Activating the cholinergic anti-inflammatory pathway may be a novel anti-inflammation strategy for Covid -19 infection. Anavex 3-71 is one example of an agonist of the Cholinergic Receptor Muscarinic M1.
Abnormal, body-wide inflammation and blood clotting were identified early in the pandemic as central features of severe COVID-19, with the two thought to be interrelated, say the study authors. As blood components that react to injuries in vessels by triggering inflammation, and by becoming sticky to clump together in clots, platelets have been suggested as a culprit for the observed damage.
Protein signals given off by platelets—cell fragments apparently contribute to blood clotting—create inflammation, abnormal clotting, and damage to vessels when exposed to the pandemic virus.
ANAVEX®3-71, an oral small molecule agonist of both SIGMAR1 and CHRM1 (Cholinergic Receptor Muscarinic M1). ANAVEX 3-71, among other things, could be a therapeutic advantage in treating protein-aggregation diseases.
See supporting articles 1-5 below:
1. ANAVEX®3-71, an oral small molecule agonist of both SIGMAR1 and CHRM1 (Cholinergic Receptor Muscarinic M1) ...
Our preclinical findings for ANAVEX 3-71 demonstrate its significant potential to enhance neuroprotection and cognition via concomitant activation of sigma-1 receptor and M1 muscarinic acetylcholine receptor (M1R), which could be a therapeutic advantage in treating Alzheimer’s and other related protein-aggregation diseases,” said study author Abraham Fisher, PhD.
2. Activating Cholinergic Anti-Inflammatory Pathway (CAP): A Novel Anti-Inflammation Strategy for COVID-19 Infection
Due to therapeutic dilemma of current drugs, more anti-inflammation approaches are needed. The CAP represents a neural mechanism of inflammation inhibition, first identified by Tracey KJ in 2000 (26). They found parasympathetic nervous system activity influences circulating TNF amounts and the shock response to endotoxaemia, which they call the ‘cholinergic anti-inflammatory pathway’ (26). The finding of CAP attracts considerable attention during the past 20 years and are well clarified now. In the presence of peripheral inflammation, afferent signals of vagal nerve are fired, notify the CNS and in turn activate an opposing efferent vagal nerve. The efferent vagus nerve then activates the splenic nerve to release its neurotransmitters including norepinephrine in the spleen. Subsequently, norepinephrine activates choline acetyltransferase-expressing T cells possibly via adrenergic receptors (AR), and promotes the production and release of T cell-derived acetylcholine (ACh). The ACh then interacts with a7 subunit-containing nicotinic receptor (a7nAChR) on macrophages and other immune cells, inhibits the release of pro-inflammatory cytokines and protects the body against damage. The efferent arm of this ‘inflammatory reflex’ is the CAP (27–29).
The integrity of the inflammatory reflex is critically dependent on expression of the a7nAChR (27, 30). In addition to immune cells, a7nAChR is also wide-spread expressed in other different cells (Figure 1), including neurons and glial cells (31–33). In endotoxemia, the stimulation of vagus nerve attenuated systemic TNF levels in animals with a7nAChR deficiency in the nervous system, but failed in animals with an a7nAChR deficient immune system (30), identifying the a7nAChR expressed on macrophages and other immune cells as a main mediator of CAP output (28). Intracellular mechanisms are mainly involved in the suppression of NF-?B nuclear translocation, activation of a JAK2/STAT3 cascade, and inhibition of inflammasome activation triggered by the activation of a7nAChR on mitochondria, resulting in the inhibition of TNF, IL-1ß, and other proinflammatory cytokines (34–37). .............
The regulation manner that neural inhibition in inflammation is faster, more effective and localized when compared to humoral ones. More importantly, it can simultaneously inhibit multiple proinflammatory cytokines, such as TNF, IL-1ß, TNF-a, etc. Stimulation of the vagus nerve or activation of a7nAChR has been effective in attenuating the production of the pro-inflammatory cytokines and improving the survival of animals in various inflammatory diseases, especially sepsis. Recently, activating the CAP has also been suggested a therapeutic strategy for respiratory diseases (38). Therefore, this pathway is likely to be a hopeful therapeutic intervention in COVID-19 infection.
3. Platelets Are Key to Blood Vessel Damage in Patients with COVID-19
Abnormal crosstalk between blood platelets and cells lining blood vessels is one cause of deadly organ damage in patients with severe COVID-19, a new study finds.
Led by researchers from NYU Grossman School of Medicine, the study revealed the protein signals given off by platelets—cell fragments that contribute to blood clotting—create inflammation, abnormal clotting, and damage to vessels when exposed to the pandemic virus.
Published online September 8 in Science Advances, the study identified two related genes, S1000A8 and S1000A9, that are turned up in the platelets of patients with COVID-19, causing them to make more of myeloid-related proteins (MRP) 8 and 14. Higher levels of the two proteins, known to operate as a pair and be present in large amounts in immune cells, were linked in the study to higher levels of clotting and inflammation in vessels, greater disease severity, and longer hospital stays.
In support of the theory that platelets are at the core of blood vessel damage in COVID-19, the research team also presented evidence that approved medications known to block platelet activation via the platelet surface protein P2Y12 (clopidogrel or ticagrelor) reduced COVID-19–related inflammation in vessels. The study also found that COVID-19–exposed platelets change cells lining blood vessels (endothelial cells) largely through a protein called P-selectin, which makes platelets stickier and more likely to form clots.
“Our findings reveal a new role for platelets in COVID-19 blood vessel damage and may explain in large part what makes the COVID-19 virus so much more deadly than its relatives that cause the common cold,” says corresponding author Tessa J. Barrett, PhD, research assistant professor in the Department of Medicine at NYU Langone Health.
4. Better Understanding How COVID-19 Causes Severe Cases
Abnormal, body-wide inflammation and blood clotting were identified early in the pandemic as central features of severe COVID-19, with the two thought to be interrelated, say the study authors. As blood components that react to injuries in vessels by triggering inflammation, and by becoming sticky to clump together in clots, platelets have been suggested as a culprit for the observed damage. Further, evidence is mounting that the interplay between platelets and endothelial cells may be important to these disease mechanisms.
5. The Impact of COVID-19 Disease on Platelets and Coagulation
.....COVID-19 causes a spectrum of disease, with frequent involvement of the hemostatic system [9, 10]. Severe pulmonary inflammation causes activation and damage of the pulmonary vasculature and may trigger pulmonary thrombosis early in the disease course [11]. There is a high incidence of venous thromboembolism (VTE) in hospitalized COVID-19 patients, particularly those with severe illness. The incidence of thrombotic complications is 16–69% in patients with COVID-19 admitted to intensive care [3, 10, 12, 13]; the incidence was highest in Llitjos et al. (69%) due to active ultrasound surveillance for deep-vein thrombosis (DVT). The incidence of venous and possibly arterial thrombosis remains high in COVID-19 patients despite administering standard thromboprophylaxis [3]. In one Italian COVID-19 study, the incidence of VTE (despite thromboprophylaxis) was 27.6% in the ICU and 6.6% in the general ward. The rate of ischemic stroke and acute coronary syndrome was 2.5 and 1.1%, respectively [14].
Hypercoagulability due to severe viral pneumonia is not novel. This increased VTE incidence in COVID-19 patients is similar to that seen in patients with other epidemic coronavirus pneumonias, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS-CoV) [15, 16]. H1N1 influenza carried an 18-fold increased risk of developing VTE when compared to critically ill patients with ARDS with no H1N1 influenza infection [17].
The SARS-CoV-2 virus does not appear to have intrinsic procoagulant effects itself; rather, the coagulopathy is most likely the result of the profound COVID-19 inflammatory response and endothelial activation/damage [18]. Recent COVID-19 autopsy reports demonstrate pulmonary endothelial viral inclusions and apoptosis, increased angiogenesis, and increased capillary microthrombi [19, 20].
Patients with COVID-19 pneumonia exhibit coagulation abnormalities, most commonly elevated levels of fibrinogen and D-dimer, often with mild thrombocytopenia [18, 21]. Elevated D-dimer has been associated with a higher mortality rate. A subset of COVID-19 patients can have abnormally short PT and aPTT [15]. The shortened aPTT is often related to elevated Factor VIII (FVIII) [22] as an acute-phase response. In more severely affected patients, a disseminated intravascular coagulopathy (DIC)-like state can develop with relatively mild prolongation of the PT and aPTT (while fibrinogen tends to remain normal/elevated) [18]. However, D-dimer levels are elevated far out of proportion to any abnormalities detected in the PT/INR, aPTT, fibrinogen level, or platelet count; these findings are unusual for DIC, as defined by the criteria of the International Society of Thrombosis and Hemostasis (ISTH) [23]. Unlike the pattern seen in classic DIC from bacterial sepsis or trauma, in COVID-19 prolongation of the aPTT and/or PT is minimal [24], thrombocytopenia is mild (a platelet count of 100–150 ×109/L), hypofibrinogenemia is rare, and laboratory results supporting hyperfibrinolysis are uncommon [25]. COVID-19-associated coagulopathy is the term used to describe this spectrum of coagulation changes. Three stages of COVID-19-associated coagulopathy have been proposed: stage 1 showing elevated D-dimer, stage 2 showing elevated D-dimer together with mildly prolonged PT/INR and aPTT and mild thrombocytopenia, and stage 3 with critical illness and laboratory studies progressing towards classic DIC [11].
Here, we will discuss what is known about COVID-19-associated changes in platelet count, activation states, and production; we will review the association of these platelet parameters with COVID-19 outcomes. Additionally, we will review the predominantly procoagulant changes seen in the coagulation system during COVID-19 infection and their association with COVID-19 mortality....
