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).