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1.
Sci Rep ; 12(1): 17145, 2022 Oct 13.
Article in English | MEDLINE | ID: covidwho-2062274

ABSTRACT

mRNA vaccines for SARS-CoV-2 have been widely used and saving millions of people in the world. How efficiently proteins are produced from exogenous mRNAs in the embryonic brain, however, is less known. Here we show that protein expression occurs highly efficiently in neural stem cells, in a very narrow time window after mRNA electroporation in the embryonic mouse brain, where plasmids have been successfully transfected. Protein expression is detected 1 h and 12 h after the electroporation of mRNAs and plasmids, respectively. The delivery of exogenous mRNAs may be useful for not only vaccines but also functional analysis in the brain.


Subject(s)
COVID-19 Vaccines , COVID-19 , Animals , Brain/metabolism , COVID-19/genetics , Electroporation , Humans , Mice , Plasmids , RNA, Messenger/genetics , RNA, Messenger/metabolism , SARS-CoV-2
2.
Eur J Neurol ; 29(12): 3676-3692, 2022 12.
Article in English | MEDLINE | ID: covidwho-2052437

ABSTRACT

BACKGROUND AND PURPOSE: In the central nervous system, a multitude of changes have been described associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, such as microglial activation, perivascular lymphocyte cuffing, hypoxic-ischaemic changes, microthrombosis, infarcts or haemorrhages. It was sought here to assess the vascular basement membranes (vBMs) and surrounding perivascular astrocytes for any morphological changes in acute respiratory syndrome (coronavirus disease 2019, COVID-19) patients. METHODS: The light microscopy morphology of the vBMs and perivascular astrocytes from brains of 14 patients with confirmed SARS-CoV-2 infection was analysed and compared to four control patients utilizing fluorescent immunohistochemistry for collagen IV and astrocytes (GFAP), endothelia (CD31), tight junction 1 (TJ1) adhesion protein, as well as the aquaporin 4 (AQP4) water channel. On 2D and 3D deconvoluted images from the cortex and white matter, vessel densities, diameters, degree of gliosis, collagen IV/GFAP and GFAP/AQP4 colocalizations were calculated, as well as the fractal dimension of astrocytes and vBMs viewed in tangential planes. RESULTS: Fractal dimension analysis of the GFAP-stained astrocytes revealed lower branching complexities and decreased GFAP/collagen IV colocalization for COVID-19 patients. Interestingly, vBMs showed significantly increased irregularities (fractal dimension values) compared to controls. Vessel diameters were increased in COVID-19 cases, especially for the white matter, TJ1 protein decreased its colocalization with the endothelia, and AQP4 reduced its co-expression in astrocytes. CONCLUSIONS: Our data on the irregularity of the basement membranes, loss of endothelial tight junction, reduction of the astrocyte end-feet and decrease of AQP4 suggest subtle morphological changes of the blood-brain barrier in COVID-19 brains that could be linked with indirect inflammatory signalling or hypoxia/hypercapnia.


Subject(s)
Astrocytes , COVID-19 , Humans , SARS-CoV-2 , Aquaporin 4 , Brain/metabolism , Collagen/metabolism , Glial Fibrillary Acidic Protein
3.
Int J Mol Sci ; 23(17)2022 Aug 25.
Article in English | MEDLINE | ID: covidwho-2023745

ABSTRACT

Discovery of the microbiota-gut-brain axis has led to proposed microbe-based therapeutic strategies in mental health, including the use of mood-altering bacterial species, termed psychobiotics. However, we still have limited understanding of the key signaling pathways engaged by specific organisms in modulating brain function, and evidence suggests that bacteria with broadly similar neuroactive and immunomodulatory actions can drive different behavioral outcomes. We sought to identify pathways distinguishing two psychoactive bacterial strains that seemingly engage similar gut-brain signaling pathways but have distinct effects on behaviour. We used RNAseq to identify mRNAs differentially expressed in the blood and hippocampus of mice following Lacticaseibacillus rhamnosus JB-1, and Limosilactobacillus reuteri 6475 treatment and performed Gene Set Enrichment Analysis (GSEA) to identify enrichment in pathway activity. L. rhamnosus, but not L. reuteri treatment altered several pathways in the blood and hippocampus, and the rhamnosus could be clearly distinguished based on mRNA profile. In particular, L. rhamnosus treatment modulated the activity of interferon signaling, JAK/STAT, and TNF-alpha via NF-KB pathways. Our results highlight that psychobiotics can induce complex changes in host gene expression, andin understanding these changes, we may help fine-tune selection of psychobiotics for treating mood disorders.


Subject(s)
Lactobacillus rhamnosus , Probiotics , Affect , Animals , Brain/metabolism , Hippocampus , Male , Mice , Probiotics/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism
4.
Int J Environ Res Public Health ; 19(17)2022 Sep 03.
Article in English | MEDLINE | ID: covidwho-2010044

ABSTRACT

Psychobiotics are defined as probiotics, mainly of the genus Lactobacillus and Bifidobacterium, that confer mental health benefits to the host when consumed in a particular quantity through the interaction with commensal gut microbiota. The gut microbiota, which means a diverse and dynamic population of microorganisms harboring the gastrointestinal tract, communicates with the brain and vice versa through the brain-gut axis. The mechanisms of action of psychobiotics may be divided into four groups: synthesis of neurotransmitters and neurochemicals, regulation of the HPA axis, influence on the immune system, and synthesis of metabolites. Recent years showed that the COVID-19 pandemic affected not only physical, but also mental health. Social isolation, fear of infection, the lack of adequate vaccine, disinformation, increased number of deaths, financial loss, quarantine, and lockdown are all factors can cause psychiatric problems. The aim of this review was to discuss the potential role of psychobiotic in light of the current problems, based on in vitro and in vivo studies, meta-analyses, clinical trials evidence, and registered studies assessing probiotics' therapeutic administration in the prevention or treatment of symptoms or side effects of COVID-19.


Subject(s)
COVID-19 , Probiotics , Brain/metabolism , COVID-19/epidemiology , Communicable Disease Control , Humans , Hypothalamo-Hypophyseal System , Mental Health , Pandemics , Pituitary-Adrenal System , Probiotics/pharmacology , Probiotics/therapeutic use
5.
Eur J Nucl Med Mol Imaging ; 50(1): 90-102, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1999921

ABSTRACT

PURPOSE: We evaluated brain metabolic dysfunctions and associations with neurological and biological parameters in acute, subacute and chronic COVID-19 phases to provide deeper insights into the pathophysiology of the disease. METHODS: Twenty-six patients with neurological symptoms (neuro-COVID-19) and [18F]FDG-PET were included. Seven patients were acute (< 1 month (m) after onset), 12 subacute (4 ≥ 1-m, 4 ≥ 2-m and 4 ≥ 3-m) and 7 with neuro-post-COVID-19 (3 ≥ 5-m and 4 ≥ 7-9-m). One patient was evaluated longitudinally (acute and 5-m). Brain hypo- and hypermetabolism were analysed at single-subject and group levels. Correlations between severity/extent of brain hypo- and hypermetabolism and biological (oxygen saturation and C-reactive protein) and clinical variables (global cognition and Body Mass Index) were assessed. RESULTS: The "fronto-insular cortex" emerged as the hypometabolic hallmark of neuro-COVID-19. Acute patients showed the most severe hypometabolism affecting several cortical regions. Three-m and 5-m patients showed a progressive reduction of hypometabolism, with limited frontal clusters. After 7-9 months, no brain hypometabolism was detected. The patient evaluated longitudinally showed a diffuse brain hypometabolism in the acute phase, almost recovered after 5 months. Brain hypometabolism correlated with cognitive dysfunction, low blood saturation and high inflammatory status. Hypermetabolism in the brainstem, cerebellum, hippocampus and amygdala persisted over time and correlated with inflammation status. CONCLUSION: Synergistic effects of systemic virus-mediated inflammation and transient hypoxia yield a dysfunction of the fronto-insular cortex, a signature of CNS involvement in neuro-COVID-19. This brain dysfunction is likely to be transient and almost reversible. The long-lasting brain hypermetabolism seems to reflect persistent inflammation processes.


Subject(s)
COVID-19 , Positron-Emission Tomography , Humans , COVID-19/diagnostic imaging , Fluorodeoxyglucose F18/metabolism , Brain/diagnostic imaging , Brain/metabolism , Inflammation/metabolism
6.
FASEB J ; 36(9): e22494, 2022 09.
Article in English | MEDLINE | ID: covidwho-1997082

ABSTRACT

In a rat middle cerebral artery occlusion (MACo) model of ischemic stroke, intracerebroventricular administration of human recombinant hepatocyte growth factor (HGF) mitigated motor impairment and cortical infarction. Recombinant HGF reduced MCAo-induced TNFα and IL1ß expression, and alleviated perilesional reactivation of microglia and astrocyte. All of the aforementioned beneficial effects of HGF were antagonized by an inhibitor to the type II transmembrane serine protease matriptase (MTP). MCAo upregulated MTP mRNA and protein in the lesioned cortex. MTP protein, not the mRNA, was increased further by recombinant HGF but reduced when MTP inhibitor (MTPi) was added to the treatment. Changes of the endogenous active HGF by MCAo, HGF or MTPi paralleled with the changes of MTP protein under the same conditions whilst neither HGF mRNA nor the total endogenous HGF protein were altered. These data showed that the therapeutic effects of HGF in stroke brain is attributed to its proteolytic activation and that MTP is a main protease of the event. MCAo enhanced MTP mRNA and thus protein expression; the initial use of the recombinant active HGF stabilized MCAo-induced MTP protein and subsequent activation of endogenous latent HGF which in turn stabilized further MTP protein. A reciprocal regulation between MTP and HGF appears to be present where MTP promotes HGF activation and the active HGF prevents MTP protein turnover. This study, for the first time, shows that MTP can participate in neural protection in stroke brain through activation of HGF. The cycles of HGF-MTP regulation achieved preservation of the neurological activity.


Subject(s)
Hepatocyte Growth Factor , Stroke , Animals , Brain/metabolism , Hepatocyte Growth Factor/genetics , Hepatocyte Growth Factor/metabolism , Humans , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/metabolism , Neuroprotection , RNA, Messenger/metabolism , Rats , Serine Endopeptidases , Serine Proteases/metabolism , Stroke/metabolism
7.
Int J Mol Sci ; 23(15)2022 Jul 29.
Article in English | MEDLINE | ID: covidwho-1994079

ABSTRACT

We present a case report on an older woman with unspecific symptoms and predominant long-term gastrointestinal disturbances, acute overall health deterioration with loss of autonomy for daily activities, and cognitive impairment. Autopsy revealed the presence of alpha-synuclein deposits spread into intestinal mucosa lesions, enteric plexuses, pelvic and retroperitoneal nerves and ganglia, and other organs as well as Lewy pathology in the central nervous system (CNS). Moreover, we isolated norovirus from the patient, indicating active infection in the colon and detected colocalization of norovirus and alpha-synuclein in different regions of the patient's brain. In view of this, we report a concomitant norovirus infection with synthesis of alpha-synuclein in the gastrointestinal mucosa and Lewy pathology in the CNS, which might support Braak's hypothesis about the pathogenic mechanisms underlying synucleinopathies.


Subject(s)
Caliciviridae Infections , Cognitive Dysfunction , Lewy Body Disease , Norovirus , Aged , Brain/metabolism , Caliciviridae Infections/complications , Caliciviridae Infections/pathology , Cognitive Dysfunction/pathology , Female , Humans , Lewy Body Disease/pathology , Norovirus/metabolism , alpha-Synuclein/metabolism
9.
Biochem Biophys Res Commun ; 626: 66-71, 2022 10 20.
Article in English | MEDLINE | ID: covidwho-1966379

ABSTRACT

Increasing evidence suggests incomplete recovery of COVID-19 patients, who continue to suffer from cardiovascular diseases, including cerebral vascular disorders (CVD) and neurological symptoms. Recent findings indicate that some of the damaging effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, especially in the brain, may be induced by the spike protein, leading to the disruption of the initial blood-brain barrier (BBB). SARS-CoV-2-infected cells and animals exhibit age-dependent pathogenesis. In this study, we identified endothelial BACE1 as a critical mediator of BBB disruption and cellular senescence induced by the SARS-CoV-2 spike S1 subunit protein. Increased BACE1 in human brain microvascular endothelial cells (HBMVEC) decreases the levels of tight junction proteins, including ZO-1, occludin, and claudins. Moreover, BACE1 overexpression leads to the accumulation of p16 and p21, typical hallmarks of cellular senescence. Our findings show that the SARS-CoV-2 spike S1 subunit protein upregulated BACE1 expression in HBMVECs, causing endothelial leakage. In addition, the SARS-CoV-2 spike S1 subunit protein induced p16 and p21 expression, indicating BACE1-mediated cellular senescence, confirmed by ß-Gal staining in HBMVECs. In conclusion, this study demonstrated that BACE1-mediated endothelial cell damage and senescence may be linked to CVD after COVID-19 infection.


Subject(s)
COVID-19 , Cardiovascular Diseases , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Brain/metabolism , Cardiovascular Diseases/metabolism , Endothelial Cells/metabolism , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
10.
J Proteome Res ; 21(9): 2137-2145, 2022 09 02.
Article in English | MEDLINE | ID: covidwho-1960230

ABSTRACT

SARS-coronavirus 2 (SARS-CoV-2) that caused the coronavirus disease 2019 (COVID-19) pandemic has posed to be a global challenge. An increasing number of neurological symptoms have been linked to the COVID-19 disease, but the underlying mechanisms of such symptoms and which patients could be at risk are not yet established. The suggested key receptor for host cell entry is angiotensin I converting enzyme 2 (ACE2). Previous studies on limited tissue material have shown no or low protein expression of ACE2 in the normal brain. Here, we used stringently validated antibodies and immunohistochemistry to examine the protein expression of ACE2 in all major regions of the normal brain. The expression pattern was compared with the COVID-19-affected brain of patients with a varying degree of neurological symptoms. In the normal brain, the expression was restricted to the choroid plexus and ependymal cells with no expression in any other brain cell types. Interestingly, in the COVID-19-affected brain, an upregulation of ACE2 was observed in endothelial cells of certain patients, most prominently in the white matter and with the highest expression observed in the patient with the most severe neurological symptoms. The data shows differential expression of ACE2 in the diseased brain and highlights the need to further study the role of endothelial cells in COVID-19 disease in relation to neurological symptoms.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Angiotensin-Converting Enzyme 2/genetics , Brain/metabolism , Endothelial Cells/metabolism , Humans , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2
11.
Ageing Res Rev ; 80: 101687, 2022 09.
Article in English | MEDLINE | ID: covidwho-1936063

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to impact our lives by causing widespread illness and death and poses a threat due to the possibility of emerging strains. SARS-CoV-2 targets angiotensin-converting enzyme 2 (ACE2) before entering vital organs of the body, including the brain. Studies have shown systemic inflammation, cellular senescence, and viral toxicity-mediated multi-organ failure occur during infectious periods. However, prognostic investigations suggest that both acute and long-term neurological complications, including predisposition to irreversible neurodegenerative diseases, can be a serious concern for COVID-19 survivors, especially the elderly population. As emerging studies reveal sites of SARS-CoV-2 infection in different parts of the brain, potential causes of chronic lesions including cerebral and deep-brain microbleeds and the likelihood of developing stroke-like pathologies increases, with critical long-term consequences, particularly for individuals with neuropathological and/or age-associated comorbid conditions. Our recent studies linking the blood degradation products to genome instability, leading to cellular senescence and ferroptosis, raise the possibility of similar neurovascular events as a result of SARS-CoV-2 infection. In this review, we discuss the neuropathological consequences of SARS-CoV-2 infection in COVID survivors, focusing on possible hemorrhagic damage in brain cells, its association to aging, and the future directions in developing mechanism-guided therapeutic strategies.


Subject(s)
COVID-19 , Nervous System Diseases , Aged , Brain/metabolism , COVID-19/complications , Hemorrhage , Humans , Nervous System Diseases/pathology , SARS-CoV-2
12.
CNS Drugs ; 36(7): 739-770, 2022 07.
Article in English | MEDLINE | ID: covidwho-1930607

ABSTRACT

While the intranasal administration of drugs to the brain has been gaining both research attention and regulatory success over the past several years, key fundamental and translational challenges remain to fully leveraging the promise of this drug delivery pathway for improving the treatment of various neurological and psychiatric illnesses. In response, this review highlights the current state of understanding of the nose-to-brain drug delivery pathway and how both biological and clinical barriers to drug transport using the pathway can been addressed, as illustrated by demonstrations of how currently approved intranasal sprays leverage these pathways to enable the design of successful therapies. Moving forward, aiming to better exploit the understanding of this fundamental pathway, we also outline the development of nanoparticle systems that show improvement in delivering approved drugs to the brain and how engineered nanoparticle formulations could aid in breakthroughs in terms of delivering emerging drugs and therapeutics while avoiding systemic adverse effects.


Subject(s)
Mental Disorders , Administration, Intranasal , Brain/metabolism , Drug Delivery Systems , Humans , Mental Disorders/drug therapy , Mental Disorders/metabolism , Nose , Pharmaceutical Preparations/metabolism
13.
Biomolecules ; 12(7)2022 07 11.
Article in English | MEDLINE | ID: covidwho-1928474

ABSTRACT

The number of deaths has been increased due to COVID-19 infections and uncertain neurological complications associated with the central nervous system. Post-infections and neurological manifestations in neuronal tissues caused by COVID-19 are still unknown and there is a need to explore how brainstorming promoted congenital impairment, dementia, and Alzheimer's disease. SARS-CoV-2 neuro-invasion studies in vivo are still rare, despite the fact that other beta-coronaviruses have shown similar properties. Neural (olfactory or vagal) and hematogenous (crossing the blood-brain barrier) pathways have been hypothesized in light of new evidence showing the existence of SARS-CoV-2 host cell entry receptors into the specific components of human nerve and vascular tissue. Spike proteins are the primary key and structural component of the COVID-19 that promotes the infection into brain cells. Neurological manifestations and serious neurodegeneration occur through the binding of spike proteins to ACE2 receptor. The emerging evidence reported that, due to the high rate in the immediate wake of viral infection, the olfactory bulb, thalamus, and brain stem are intensely infected through a trans-synaptic transfer of the virus. It also instructs the release of chemokines, cytokines, and inflammatory signals immensely to the blood-brain barrier and infects the astrocytes, which causes neuroinflammation and neuron death; and this induction of excessive inflammation and immune response developed in more neurodegeneration complications. The present review revealed the pathophysiological effects, molecular, and cellular mechanisms of possible entry routes into the brain, pathogenicity of autoantibodies and emerging immunotherapies against COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Blood-Brain Barrier/metabolism , Brain/metabolism , Humans , Spike Glycoprotein, Coronavirus/chemistry
14.
Cell Mol Life Sci ; 79(7): 361, 2022 Jun 13.
Article in English | MEDLINE | ID: covidwho-1888837

ABSTRACT

COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.


Subject(s)
COVID-19 , Melatonin , Angiotensin-Converting Enzyme 2 , Animals , Brain/metabolism , COVID-19/drug therapy , Endothelial Cells/metabolism , Melatonin/pharmacology , Melatonin/therapeutic use , Mice , Mice, Transgenic , Peptidyl-Dipeptidase A , SARS-CoV-2
15.
Int J Mol Sci ; 23(11)2022 May 24.
Article in English | MEDLINE | ID: covidwho-1884204

ABSTRACT

Alzheimer's disease (AD) is a complex chronic disease of the brain characterized by several neurodegenerative mechanisms and is responsible for most dementia cases in the elderly. Declining immunity during ageing is often associated with peripheral chronic inflammation, and chronic neuroinflammation is a constant component of AD brain pathology. In the Special Issue published in 2021 eight papers were collected regarding different aspects of neurodegeneration associated with AD. Five papers presented and discussed infectious agents involved in brain AD pathology and three discussed data regarding receptors regulation and possible treatment of the disease. Below I will discuss and further elaborate on topics related to infections, inflammation, and neurodegenerative pathways in AD and brain senescence. The topic presented here may contribute to early intervention protocols for preventing or slowing the progression of cognitive deterioration in the elderly.


Subject(s)
Alzheimer Disease , Cognition Disorders , Aged , Alzheimer Disease/metabolism , Brain/metabolism , Humans , Inflammation/complications , Neurons/metabolism
16.
Reprod Toxicol ; 111: 34-48, 2022 08.
Article in English | MEDLINE | ID: covidwho-1819592

ABSTRACT

The possible neurodevelopmental consequences of SARS-CoV-2 infection are presently unknown. In utero exposure to SARS-CoV-2 has been hypothesized to affect the developing brain, possibly disrupting neurodevelopment of children. Spike protein interactors, such as ACE2, have been found expressed in the fetal brain, and could play a role in potential SARS-CoV-2 fetal brain pathogenesis. Apart from the possible direct involvement of SARS-CoV-2 or its specific viral components in the occurrence of neurological and neurodevelopmental manifestations, we recently reported the presence of toxin-like peptides in plasma, urine and fecal samples specifically from COVID-19 patients. In this study, we investigated the possible neurotoxic effects elicited upon 72-hour exposure to human relevant levels of recombinant spike protein, toxin-like peptides found in COVID-19 patients, as well as a combination of both in 3D human iPSC-derived neural stem cells differentiated for either 2 weeks (short-term) or 8 weeks (long-term, 2 weeks in suspension + 6 weeks on MEA) towards neurons/glia. Whole transcriptome and qPCR analysis revealed that spike protein and toxin-like peptides at non-cytotoxic concentrations differentially perturb the expression of SPHK1, ELN, GASK1B, HEY1, UTS2, ACE2 and some neuronal-, glia- and NSC-related genes critical during brain development. Additionally, exposure to spike protein caused a decrease of spontaneous electrical activity after two days in long-term differentiated cultures. The perturbations of these neurodevelopmental endpoints are discussed in the context of recent knowledge about the key events described in Adverse Outcome Pathways relevant to COVID-19, gathered in the context of the CIAO project (https://www.ciao-covid.net/).


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Brain/metabolism , Child , Humans , Neuroglia , Neurons/metabolism , Peptides , Spike Glycoprotein, Coronavirus/metabolism
17.
Aging Cell ; 21(4): e13575, 2022 04.
Article in English | MEDLINE | ID: covidwho-1788808

ABSTRACT

Dopamine (DA) signaling via G protein-coupled receptors is a multifunctional neurotransmitter and neuroendocrine-immune modulator. The DA nigrostriatal pathway, which controls the motor coordination, progressively degenerates in Parkinson's disease (PD), a most common neurodegenerative disorder (ND) characterized by a selective, age-dependent loss of substantia nigra pars compacta (SNpc) neurons, where DA itself is a primary source of oxidative stress and mitochondrial impairment, intersecting astrocyte and microglial inflammatory networks. Importantly, glia acts as a preferential neuroendocrine-immune DA target, in turn, counter-modulating inflammatory processes. With a major focus on DA intersection within the astrocyte-microglial inflammatory network in PD vulnerability, we herein first summarize the characteristics of DA signaling systems, the propensity of DA neurons to oxidative stress, and glial inflammatory triggers dictating the vulnerability to PD. Reciprocally, DA modulation of astrocytes and microglial reactivity, coupled to the synergic impact of gene-environment interactions, then constitute a further level of control regulating midbrain DA neuron (mDAn) survival/death. Not surprisingly, within this circuitry, DA converges to modulate nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/ß-catenin signaling, a key pathway for mDAn neurogenesis, neuroprotection, and immunomodulation, adding to the already complex "signaling puzzle," a novel actor in mDAn-glial regulatory machinery. Here, we propose an autoregulatory feedback system allowing DA to act as an endogenous Nrf2/Wnt innate modulator and trace the importance of DA receptor agonists applied to the clinic as immune modifiers.


Subject(s)
Dopamine , Parkinson Disease , Aged , Brain/metabolism , Dopamine/metabolism , Dopaminergic Neurons/metabolism , GA-Binding Protein Transcription Factor , Humans , NF-E2-Related Factor 2/metabolism , Neuroglia/metabolism , Parkinson Disease/metabolism
18.
Eur J Nucl Med Mol Imaging ; 49(9): 3197-3202, 2022 07.
Article in English | MEDLINE | ID: covidwho-1756789

ABSTRACT

BACKGROUND: This multicentre study aimed to provide a qualitative and consensual description of brain hypometabolism observed through the visual analysis of 18F-FDG PET images of patients with suspected neurological long COVID, regarding the previously reported long-COVID hypometabolic pattern involving hypometabolism in the olfactory bulbs and other limbic/paralimbic regions, as well as in the brainstem and cerebellum. METHODS: From the beginning of August 2021 to the end of October 2021, the brain 18F-FDG PET scans of patients referred for suspected neurological long COVID with positive reverse transcription polymerase chain reaction (RT-PCR) and/or serology tests for SARS-CoV-2 infection were retrospectively reviewed in three French nuclear medicine departments (143 patients; 47.4 years old ± 13.6; 98 women). Experienced nuclear physicians from each department classified brain 18F-FDG PET scans according to the same visual interpretation analysis as being normal, mildly to moderately (or incompletely) affected, or otherwise severely affected within the previously reported long-COVID hypometabolic pattern. RESULTS: On the 143 brain 18F-FDG PET scans performed during this 3-month period, 53% of the scans were visually interpreted as normal, 21% as mildly to moderately or incompletely affected, and 26% as severely affected according to the COVID hypometabolic pattern. On average, PET scans were performed at 10.9 months from symptom onset (± 4.8). Importantly, this specific hypometabolic pattern was similarly identified in the three nuclear medicine departments. Typical illustrative examples are provided to help nuclear physicians interpret long-COVID profiles. CONCLUSION: The proposed PET metabolic pattern is easily identified upon visual interpretation in clinical routine for approximately one half of patients with suspected neurological long COVID, requiring special consideration for frontobasal paramedian regions, the brainstem and the cerebellum, and certainly further adapted follow-up and medical care, while the second half of patients have normal brain PET metabolism on average 10.9 months from symptom onset.


Subject(s)
COVID-19 , Fluorodeoxyglucose F18 , Brain/diagnostic imaging , Brain/metabolism , COVID-19/complications , COVID-19/diagnostic imaging , Female , Fluorodeoxyglucose F18/metabolism , Humans , Middle Aged , Positron-Emission Tomography/methods , Radiopharmaceuticals/metabolism , Retrospective Studies , SARS-CoV-2
19.
Int J Mol Sci ; 23(4)2022 Feb 10.
Article in English | MEDLINE | ID: covidwho-1715394

ABSTRACT

Tuberculosis (TB) is one of the ten leading causes of death worldwide. Patients with TB have been observed to suffer from depression and anxiety linked to social variables. Previous experiments found that the substantial pulmonary inflammation associated with TB causes neuroinflammation, neuronal death, and behavioral impairments in the absence of brain infection. Curcumin (CUR) is a natural product with antioxidant, anti-inflammatory and antibacterial activities. In this work, we evaluated the CUR effect on the growth control of mycobacteria in the lungs and the anti-inflammatory effect in the brain using a model of progressive pulmonary TB in BALB/c mice infected with drug-sensitive mycobacteria (strain H37Rv). The results have shown that CUR decreased lung bacilli load and pneumonia of infected animals. Finally, CUR significantly decreased neuroinflammation (expression of TNFα, IFNγ and IL12) and slightly increased the levels of nuclear factor erythroid 2-related to factor 2 (Nrf2) and the brain-derived neurotrophic factor (BDNF) levels, improving behavioral status. These results suggest that CUR has a bactericidal effect and can control pulmonary mycobacterial infection and reduce neuroinflammation. It seems that CUR has a promising potential as adjuvant therapy in TB treatment.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antitubercular Agents/pharmacology , Brain/microbiology , Curcumin/pharmacology , Lung/microbiology , Tuberculosis, Pulmonary/drug therapy , Tuberculosis/drug therapy , Animals , Brain/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Disease Models, Animal , Inflammation/drug therapy , Inflammation/metabolism , Lung/metabolism , Male , Mice , Mice, Inbred BALB C , Mycobacterium tuberculosis/drug effects , Tuberculosis/metabolism , Tuberculosis, Pulmonary/metabolism
20.
Brain Behav Immun ; 102: 89-97, 2022 05.
Article in English | MEDLINE | ID: covidwho-1682933

ABSTRACT

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.


Subject(s)
COVID-19 , Pandemics , Biomarkers/metabolism , Brain/metabolism , Communicable Disease Control , Humans , Receptors, GABA/metabolism , SARS-CoV-2
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