Figure 1.: The mechanism of COVID-19 infection and pathway for
CNS invasion and associated CNS complications. The COVID-19 can enter
the CNS through the olfactory, neuronal, and BBB pathways. The main way
that the CNS is harmed is by cytokine storm syndrome, which not only
harms neurons but also messes with the BBB’s normal functioning.
As per the available information and the authors’ perspective, the virus
can enter the central nervous system (CNS) through the olfactory nerve,
most likely using transsynaptic and likely axonal transport. In
addition, the hematogenous route has been identified as the second way
the virus might enter the brain. (2-4).
According to fierce evidence, damaging the zones of the brain relating
to memory by SARS-CoV-2 virus gives rise to elevating in proinflammatory
cytokines such as IL-6, TNFα (39), and IL-1β (40). The implication of
this event is to inactivate the synthesis of all forms of nitric oxide
synthases (NOSs), which in turn gives rise to reducing the generation of
NO that acts as one of the key mediators of local inflammation (41-43).
Noteworthy, hippocampus zone that has a unique role in memory is shrunk
as a result of exceed release of cytokines, culminating in hippocampal
atrophy (44).
In addition, ACE2 acting as the host receptor of SARS-CoV-2 virus (45,
46) can regulate normal brain function through provoking
brain-derived
neurotrophic factor (BDNF) activity (47). BDNF has remarkable role to
attenuate neuronal inflammation (48) and microglial activation (49);
thus, the low levels of BDNF, influenced by COVID-19 infection, are
relevant to cognitive impairment (49-51).
Both IL-6 and TNFα, furthermore, pass the BBB and then activate
microglia (52). These activation leads to releasing IL-1β, the receptors
for which are specifically concentrated in the postsynaptic sections of
hippocampal neurons (53). This event makes the hippocampus susceptible
to IL-1β, which has been shown to interfere with
LTP and memory (54).