NRICM101 in combatting COVID-19 induced brain fog: Neuroprotective effects and neurovascular integrity preservation in hACE2 mice

Abstract

Amidst growing concerns over COVID-19 aftereffects like fatigue and cognitive issues, NRICM101, a traditional Chinese medicine, has shown promise. Used by over 2 million people globally, it notably reduces hospitalizations and intubations in COVID-19 patients. To explore whether NRICM101 could combat COVID-19 brain fog, we tested NRICM101 on hACE2 transgenic mice administered the S1 protein of SARS-CoV-2, aiming to mitigate S1-induced cognitive issues by measuring animal behaviors, immunohistochemistry (IHC) staining, and next-generation sequencing (NGS) analysis. The study revealed that S1 protein-administered mice displayed marked signs of brain fog, characterized by reduced learning, memory, and nesting abilities. However, NRICM101 treatment in these animals ameliorated all these cognitive functions. S1 protein administration in mice induced notable inflammation, leading to the death of neurons (NeuN+) and neural stem cells (DCX+) in hACE2 transgenic mice. This was accompanied by heightened microglia activation (IBA1+/CD68+), increased cytokine production (IL1β, IL6), induction of neutrophil extracellular traps (NET), inflammation (NLRP3, CD11b), and platelet (CD31, vWF) and complement (C3) activation, ultimately damaging neurovasculature and disrupting the blood-brain barrier (B.B.B.). Administration of NRICM101 effectively alleviated all these pathological changes. In conclusion, NRICM101 has the potential to prevent COVID-19-associated brain fog by bolstering neurovascular integrity and protecting neurons and neural stem cells. This is achieved by the inhibition of S1 protein-induced complement activation, which in turn leads to the prevention of damage to the neurovasculature and the subsequent death of neurons.