SARS-CoV-2 S1 protein causes brain inflammation by reducing intracerebral acetylcholine production

Oka, Naoki; Shimada, Kenichi; Ishii, Azusa; Kobayashi, Nobuyuki; Kondo, Kazuhiro

doi:10.1016/j.isci.2023.106954

Cited by 8 publications

(4 citation statements)

References 68 publications

(78 reference statements)

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“…concentrations of substrates (2,5,10,25, and 50 μM for BTCI). To obtain estimates of the inhibition type, reciprocal plots of 1/V versus 1/[S] were constructed by using the reported method with minor modifications.…”

Section: Kinetic Analysis Of Hbuche Inhibitionmentioning

confidence: 99%

“…Significant reduction of ACh levels in the brain can lead to a series of typical pathological features of AD, such as cognitive impairment, significant memory decline, and brain inflammation. [ 5 ] Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are responsible for the hydrolysis and metabolism of ACh, controlling the level of ACh in the human body. Under physiological conditions, 90% of ACh hydrolysis in the human body is catalyzed by AChE.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and activity evaluation of novel multitargeted l‐tryptophan derivatives with powerful antioxidant activity against Alzheimer's disease

Zeng,

Cheng,

et al. 2024

Archiv der Pharmazie

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Alzheimer's disease (AD) is a multifactorial neurological disease, and the multitarget directed ligand (MTDL) strategy may be an effective approach to delay its progression. Based on this strategy, 27 derivatives of l‐tryptophan, 3a‐1–3d‐1, were designed, synthesized, and evaluated for their biological activity. Among them, IC50 (inhibitor concentration resulting in 50% inhibitory activity) values of compounds 3a‐18 and 3b‐1 were 0.58 and 0.44 μM for human serum butyrylcholinesterase (hBuChE), respectively, and both of them exhibited more than 30‐fold selectivity for human serum acetylcholinesterase. Enzyme kinetics studies showed that these two compounds were mixed inhibitors of hBuChE. In addition, these two derivatives possessed extraordinary antioxidant activity in OH radical scavenging and oxygen radical absorption capacity fluorescein assays. Meanwhile, these compounds could also prevent β‐amyloid (Aβ) self‐aggregation and possessed low toxicity on PC12 and AML12 cells. Molecular modeling studies revealed that these two compounds could interact with the choline binding site, acetyl binding site, and peripheral anionic site to exert submicromolar BuChE inhibitory activity. In the vitro blood–brain barrier permeation assay, compounds 3a‐18 and 3b‐1 showed enough blood–brain barrier permeability. In drug‐likeness prediction, compounds 3a‐18 and 3b‐1 showed good gastrointestinal absorption and a low risk of human ether‐a‐go‐go‐related gene toxicity. Therefore, compounds 3a‐18 and 3b‐1 are potential multitarget anti‐AD lead compounds, which could work as powerful antioxidants with submicromolar selective inhibitory activity for hBuChE as well as prevent Aβ self‐aggregation.

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Section: Kinetic Analysis Of Hbuche Inhibitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and activity evaluation of novel multitargeted l‐tryptophan derivatives with powerful antioxidant activity against Alzheimer's disease

Zeng,

Cheng,

et al. 2024

Archiv der Pharmazie

View full text Add to dashboard Cite

show abstract

“…S protein also causes injuries in other systems. Nasal inoculation of adenovirus vector expression S1 protein caused olfactory bulb damage and brain inflammation in mice via elevating calcium and decreasing intracerebral acetylcholine production (103). In mice with collageninduced arthritis, Lee et al showed that injection of a plasmid encoding S protein exacerbated arthritis via inducing inflammation, autoantibody, and thrombosis (104).…”

Section: Structural Protein-evoked Lung Injury S Proteinmentioning

confidence: 99%

Multifaceted role of SARS-CoV-2 structural proteins in lung injury

Zheng,

Qiu,

Qian

et al. 2024

Front. Immunol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus to cause acute respiratory distress syndrome (ARDS) and contains four structural proteins: spike, envelope, membrane, and nucleocapsid. An increasing number of studies have demonstrated that all four structural proteins of SARS-CoV-2 are capable of causing lung injury, even without the presence of intact virus. Therefore, the topic of SARS-CoV-2 structural protein-evoked lung injury warrants more attention. In the current article, we first synopsize the structural features of SARS-CoV-2 structural proteins. Second, we discuss the mechanisms for structural protein-induced inflammatory responses in vitro. Finally, we list the findings that indicate structural proteins themselves are toxic and sufficient to induce lung injury in vivo. Recognizing mechanisms of lung injury triggered by SARS-CoV-2 structural proteins may facilitate the development of targeted modalities in treating COVID-19.

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“…The precise contribution of persistent systemic or neuroinflammatory response versus viral invasion of neurons to the development of neurologic and neuropsychiatric symptoms in COVID-19 is still under investigation [ 24 , 51 ]. Emerging evidence suggests that direct neural infection plays a secondary role, while dysregulation of immune-inflammatory pathways plays a more significant role in the development of neurologic and neuropsychiatric symptoms [ 52 ].…”

Section: Mechanisms Underlying Covid-19 Effects On the Brainmentioning

confidence: 99%

Long COVID, the Brain, Nerves, and Cognitive Function

Reiss

Greene

Dayaramani

et al. 2023

Neurology International

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SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are an increasing issue in patients who have been infected with COVID-19 and may be a result of viral-associated systemic and central nervous system inflammation or may arise from a virus-induced hypercoagulable state. COVID-19 may incite changes in brain function with a wide range of lingering symptoms. Patients often experience fatigue and may note brain fog, sensorimotor symptoms, and sleep disturbances. Prolonged neurological and neuropsychiatric symptoms are prevalent and can interfere substantially in everyday life, leading to a massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection causes neurological sequelae are an important subject of ongoing research. Inflammation- induced blood-brain barrier permeability or viral neuro-invasion and direct nerve damage may be involved. Though the mechanisms are uncertain, the resulting symptoms have been documented from numerous patient reports and studies. This review examines the constellation and spectrum of nervous system symptoms seen in long COVID and incorporates information on the prevalence of these symptoms, contributing factors, and typical course. Although treatment options are generally lacking, potential therapeutic approaches for alleviating symptoms and improving quality of life are explored.

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SARS-CoV-2 S1 protein causes brain inflammation by reducing intracerebral acetylcholine production

Cited by 8 publications

References 68 publications

Design, synthesis, and activity evaluation of novel multitargeted l‐tryptophan derivatives with powerful antioxidant activity against Alzheimer's disease

Design, synthesis, and activity evaluation of novel multitargeted l‐tryptophan derivatives with powerful antioxidant activity against Alzheimer's disease

Multifaceted role of SARS-CoV-2 structural proteins in lung injury

Long COVID, the Brain, Nerves, and Cognitive Function

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