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.