The coronavirus disease-19 (COVID-19) pandemic has emerged as one of the major outbreaks to be mentioned in history in coming times. Like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a respiratory virus infecting the lungs with fever, dry cough, and acute pneumonia being the major symptoms. It infects epithelial cells expressing angiotensin converting enzyme 2 (ACE2) receptor, which is crucial for viral entry. Based on evolving clinical evidence, it is now unfitting to label SARS-CoV-2 as just a respiratory virus, as lately there are various reports that substantiate its pathogenicity in other organs of the body, including brain. In this review, we discuss the epidemiology of SARS-CoV-2 in comparison to SARS and MERS along with possibilities of viral entry into central nervous system (CNS) tissues. The review provides detailed information about the virulence, epidemiology, and insights into molecular pathways involved in the infectivity of the SARS-CoV-2 virus, along with an in-depth view of current concepts about the neurological significance of the SARS-CoV-2 virus and its neuropathological competence. The review also touches upon our current understanding of placental transmission of SARS-CoV-2, an important aspect of vertical transmission. Furthermore, the review provides a current update on strategies that have been used, are being used, or are under trial for treating the disease.

Amyloid beta is a major constituent of the plaques found in the brains of patients suffering from Alzheimer's disease (AD). A growing body of research work suggests that neuroinflammation plays important roles in the development of AD. Thus, considerable efforts are directed towards identification of compounds that can reduce or inhibit neuroinflammation. Here, we show that sinomenine, a compound present in a Chinese medicinal plant, Sinomenium acutum, inhibits oligomeric amyloid beta-induced production of reactive oxygen species (ROS), nitric oxide (NO) and inflammation-related molecules from astrocytic cells. The conditioned medium from oligomeric amyloid beta-treated astrocytic cells induces cell death in the hippocampal neuronal cells. Importantly, sinomenine inhibits this cell death. In addition, this compound has inhibitory effects on the production of ROS, NO and inflammationrelated factors from oligomeric amyloid-beta treated human astrocytes. Finally, the conditioned medium from oligomeric amyloid beta-treated human astrocytes induces cell death in the primary culture of human neurons, which is inhibited by sinomenine. Thus, sinomenine inhibits amyloid beta-induced production of toxic factors from astrocytes, and confers protection to hippocampal neuronal cells as well as human neurons against indirect toxicity. The results suggest that this compound could provide beneficial effects in AD and other neurodegenerative conditions by reducing inflammation and neuronal cell death.

Fetal neural stem cells (FNSCs) present in the human fetal brain, differentiate into cells of neuronal and glial lineages. The developing fetus is exposed to lower oxygen concentrations compared to adults and this physiological hypoxia may in uence the growth and differentiation of the FNSCs. This study aimed to evaluate the effect of hypoxia on the differentiation potential of human FNSCs isolated from the subventricular zone of aborted fetal brains (n = 5). FNSCs were isolated, expanded, and characterized by Nestin and Sox2 expression, using immunocytochemistry and owcytometry respectively. These FNSCs were exposed to 20% oxygen (normoxia) and 0.2% oxygen (hypoxia) concentrations for 48 hours, and hypoxia exposure (n = 5) was validated. Whole transcriptome analyses (Genespring GX13) of FNSCs exposed to hypoxia (Agilent 4x44K human array slides), highlighted that genes associated with neurogenesis were enriched on exposure to hypoxia. The pathway analysis of these enriched genes (using Metacore) showed that the involvement of WNT signaling pathway. Microarray analyses was validated using neuronal and glial lineage commitment markers, namely NEUROG1, NEUROG2, ASCL1, DCX, GFAP, OLIG2 and NKX2.2 using qPCR (n = 9). DCX and GFAP protein expression were analysed by western blotting (n = 3). This demonstrated upregulation of the neuronal commitment markers on hypoxia exposure, while no change was observed in astrocytic and oligodendrocyte lineage commitment markers. Increased expression of downstream targets of the WNT signaling pathway, TCF4 and ID2, by qPCR (n = 9), and increased protein expression of CTNNB1 (β-catenin) and ID2 by western blot (n = 3), indicated its involvement in mediating neuronal differentiation on exposure to hypoxia.

Hypoxic ischemic injury to the fetal and neonatal brain is a leading cause of death and disability worldwide. Although animal and culture studies suggest that glutamate excitotoxicity is a primary contributor to neuronal death following hypoxia, the molecular mechanisms, and roles of various neural cells in the development of glutamate excitotoxicity in humans, is not fully understood. In this study, we developed a culture model of human fetal neural stem cell (FNSC)-derived astrocytes and examined their glutamate uptake in response to hypoxia. We isolated, established, and characterized cultures of FNSCs from aborted fetal brains and differentiated them into astrocytes, characterized by increased expression of the astrocyte markers glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 1 (EAAT1) and EAAT2, and decreased expression of neural stem cell marker Nestin. Differentiated astrocytes were exposed to various oxygen concentrations mimicking normoxia (20% and 6%), moderate and severe hypoxia (2% and 0.2%, respectively). Interestingly, no change was observed in the expression of the glutamate transporter EAAT2 or glutamate uptake by astrocytes, even after exposure to severe hypoxia for 48 h. These results together suggest that human FNSC-derived astrocytes can maintain glutamate uptake after hypoxic injury and thus provide evidence for the possible neuroprotective role of astrocytes in hypoxic conditions.

Fetal neural stem cells (FNSCs) present in the human fetal brain, differentiate into cells of neuronal and glial lineages. The developing fetus is exposed to lower oxygen concentrations compared to adults and this physiological hypoxia may influence the growth and differentiation of the FNSCs. This study aimed to evaluate the effect of hypoxia on the differentiation potential of human FNSCs isolated from the sub-ventricular zone of aborted fetal brains (n = 5). FNSCs were isolated, expanded, and characterized by Nestin and Sox2 expression, using immunocytochemistry and flowcytometry respectively. These FNSCs were exposed to 20% oxygen (normoxia) and 0.2% oxygen (hypoxia) concentrations for 48 hours, and hypoxia exposure (n = 5) was validated. Whole transcriptome analyses (Genespring GX13) of FNSCs exposed to hypoxia (Agilent 4x44K human array slides), highlighted that genes associated with neurogenesis were enriched on exposure to hypoxia. The pathway analysis of these enriched genes (using Metacore) showed that the involvement of WNT signaling pathway. Microarray analyses was validated using neuronal and glial lineage commitment markers, namely NEUROG1, NEUROG2, ASCL1, DCX, GFAP, OLIG2 and NKX2.2 using qPCR (n = 9). DCX and GFAP protein expression were analysed by western blotting (n = 3). This demonstrated upregulation of the neuronal commitment markers on hypoxia exposure, while no change was observed in astrocytic and oligodendrocyte lineage commitment markers. Increased expression of downstream targets of the WNT signaling pathway, TCF4 and ID2, by qPCR (n = 9), and increased protein expression of CTNNB1 (β-catenin) and ID2 by western blot (n = 3), indicated its involvement in mediating neuronal differentiation on exposure to hypoxia.