The mechanism underlying the pathogenesis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in humans is poorly understood, although the cellular receptors which facilitate the virus fusion have been identified. Although the major symptoms of the infection have been identified as acute respiratory distress, pneumonia, and fever, recently, symptoms involving nervous system dysfunctions, including encephalopathy and stroke, have been detected. Herein, we comprehensively review the evidence that SARS-CoV-2 infection involves a neurotropic mechanism including a nose-brain-lung axis suggesting implications in therapy development.
Neurotropism-targeted COVID-19 treatment approach
Thus far, there have been ~300 clinical trials registered in the National Institute of Health (www.clinicaltrials.gov) on treatments for SAR-CoV-2. Most of these trials focus on antiviral drugs, without any due consideration of the neurotropism of the virus. To our knowledge there are more than 160 antiviral agents are available. Screening of these compounds with the intent to identify those that lack neurodegenerative properties or those that possess neuro-regenerative effects may be useful in identifying safe and effective drugs for SARS-CoV-2. It is interesting that one small clinical study relating to SARS-CoV-2 of the effects of mesenchymal stem cells (MSCs), which are known to exert anti-inflammatory and neuro-regenerative activities in brain disorders, showed excellent efficacy, i.e., all 7 of 7 patients showed symptom reduction in 2 days after MSC transplantation. This study has provided a basis for several MSC-based either observational or phase 1-3 trials, which are currently recruiting. In addition, there are several other clinical trials which are registered but have not yet begun to recruit. Given the pivotal role of neuropathology of SARS-CoV-2 and neuronal control of breathing, future therapies should target neurotropism of the virus and combine anti-neuroinflammatory and neuro-regenerative features.
Future therapeutic implications
Several lines of evidence on coronaviruses and exploratory studies in SARS-CoV-2 have demonstrated the involvement of viral neurotropism in the brain stem respiratory center, whose components control breathing, but it is unclear which of these three different pathways offer a potential method of invasion for the virus, and they are not necessarily mutually exclusive. The viral entry of SARS-CoV-2 may be via circulatory in one patient and via oronasal or peripheral sensory neurons in another. Each of these pathways warrants further investigation to determine the neurotropism of SARS-CoV-2, and how these pathways may be exploited to treat patients in the future.
Also, it is evident that one particular approach that is under intense investigation is the development of potential SARS-CoV-2 treatment using MSCs, which have shown neuro-regenerative properties in several brain disorders including traumatic brain injury (TBI)[46]. One of the issues in using MSCs in inflammatory conditions is that MSCs undergo apoptosis or differentiation due to cytokines being released in those inflammatory tissues. It has been reported that pretreatment of TBI animals first with an anti-inflammatory agent followed by MSC treatments significantly increases the efficacy of MSCs[46]. Whether a similar strategy would be more successful in COVID-19 remains to be elucidated. Given the pace and expansiveness of the COVID-19 super pandemic and the fact that the rebound infection may continue for several months to years or could be a seasonal respiratory virus infection similar to influenza and respiratory syncytial virus, it may be prudent to test these possibilities.
Reference & Source information: https://nnjournal.net/
Read more on: