SARS-CoV-2 Spike Protein Induces Cognitive Deficit and Anxiety-like Behavior in Mouse via Non-cell Autonomous Hippocampal Neuronal Death

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is accompanied by chronic neurological sequelae such as cognitive decline and mood disorder, but the underlying mechanisms have not yet been elucidated. In this study, we explored the possibility that the brain-infiltrating SARS-CoV-2 spike protein contributes to the development of neurological symptoms observed in COVID-19 patients. Our behavioral study showed that administration of SARS-CoV-2 spike protein S1 subunit (S1 protein) to mouse hippocampus induced cognitive deficit and anxiety-like behavior in vivo. These neurological symptoms were accompanied by neuronal cell death in the dorsal and ventral hippocampus as well as glial cell activation. Interestingly, the S1 protein did not directly induce hippocampal cell death in vitro. Rather, it exerted neurotoxicity via glial cell activation, partially through interleukin-1β induction. In conclusion, our data suggest a novel pathogenic mechanism for the COVID-19-associated neurological symptoms that involves glia activation and non-cell autonomous hippocampal neuronal death by the brain-infiltrating S1 protein.

Heterocyclic Cathinones as Inhibitors of Kynurenine Aminotransferase II—Design, Synthesis, and Evaluation

Kynurenic acid is a neuroprotective metabolite of tryptophan formed by kynurenine aminotransferase (KAT) catalyzed transformation of kynurenine. However, its high brain levels are associated with cognitive deficit and with the pathophysiology of schizophrenia. Although several classes of KAT inhibitors have been published, the search for new inhibitor chemotypes is crucial for the process of finding suitable clinical candidates. Therefore, we used pharmacophore modeling and molecular docking, which predicted derivatives of heterocyclic amino ketones as new potential irreversible inhibitors of kynurenine aminotransferase II. Thiazole and triazole-based amino ketones were synthesized within a SAR study and their inhibitory activities were evaluated in vitro. The observed activities confirmed our computational model and, moreover, the best compounds showed sub-micromolar inhibitory activity with 2-alaninoyl-5-(4-fluorophenyl)thiazole having IC50 = 0.097 µM.

Spatial variation of perfusion MRI reflects cognitive decline in mild cognitive impairment and early dementia

Cerebral blood flow (CBF) measured with arterial spin labelling (ASL) magnetic resonance imaging (MRI) reflects cerebral perfusion, related to metabolism, and arterial transit time (ATT), related to vascular health. Our aim was to investigate the spatial coefficient of variation (sCoV) of CBF maps as a surrogate for ATT, in volunteers meeting criteria for subjective cognitive decline (SCD), amnestic mild cognitive impairment (MCI) and probable Alzheimer’s dementia (AD). Whole-brain pseudo continuous ASL MRI was performed at 3 T in 122 participants (controls = 20, SCD = 44, MCI = 45 and AD = 13) across three sites in New Zealand. From CBF maps that included all grey matter, sCoV progressively increased across each group with increased cognitive deficit. A similar overall trend was found when examining sCoV solely in the temporal lobe. We conclude that sCoV, a simple to compute imaging metric derived from ASL MRI, is sensitive to varying degrees of cognitive changes and supports the view that vascular health contributes to cognitive decline associated with Alzheimer’s disease.

Solar Retinopathy: Case Report

Aims: To describe a solar retinopathy. Presentation of Case: ALPN, 29 years old, male, with cognitive deficit that started after a car accident that occurred at the age of 6 years, attends the ophthalmology clinic of the University Hospital Antônio Pedro, Rio de Janeiro, Brazil with complaints of decreased visual acuity and metamorphopsia in both eyes (AO) started approximately 8 months ago. Family members reported that after the accident, the patient had the habit of spending mornings and afternoons looking at the sun. Discussion: Solar retinopathy is caused by the photochemical and thermal effects of ultraviolet radiation on retinal cells, especially in the outer retina and retinal pigment epithelium (RPE). Symptoms can start a few hours after direct observation of the sun, and in most cases a bilateral involvement, although asymmetrically with variable visual acuity. Conclusions: A Solar retinopathy has a multifactorial origin, as it is related to the exposure time and the susceptibility of each individual. The use of hats and sunglasses with protection against ultraviolet rays and anti-reflection are effective preventive measures to be adopted if there is a need for exposure and observation of sunlight.

Neuroprotective Effect of Celastrus Paniculatus Seed Extract in Epilepsy and Epilepsy-Associated Cognitive Deficits

Purpose: Cognitive deficit is one of the common comorbidity accompanying epilepsy. The present study evaluated the effect of Celastrus paniculatus (C- paniculatus) seed extract on seizure severity and cognitive deficit following Pentylenetetrazole (PTZ) -induced chemical kindling model. Methods : PTZ kindling model was developed by daily administration of sub-convulsive dose of PTZ 30 mg/kg for 4 weeks. After 4 weeks of induction, the following treatment namely Sodium valproic acid (SVA) 200 mg/kg, C- paniculatus 500 mgkg, Pergolide 2 mg/kg alone and combination groups C- paniculatus 250 mgkg+ Pergolide 1 mg/kg and C- paniculatus 250 mgkg+ SVA 100 mg/kg were administered 30 minute prior to PTZ 30 mg/kg injection for a period of next 14 days. Neurobehavioral parameters Morris water maze test (MWM), Grip strength test (GPS) brain superoxide dismutase (SOD), Catalase, reduced glutathione (GSH) and dopamine level. Hematoxylin & Eosin (H&E) staining of hippocampus pyramidal layers Cornu ammonis (CA1), CA2, CA3, dentate gyrus (DG), and frontal cortex were assessed. Results: C- paniculatus 500 mg/kg alone and combination groups C- paniculatus 250 mgkg+ Pergolide 1 mg/kg and Celastrus paniculatus 250 mgkg+ SVA 100 mg/kg significantly (p<0.05) reduced the seizure score, mean latency time, and distance traveled in MWM. However, no significant effect was seen in grip strength test. Biochemical analysis showed elevated antioxidant markers namely GSH, catalase, and SOD & elevated dopamine levels. C- paniculatus and its combination were also found significantly (p<0.05) protected against neuronal loss in hippocampus and frontal cortex as evidenced by H&E staining. Conclusion: C- paniculatus alone and its combination may have the potential to treat epilepsy and associated cognitive deficits.