Coronavirus Disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a “cytokine storm,” and neuroinflammation. COVID-19’s upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy Bodies made of α-Synuclein protein encoded by synuclein alpha (SNCA). This study presents the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN’s Ingenuity Pathway Analysis, the study identifies the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream Effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation.

Objective: To investigate the analgesic activity of methanolic extract of Entada phaseoloides (MEEP) along with its molecular mechanistic pathway. Methods: Swiss albino female mice and Wistar rats of either sex were administered orally with MEEP extracts (100, 200 and 400 mg/kg) and pentazocine, tramadol and diclofenac sodium, as standard drugs. Following administration, anti-nociceptive activity was evaluated using an acetic acid-induced writhing test, Eddy’s hot plate, and hot water immersion test. Serum was collected for molecular expression of various proteins and genes using Reverse Transcriptase PCR and Western Blotting. Results: Acetic acid writhing test, a frequently used method to assess peripheral analgesic activity, revealed that MEEP reduced peripherally induced pain in a dose-dependent manner. Likewise, Eddy’s hot plate and hot water immersion methods, often implicated for testing central analgesic activities, showed that MEEP is bestowed with the capability to counteract analgesia in a dose and time-dependent manner. Pro-inflammatory cytokines and factors like COX-2, IL-6, TNF-α, and NF-κB that cause inflammatory responses and pain were significantly reduced, suggesting its analgesic and anti-inflammatory potential. This analgesic and the anti-inflammatory role played by MEEP is also supported by the up-regulation of anti-inflammatory cytokine IL-10 and COMT and COX-1 enzyme demonstrated no significant difference between the groups. Conclusion: The study revealed the weak peripheral and potent central analgesic property MEEP by modulating pro-inflammatory and anti-inflammatory pathways.