Substance P Plays A Key Role In COVID-19 Pathogenesis!

COVID-19 News: In late 2019 and early 2020, the world faced an unprecedented health crisis as SARS-CoV-2, the virus responsible for COVID-19, spread rapidly, leading to a global pandemic. This virus wreaks havoc on the human body by damaging endothelial cells, causing microthrombosis, capillary constriction, and pericyte malfunction. These disruptions lead to impaired oxygen exchange in the lungs, hypoxemia, and tissue hypoxia, which in turn can cause severe complications, including cognitive dysfunction and prolonged disease duration. This COVID-19 News report delves into the role of the neuropeptide Substance P (SP) in the etiology of COVID-19 and explores potential therapeutic strategies to mitigate the impact of the virus.

Pathway of SP involvement in respiratory infection 

Discovery and Functions of Substance P
Substance P was discovered by Von Euler and Gaddum in 1931, who identified it as a hypotensive and spasmogenic component in brain and intestinal extracts.
https://pubmed.ncbi.nlm.nih.gov/16994201/
 
Later, Leeman's team isolated and characterized SP from the hypothalamus of cattle.
https://www.nature.com/articles/newbio232086a0
 
SP is a versatile peptide, known for its roles in neuromodulation, inflammation, and immune responses. It affects vascular dilation, smooth muscle contractions, and neural excitatory potential, and is involved in bronchoconstriction under pathological conditions. The gene encoding SP, TAC-1, has unique networking capabilities, making it susceptible to involvement in various diseases, including cancer, sudden infant death syndrome (SIDS), and traumatic brain injury (TBI).
 
Substance P: A Peptide with Unique Features
In 1976, Peter Oehme theorized that SP encodes distinct information, acting directly on smooth muscle and sensory neurons, and indirectly influencing other transmitter systems like acetylcholine.
https://www.science.org/doi/abs/10.1126/science.6154313
 
This theory was supported by studies showing SP's dual effect on pain threshold and its impact on behavior in stress models. Oehme and Karl Hecht's research highlighted SP's role as a regulatory peptide in stress processes. Further studies revealed SP's interaction with the aminergic system and its influence on synaptic transmission in mast cells. These findings opened the door to exploring SP's therapeutic potential, particularly in respiratory tract diseases.
 
The Role of Substance P in Respiratory Diseases
Research indicates that SP plays a significant role in respiratory tract diseases, including COVID-19. SP contributes to infection and nociception symptoms, airway hypersensitivity, and varying patterns of COVID-19 disea se severity across age groups. Notably, SP secretion correlates with viral load, explaining the high mortality rates among COVID-19 patients with underlying conditions like diabetes, hypertension, and cardiac diseases. SP's involvement in ventilatory function and cytokine storming suggests that it could be a key player in severe inflammation during COVID-19. Aprepitant, an NK-1R antagonist, has been proposed as a potential therapeutic agent to inhibit SP's receptor and mitigate cytokine storming.
 
SP and NK-1R in Immune Response and Inflammation
SP and its receptor NK-1R are expressed in various cell types, including vascular endothelial cells, fibroblasts, white blood cells, and neurons. When SP binds to NK-1R, it triggers a signaling cascade that leads to the production of pro-inflammatory cytokines, illustrating the interplay between the immune and nervous systems. SP promotes vasodilation, increases vascular permeability, and facilitates leukocyte extravasation, enhancing immune cell migration to infection sites. It also directly influences immune cell activation, contributing to the cytokine storm phenomenon observed in severe COVID-19 cases.
 
SP in Neurological Conditions and Post-COVID Complications
SP is implicated in long-term neurological consequences, such as Parkinson's disease (PD) and chronic post-COVID-19 olfactory impairment. Research has shown that SP and NK-1R are involved in neuroinflammatory processes in olfactory neurons, with elevated SP levels correlating with motor impairments in PD. This highlights the potential of SP as a biomarker or therapeutic target for PD and post-COVID-19 complications. The overexpression of SP in olfactory neurons of COVID-19 patients with persistent olfactory impairment suggests a role in chronic inflammation and smell recovery.
 
The Importance of Endothelial Cells in COVID-19
Endothelial dysfunction is a hallmark of severe COVID-19, contributing to vascular injury, arterial hypertension, cardiac damage, and neurological problems. SARS-CoV-2 targets the ACE-2 enzyme on endothelial cells, disrupting the balance of angiotensin and bradykinins, leading to cytokine storming and endothelial damage. Understanding the interactions between SP, endothelial cells, and the virus is crucial for developing effective treatments.
 
Potential Therapeutic Strategies
Several therapeutic strategies are being explored to combat COVID-19:
 
-NK-1R Antagonists: Drugs like aprepitant, fosapitant, and tardipitant show promise in reducing inflammation by inhibiting NK-1R signaling. Clinical trials have demonstrated their potential to decrease pro-inflammatory cytokines and mitigate cytokine storms.
 
-Dexamethasone: A powerful corticosteroid, dexamethasone reduces inflammatory responses and has proven effective in managing severe respiratory distress in COVID-19 patients.
 
-Neprilysin (NEP): NEP degrades SP and protects against pulmonary inflammation and fibrosis. Research suggests NEP inhibitors could be beneficial in reducing inflammatory cytokines and improving lung histology.
 
-ACE-2/AT1R Modulation: Balancing the ACE-2/ACE ratio is critical for preventing pulmonary injury and managing cytokine storms. Human recombinant soluble ACE-2 (hrsACE-2) shows potential in protecting against SARS-CoV-2 infection.
 
-Neuropilin-1 Inhibition: Targeting the Neuropilin-1 receptor, along with ACE-2 and NK-1R, may provide a comprehensive approach to inhibiting viral entry and immune response exacerbation.
 
Future Perspectives
The relationship between SP and COVID-19 opens up new avenues for research and therapeutic interventions. Understanding the role of SP in regulating the immune response could lead to targeted preventative measures and treatments.
 
Combining COVID-19 research with stress studies may provide insights into managing post-COVID-19 symptoms, such as sleep disturbances. Investigating SP's effects on endothelial cells and angiogenesis, as well as its interactions with the virus, could pave the way for novel diagnostic and therapeutic tools.
 
In conclusion, Substance P is a powerful peptide with significant implications for COVID-19 treatment and prevention. Its role in immune modulation, inflammation, and neurological conditions makes it a promising target for future research and therapeutic development.
 
The study findings by the researchers from Lahore Medical Research Center, National Institute of Health, Bethesda, MD-USA and Leibniz-Research Institute of Molecular Pharmacology (FMP)-Germany was published in the peer reviewed journal: Frontiers in Neurology.
https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1370454/full
 
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