Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated Human Microglia: Implications for Neuro-COVID.

Emerging clinical data from the current COVID-19 pandemic suggests that ~ 40% of COVID-19 patients develop neurological symptoms attributed to viral encephalitis while in COVID long haulers chronic neuro-inflammation and neuronal damage result in a syndrome described as Neuro-COVID. We hypothesize that SAR-COV2 induces mitochondrial dysfunction and activation of the mitochondrial-dependent intrinsic apoptotic pathway, resulting in microglial and neuronal apoptosis. The goal of our study was to determine the effect of SARS-COV2 on mitochondrial biogenesis and to monitor cell apoptosis in human microglia non-invasively in real time using Raman spectroscopy, providing a unique spatio-temporal information on mitochondrial function in live cells. We treated human microglia with SARS-COV2 spike protein and examined the levels of cytokines and reactive oxygen species (ROS) production, determined the effect of SARS-COV2 on mitochondrial biogenesis and examined the changes in molecular composition of phospholipids. Our results show that SARS- COV2 spike protein increases the levels of pro-inflammatory cytokines and ROS production, increases apoptosis and increases the oxygen consumption rate (OCR) in microglial cells. Increases in OCR are indicative of increased ROS production and oxidative stress suggesting that SARS-COV2 induced cell death. Raman spectroscopy yielded significant differences in phospholipids such as Phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC), which account for ~ 80% of mitochondrial membrane lipids between SARS-COV2 treated and untreated microglial cells. These data provide important mechanistic insights into SARS-COV2 induced mitochondrial dysfunction which underlies neuropathology associated with Neuro-COVID.

Melatonin multifaceted pharmacological actions on melatonin receptors converging to abrogate COVID-19.

Data indicate that controlling inflammatory responses to COVID-19 may be as important as antiviral therapies or could be an important adjunctive approach. Melatonin possesses anti-inflammation, antioxidation, and immune-enhancing features directly and/or indirectly through its own receptor signaling and is therefore well suited to reduce the severity of COVID-19. Studies have proposed that melatonin regulates COVID-19-associated proteins directly through regulation of molecules such as calmodulin (CALM) 1 and CALM 2, calreticulin (CalR), or myeloperoxidase (MPO) and/or indirectly through actions on GPCR (eg, MTNR1A, MTNR1B) and nuclear (eg, RORα, RORß) melatonin receptor signaling. However, the exact mechanism(s) and doses by which melatonin reduces the severity of COVID-19 is still open for debate, warranting the need for further testing of melatonin in placebo-controlled randomized clinical trials for COVID-19.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the Nervous System: Implications of COVID-19 in Neurodegeneration.

Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), began in December 2019, in Wuhan, China and was promptly declared as a pandemic by the World Health Organization (WHO). As an acute respiratory disease, COVID-19 uses the angiotensin-converting enzyme 2 (ACE2) receptor, which is the same receptor used by its predecessor, SARS-CoV, to enter and spread through the respiratory tract. Common symptoms of COVID-19 include fever, cough, fatigue and in a small population of patients, SARS-CoV-2 can cause several neurological symptoms. Neurological malaise may include severe manifestations, such as acute cerebrovascular disease and meningitis/encephalitis. Although there is evidence showing that coronaviruses can invade the central nervous system (CNS), studies are needed to address the invasion of SARS-CoV-2 in the CNS and to decipher the underlying neurotropic mechanisms used by SARS-CoV-2. This review summarizes current reports on the neurological manifestations of COVID-19 and addresses potential routes used by SARS-CoV-2 to invade the CNS.