These may be related to the recent finding that the spike protein expressed in response to mRNA vaccines was detected in the circulation as early as 1 day post vaccination and became undetectable by day 14 . that may help decipher the pathogenesis of long-COVID. One paper reported perivascular inflammation in brains of deceased patients with COVID-19, while others showed that the spike protein could damage the endothelium in an animal model, that it could disrupt an in vitro model of the blood-brain barrier (BBB), and that it can cross the BBB resulting in perivascular inflammation. Moreover, the spike protein appears to share antigenic epitopes with human molecular chaperons resulting in autoimmunity and can activate toll-like receptors (TLRs), leading to release of inflammatory cytokines. Moreover, some antibodies produced against the spike protein may not be neutralizing, but may change its conformation rendering it more likely to bind to its receptor. As a result, one wonders whether the spike protein entering the brain or being expressed by brain cells could activate microglia, alone or together with inflammatory cytokines, since protective antibodies could not cross the BBB, leading to neuro-inflammation and contributing to long-COVID. Hence, there is urgent need to better understand the neurotoxic effects of the spike protein and to consider possible interventions to mitigate spike protein-related detrimental effects to the brain, possibly via use of small natural molecules, especially the flavonoids luteolin and quercetin. leaves were identified as potential inhibitors of SARS-CoV-23CL(pro) using large-scale screening . Another extract was reported to block TNF-induced reactive oxygen species from human aortic endothelial cells . The extract EGb 761 was beneficial in generalized anxiety disorder  and dementia , actions that may be useful for the neuropsychiatric aspects of long-COVID. Ginkgolic acid (GA) was shown to inhibit the fusion and synthesis of viral proteins . Other studies have shown that green tea catechins could be useful in COVID-19 [180, 181], especially against entry of SARS-CoV-2 . The broccoli extract sulforaphane inhibited expression of IL-6 and IL-8 induced by the SARS-CoV-2 spike protein in bronchial epithelial cells . Certain Colec11 natural flavonoids  have been proposed as prophylaxis or treatment against COVID-19 [185C189]. Such flavonoids are found in green plants and seeds and possess potent anti-oxidant, anti-inflammatory, and cytoprotective properties . However, their consumption as part of the diet does not provide sufficient systemic levels. However, there are a number of sources of pharmaceutical-grade purity (>98%) using different biomasses such as (artichoke), oregano, and Saphora japonicum. In particular, a number of studies using in silico approaches identified the flavonol quercetin and the structurally related flavone luteolin as a potential strong blockers of RBD [190C192]. Luteolin and some of its methylated analogues have a number of beneficial actions with respect to long-COVID: broad antiviral properties [193C195], inhibition of coronavirus entry [127, 196, 197], and inhibition of the serine protease required for spike protein processing [198, 199]. Furthermore, luteolin inhibits activation of both microglia [200C203] and mast cells [204, 205] via inhibition of signaling pathways involving the inflammasome [206, 207] and mTOR (Fig. ?(Fig.2)2) in both mast cells  and microglia . The novel luteolin structural analogue tetramethoxyluteolin (methoxyluteolin) is an even more potent inhibitor than luteolin [203C206]. With respect to long-COVID especially, luteolin could prevent neuro-inflammation [208C211], is neuroprotective [208, 210, 212, 213], and reduces ITK inhibitor 2 cognitive dysfunction [214C218], especially brain fog [58, 60, 62]. Quercetin has been discussed in a few recent studies [219, 220], including an open-label clinical study showing good tolerability and benefit . A double-blind, placebo-controlled, randomized study using a liposomal preparation of luteolin (PureLut) in long-COVID patients is underway. Combining quercetin with luteolin may provide additional benefits, especially when formulated in olive pomace oil (FibroProtek) that increases oral absorption, that is otherwise quite limited (<10%) . Moreover, ITK inhibitor 2 olive pomace oil provides additional ITK inhibitor 2 antiviral  and anti-inflammatory . Such liposomal preparations are available  and have been successfully used in pilot clinical trials  and reduced neuropsychiatric symptoms and associated serum IL-6 levels ..