al. , 2012). At the same time, the potential cerebroprotective effects of Ang (1-7) were also examined in a model of haemorrhagic stroke produced by intra-striatal injection of collagenase in normotensive rats(Delet al. , 1996). While neurological manifestations of COVID-19 have still explored, it is highly likely that some of these patients have the susceptibility due to the distribution of ACE2 on central nervous system.