Spikeotherapeutics: the Cholinergic Anti-inflammatory Pathway, Dysautonomia, Chronic Sympathetic Nervous System Activation and Nicotine: A Possible Way Forward.

(1) Background: Severe COVID-19 is characterised by immune dysregulation and a highly inflammatory cytokine storm with symptoms of dysautonomia. It has been proposed that this is at least partially a result of dysregulation of the cholinergic anti-inflammatory pathway and that nicotine may be a useful therapeutic intervention. Post Acute Covid Syndrome (PACS) and Post Acute Vaccination Syndrome (PACVS) are being increasingly recognised and are also characterised by prominent inflammatory markers and dysautonomia. (2) Methods: A narrative review of the literature pertaining to this topic was conducted. (3) Findings: The actions of the cholinergic system are profoundly anti-inflammatory and act via the α7nACh receptors. The spike protein has been demonstrated to contain an amino acid sequence near the RBD with homology with a-1 neurotoxins and demonstrated in silico to interact with α7nACh . The cholinergic anti- inflammatory system and actions of nicotine in that context are investigated and its possible role therapeutically explored. However, its place is limited due to widespread nicotine actions and significant adverse effects in chronic dosing. The role of background chronic sympathetic nervous system activation and dysautonomia and for other therapeutic options is therefore considered. (4) Conclusions: There are other avenues for modulation of the cholinergic system in the management of PACS/PACVS which are proposed in the stead of nicotine.