Experimental Models of SARS-COV-2 Infection in the Central Nervous System.

Coronavirus disease 2019 (COVID-19) has raised serious concerns worldwide due to its great impact on human health and forced scientists racing to find effective therapies to control the infection and a vaccine for the virus. To this end, intense research efforts have focused on understanding the viral biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19. The ever-expanding list of cases, reporting clinical neurological complications in COVID-19 patients, strongly suggests the possibility of the virus invading the nervous system. The pathophysiological processes responsible for the neurological impact of COVID-19 are not fully understood. Some neurodegenerative disorders sometimes take more than a decade to manifest, so the long-term pathophysiological outcomes of SARS-CoV-2 neurotropism should be regarded as a challenge for researchers in this field. There is no documentation on the long-term impact of SARS-CoV-2 on the human central nervous system (CNS). Most of the data relating to neurological damage during SARS-CoV-2 infection have yet to be established experimentally. The purpose of this review is to describe the knowledge gained, from experimental models, to date, on the mechanisms of neuronal invasion and the effects produced by infection. The hope is that, once the processes are understood, therapies can be implemented to limit the damage produced. Long-term monitoring and the use of appropriate and effective therapies could reduce the severity of symptoms and improve quality of life of the most severely affected patients, with a special focus on those have required hospital care and assisted respiration.

Filling the gaps on stroke research: Focus on inflammation and immunity.

For the last two decades, researchers have placed hopes in a new era in which a combination of reperfusion and neuroprotection would revolutionize the treatment of stroke. Nevertheless, despite the thousands of papers available in the literature showing positive results in preclinical stroke models, randomized clinical trials have failed to show efficacy. It seems clear now that the existing data obtained in preclinical research have depicted an incomplete picture of stroke pathophysiology. In order to ameliorate bench-to-bed translation, in this review we first describe the main actors on stroke inflammatory and immune responses based on the available preclinical data, highlighting the fact that the link between leukocyte infiltration, lesion volume and neurological outcome remains unclear. We then describe what is known on neuroinflammation and immune responses in stroke patients, and summarize the results of the clinical trials on immunomodulatory drugs. In order to understand the gap between clinical trials and preclinical results on stroke, we discuss in detail the experimental results that served as the basis for the summarized clinical trials on immunomodulatory drugs, focusing on (i) experimental stroke models, (ii) the timing and selection of outcome measuring, (iii) alternative entry routes for leukocytes into the ischemic region, and (iv) factors affecting stroke outcome such as gender differences, ageing, comorbidities like hypertension and diabetes, obesity, tobacco, alcohol consumption and previous infections like Covid-19. We can do better for stroke treatment, especially when targeting inflammation following stroke. We need to re-think the design of stroke experimental setups, notably by (i) using clinically relevant models of stroke, (ii) including both radiological and neurological outcomes, (iii) performing long-term follow-up studies, (iv) conducting large-scale preclinical stroke trials, and (v) including stroke comorbidities in preclinical research.

Experimental Models for the Study of Central Nervous System Infection by SARS-CoV-2.

INTRODUCTION: The response to the SARS-CoV-2 coronavirus epidemic requires increased research efforts to expand our knowledge of the disease. Questions related to infection rates and mechanisms, the possibility of reinfection, and potential therapeutic approaches require us not only to use the experimental models previously employed for the SARS-CoV and MERS-CoV coronaviruses but also to generate new models to respond to urgent questions. DEVELOPMENT: We reviewed the different experimental models used in the study of central nervous system (CNS) involvement in COVID-19 both in different cell lines that have enabled identification of the virus' action mechanisms and in animal models (mice, rats, hamsters, ferrets, and primates) inoculated with the virus. Specifically, we reviewed models used to assess the presence and effects of SARS-CoV-2 on the CNS, including neural cell lines, animal models such as mouse hepatitis virus CoV (especially the 59 strain), and the use of brain organoids. CONCLUSION: Given the clear need to increase our understanding of SARS-CoV-2, as well as its potential effects on the CNS, we must endeavor to obtain new information with cellular or animal models, with an appropriate resemblance between models and human patients.