Ontology type: schema:ScholarlyArticle
2021-10-18
AUTHORSRadwa N. Muhammad, Lamiaa A. Ahmed, Rania M. Abdul Salam, Kawkab A. Ahmed, Amina S. Attia
ABSTRACTDepression is an overwhelming health concern, and many patients fail to optimally respond to available standard therapies. Neuroplasticity and blood–brain barrier (BBB) integrity are the cornerstones of a well-functioning central nervous system, but they are vulnerable to an overly active NLRP3 inflammasome pathway that can also indirectly trigger the release of ET-1 and contribute to the ET system disturbance, which further damages stress resilience mechanisms. Here, the promising yet unexplored antidepressant potential of dapagliflozin (Dapa), a sodium–glucose co‐transporter‐2 inhibitor, was investigated by assessing its role in the modulation of the NLRP3 inflammasome pathway and ETBR signal transduction, and their impact on neuroplasticity and BBB integrity in an animal model of depression. Dapa (1 mg/kg/day; p.o.) with and without BQ-788 (1 mg/kg/day; i.p.), a specific ETBR blocker, were administered to adolescent male Wistar rats exposed to a 5-week chronic unpredictable stress protocol. The depressive animals demonstrated marked activation of the NLRP3 inflammasome pathway (NF-κB/NLRP3/caspase-1/IL/TNF-α), which was associated with both peripheral and central inflammatory responses. The ET system was disrupted, with noticeable reduction in miR-125a-5p and ETBR gene expression. Cortical ZO-1 expression was downregulated under the influence of NLRP3/TNF-α/miR-501-3p signaling, along with a prominent reduction in hippocampal BDNF and synapsin-1. With ETBR up-regulation being a cornerstone outcome, Dapa administration efficiently created an overall state of resilience, improved histopathological and behavioral variables, and preserved BBB function. These observations were further verified by the results obtained with BQ-788 co-administration. Thus, Dapa may exert its antidepressant action by reinforcing BBB integrity and promoting neuroplasticity through manipulation of the NLRP3/ET-1/ETBR/BDNF/ZO-1 axis, with a significant role for ETBR signaling.Graphical abstractGraphical illustration for the proposed mechanisms of the anti-depressant potential of Dapa. Dapa suppressed NLRP3 inflammasome activation and assembly with subsequent inhibition of pro-inflammatory ILs. This results in attenuation of neuro-inflammation, BBB disruption, glial cell activation, TNF-α and ET-1 release, and the enhanced production of neurotrophins. The role of ETBR signaling was emphasized; Dapa possibly augmented ETBR expression, which is thought to boost neurotrophins production. The ETBR blocker, BQ-788, suppressed most of the positive outcomes of Dapa. Finally, miR-125a-5p and miR-501-3p that played major roles in these pathological pathways were modulated by Dapa. It is not yet clear whether Dapa has a direct or rather indirect effect on their expression. BBB, blood–brain barrier; Dapa, dapagliflozin; ET-1, endothelin-1; ETBR, endothelin B receptor; IL, interleukin; NF-κB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; TNF-α, tumor necrosis factor-α. Created with BioRender.com. More... »
PAGES2664-2681
http://scigraph.springernature.com/pub.10.1007/s13311-021-01140-4
DOIhttp://dx.doi.org/10.1007/s13311-021-01140-4
DIMENSIONShttps://app.dimensions.ai/details/publication/pub.1141985432
PUBMEDhttps://www.ncbi.nlm.nih.gov/pubmed/34664178
JSON-LD is the canonical representation for SciGraph data.
TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT
[
{
"@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json",
"about": [
{
"id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11",
"inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/",
"name": "Medical and Health Sciences",
"type": "DefinedTerm"
},
{
"id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1109",
"inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/",
"name": "Neurosciences",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "Animals",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "Depression",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "Inflammasomes",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "Male",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "MicroRNAs",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "NF-kappa B",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "NLR Family, Pyrin Domain-Containing 3 Protein",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "Rats",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "Rats, Wistar",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "Signal Transduction",
"type": "DefinedTerm"
},
{
"inDefinedTermSet": "https://www.nlm.nih.gov/mesh/",
"name": "Sodium-Glucose Transporter 2 Inhibitors",
"type": "DefinedTerm"
}
],
"author": [
{
"affiliation": {
"alternateName": "Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt",
"id": "http://www.grid.ac/institutes/grid.7776.1",
"name": [
"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt"
],
"type": "Organization"
},
"familyName": "Muhammad",
"givenName": "Radwa N.",
"id": "sg:person.010061330607.14",
"sameAs": [
"https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010061330607.14"
],
"type": "Person"
},
{
"affiliation": {
"alternateName": "Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt",
"id": "http://www.grid.ac/institutes/grid.7776.1",
"name": [
"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt"
],
"type": "Organization"
},
"familyName": "Ahmed",
"givenName": "Lamiaa A.",
"type": "Person"
},
{
"affiliation": {
"alternateName": "Department of Biology, School of Pharmacy, New Giza University, Giza, Egypt",
"id": "http://www.grid.ac/institutes/None",
"name": [
"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt",
"Department of Biology, School of Pharmacy, New Giza University, Giza, Egypt"
],
"type": "Organization"
},
"familyName": "Abdul Salam",
"givenName": "Rania M.",
"type": "Person"
},
{
"affiliation": {
"alternateName": "Pathology Department, Faculty of Veterinary Medicine, Cairo University, 12211, Giza, Egypt",
"id": "http://www.grid.ac/institutes/grid.7776.1",
"name": [
"Pathology Department, Faculty of Veterinary Medicine, Cairo University, 12211, Giza, Egypt"
],
"type": "Organization"
},
"familyName": "Ahmed",
"givenName": "Kawkab A.",
"id": "sg:person.01350034322.36",
"sameAs": [
"https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01350034322.36"
],
"type": "Person"
},
{
"affiliation": {
"alternateName": "Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt",
"id": "http://www.grid.ac/institutes/grid.7776.1",
"name": [
"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt"
],
"type": "Organization"
},
"familyName": "Attia",
"givenName": "Amina S.",
"id": "sg:person.0666621004.84",
"sameAs": [
"https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0666621004.84"
],
"type": "Person"
}
],
"citation": [
{
"id": "sg:pub.10.1038/s41598-017-08055-1",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1091033730",
"https://doi.org/10.1038/s41598-017-08055-1"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1038/s41598-019-53624-1",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1122789257",
"https://doi.org/10.1038/s41598-019-53624-1"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1038/nprot.2012.044",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1020413118",
"https://doi.org/10.1038/nprot.2012.044"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1007/s00702-019-02084-y",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1121501280",
"https://doi.org/10.1007/s00702-019-02084-y"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1186/s12933-014-0148-1",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1022419393",
"https://doi.org/10.1186/s12933-014-0148-1"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1007/s10557-017-6725-2",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1085063373",
"https://doi.org/10.1007/s10557-017-6725-2"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1038/sj.npp.1301410",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1046232699",
"https://doi.org/10.1038/sj.npp.1301410"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1007/s00005-014-0310-1",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1025399559",
"https://doi.org/10.1007/s00005-014-0310-1"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1007/s11033-019-05129-3",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1121795414",
"https://doi.org/10.1007/s11033-019-05129-3"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1007/s00441-013-1581-2",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1028763041",
"https://doi.org/10.1007/s00441-013-1581-2"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1038/s41398-020-0808-8",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1127347512",
"https://doi.org/10.1038/s41398-020-0808-8"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1038/s41596-018-0011-z",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1105426012",
"https://doi.org/10.1038/s41596-018-0011-z"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1007/s13300-020-00885-z",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1129665002",
"https://doi.org/10.1007/s13300-020-00885-z"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1007/s00005-019-00543-8",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1113796674",
"https://doi.org/10.1007/s00005-019-00543-8"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1038/s41598-017-02583-6",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1085537757",
"https://doi.org/10.1038/s41598-017-02583-6"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1007/s12031-020-01597-6",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1128097367",
"https://doi.org/10.1007/s12031-020-01597-6"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1186/s13046-019-1180-5",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1115975999",
"https://doi.org/10.1186/s13046-019-1180-5"
],
"type": "CreativeWork"
},
{
"id": "sg:pub.10.1186/s12974-017-0865-y",
"sameAs": [
"https://app.dimensions.ai/details/publication/pub.1085376760",
"https://doi.org/10.1186/s12974-017-0865-y"
],
"type": "CreativeWork"
}
],
"datePublished": "2021-10-18",
"datePublishedReg": "2021-10-18",
"description": "Depression is an overwhelming health concern, and many patients fail to optimally respond to available standard therapies. Neuroplasticity and blood\u2013brain barrier (BBB) integrity are the cornerstones of a well-functioning central nervous system, but they are vulnerable to an overly active NLRP3 inflammasome pathway that can also indirectly trigger the release of ET-1 and contribute to the ET system disturbance, which further damages stress resilience mechanisms. Here, the promising yet unexplored antidepressant potential of dapagliflozin (Dapa), a sodium\u2013glucose co\u2010transporter\u20102 inhibitor, was investigated by assessing its role in the modulation of the NLRP3 inflammasome pathway and ETBR signal transduction, and their impact on neuroplasticity and BBB integrity in an animal model of depression. Dapa (1\u00a0mg/kg/day; p.o.) with and without BQ-788 (1\u00a0mg/kg/day; i.p.), a specific ETBR blocker, were administered to adolescent male Wistar rats exposed to a 5-week chronic unpredictable stress protocol. The depressive animals demonstrated marked activation of the NLRP3 inflammasome pathway (NF-\u03baB/NLRP3/caspase-1/IL/TNF-\u03b1), which was associated with both peripheral and central inflammatory responses. The ET system was disrupted, with noticeable reduction in miR-125a-5p and ETBR gene expression. Cortical ZO-1 expression was downregulated under the influence of NLRP3/TNF-\u03b1/miR-501-3p signaling, along with a prominent reduction in hippocampal BDNF and synapsin-1. With ETBR up-regulation being a cornerstone outcome, Dapa administration efficiently created an overall state of resilience, improved histopathological and behavioral variables, and preserved BBB function. These observations were further verified by the results obtained with BQ-788 co-administration. Thus, Dapa may exert its antidepressant action by reinforcing BBB integrity and promoting neuroplasticity through manipulation of the NLRP3/ET-1/ETBR/BDNF/ZO-1 axis, with a significant role for ETBR signaling.Graphical abstractGraphical illustration for the proposed mechanisms of the anti-depressant potential of Dapa. Dapa suppressed NLRP3 inflammasome activation and assembly with subsequent inhibition of pro-inflammatory ILs. This results in attenuation of neuro-inflammation, BBB disruption, glial cell activation, TNF-\u03b1 and ET-1 release, and the enhanced production of neurotrophins. The role of ETBR signaling was emphasized; Dapa possibly augmented ETBR expression, which is thought to boost neurotrophins production. The ETBR blocker, BQ-788, suppressed most of the positive outcomes of Dapa. Finally, miR-125a-5p and miR-501-3p that played major roles in these pathological pathways were modulated by Dapa. It is not yet clear whether Dapa has a direct or rather indirect effect on their expression. BBB, blood\u2013brain barrier; Dapa, dapagliflozin; ET-1, endothelin-1; ETBR, endothelin B receptor; IL, interleukin; NF-\u03baB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; TNF-\u03b1, tumor necrosis factor-\u03b1.\u00a0Created with BioRender.com.",
"genre": "article",
"id": "sg:pub.10.1007/s13311-021-01140-4",
"inLanguage": "en",
"isAccessibleForFree": false,
"isPartOf": [
{
"id": "sg:journal.1294839",
"issn": [
"1933-7213",
"1878-7479"
],
"name": "Neurotherapeutics",
"publisher": "Springer Nature",
"type": "Periodical"
},
{
"issueNumber": "4",
"type": "PublicationIssue"
},
{
"type": "PublicationVolume",
"volumeNumber": "18"
}
],
"keywords": [
"NLRP3 inflammasome pathway",
"BQ-788",
"leucine-rich repeats",
"BBB integrity",
"inflammasome pathway",
"ET-1",
"sodium-glucose co-transporter-2 inhibitors",
"blood-brain barrier integrity",
"pyrin domain-containing protein 3",
"signal transduction",
"adolescent male Wistar rats",
"chronic unpredictable stress protocol",
"domain-containing protein 3",
"pro-inflammatory IL",
"glial cell activation",
"nuclear factor kappa B",
"central inflammatory response",
"ET-1 release",
"gene expression",
"depression-like behavior",
"blood-brain barrier",
"available standard therapies",
"male Wistar rats",
"NLRP3 inflammasome activation",
"tumor necrosis factor",
"endothelin B receptor",
"central nervous system",
"oligomerization domain",
"factor kappa B",
"anti-depressant potential",
"ZO-1 expression",
"DAPA administration",
"active NLRP3",
"ETBR expression",
"BBB disruption",
"standard therapy",
"hippocampal BDNF",
"antidepressant action",
"neurotrophin production",
"BBB function",
"neuro-inflammation",
"SGLT2 inhibitors",
"antidepressant potential",
"endothelin-1",
"inflammatory response",
"necrosis factor",
"Wistar rats",
"protein 3",
"inflammasome activation",
"pathway",
"synapsin 1",
"NF-\u03baB",
"animal models",
"nervous system",
"kappa B",
"barrier integrity",
"cell activation",
"modulatory role",
"signaling",
"pathological pathways",
"B receptor",
"expression",
"stress protocol",
"marked activation",
"health concern",
"NLRP3",
"TNF",
"subsequent inhibition",
"neuroplasticity",
"prominent reduction",
"activation",
"dapagliflozin",
"enhanced production",
"ET system",
"blockers",
"EtBr",
"depression",
"major role",
"inhibitors",
"transduction",
"outcomes",
"further damage",
"resilience mechanisms",
"miRNAs",
"repeats",
"role",
"IL",
"behavioral variables",
"positive outcomes",
"indirect effects",
"integrity",
"DAPA",
"regulation",
"mechanism",
"miR",
"BDNF",
"patients",
"ZO",
"interleukin",
"neurotrophins",
"therapy",
"production",
"BBB",
"rats",
"assembly",
"administration",
"release",
"receptors",
"significant role",
"disruption",
"inhibition",
"domain",
"animals",
"reduction",
"stress",
"damage",
"cornerstone",
"potential",
"manipulation",
"response",
"modulation",
"function",
"overall state",
"factors",
"protocol",
"action",
"effect",
"disturbances",
"barriers",
"attenuation",
"resilience",
"noticeable reduction",
"axis",
"concern",
"promising",
"system disturbances",
"variables",
"impact",
"system",
"observations",
"results",
"et",
"illustration",
"influence",
"model",
"state",
"behavior"
],
"name": "Crosstalk Among NLRP3 Inflammasome, ETBR Signaling, and miRNAs in Stress-Induced Depression-Like Behavior: a Modulatory Role for SGLT2 Inhibitors",
"pagination": "2664-2681",
"productId": [
{
"name": "dimensions_id",
"type": "PropertyValue",
"value": [
"pub.1141985432"
]
},
{
"name": "doi",
"type": "PropertyValue",
"value": [
"10.1007/s13311-021-01140-4"
]
},
{
"name": "pubmed_id",
"type": "PropertyValue",
"value": [
"34664178"
]
}
],
"sameAs": [
"https://doi.org/10.1007/s13311-021-01140-4",
"https://app.dimensions.ai/details/publication/pub.1141985432"
],
"sdDataset": "articles",
"sdDatePublished": "2022-05-20T07:39",
"sdLicense": "https://scigraph.springernature.com/explorer/license/",
"sdPublisher": {
"name": "Springer Nature - SN SciGraph project",
"type": "Organization"
},
"sdSource": "s3://com-springernature-scigraph/baseset/20220519/entities/gbq_results/article/article_909.jsonl",
"type": "ScholarlyArticle",
"url": "https://doi.org/10.1007/s13311-021-01140-4"
}
]
Download the RDF metadata as: json-ld nt turtle xml License info
JSON-LD is a popular format for linked data which is fully compatible with JSON.
curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1007/s13311-021-01140-4'
N-Triples is a line-based linked data format ideal for batch operations.
curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1007/s13311-021-01140-4'
Turtle is a human-readable linked data format.
curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1007/s13311-021-01140-4'
RDF/XML is a standard XML format for linked data.
curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1007/s13311-021-01140-4'
This table displays all metadata directly associated to this object as RDF triples.
357 TRIPLES
22 PREDICATES
202 URIs
176 LITERALS
18 BLANK NODES
Subject | Predicate | Object | |
---|---|---|---|
1 | sg:pub.10.1007/s13311-021-01140-4 | schema:about | N05be2426e0dc49b2a938640beeb1aa76 |
2 | ″ | ″ | N272f6ef94270488c8e5f6578a7c0d11b |
3 | ″ | ″ | N48af6f15654047fdac4d5be879cc49ba |
4 | ″ | ″ | N5c1da7e894fa489f806e0df41ebdc6f8 |
5 | ″ | ″ | N721bba2a069a48648019cedadf307caa |
6 | ″ | ″ | N731bfe242c914aed9f21de0d11754347 |
7 | ″ | ″ | Nac660a9dcfef4582b93c40b84d2a5d54 |
8 | ″ | ″ | Nb79ba5ea56f8456babd88613415de399 |
9 | ″ | ″ | Nd5205e3227e74c48abd1acc1ee69c045 |
10 | ″ | ″ | Nf77737a7dc364eef9cbb6fbbb777e50c |
11 | ″ | ″ | Nfd9bc18db7cc469e854eb774762f172d |
12 | ″ | ″ | anzsrc-for:11 |
13 | ″ | ″ | anzsrc-for:1109 |
14 | ″ | schema:author | Na7209c7dedb0483d96d9f4e95357243e |
15 | ″ | schema:citation | sg:pub.10.1007/s00005-014-0310-1 |
16 | ″ | ″ | sg:pub.10.1007/s00005-019-00543-8 |
17 | ″ | ″ | sg:pub.10.1007/s00441-013-1581-2 |
18 | ″ | ″ | sg:pub.10.1007/s00702-019-02084-y |
19 | ″ | ″ | sg:pub.10.1007/s10557-017-6725-2 |
20 | ″ | ″ | sg:pub.10.1007/s11033-019-05129-3 |
21 | ″ | ″ | sg:pub.10.1007/s12031-020-01597-6 |
22 | ″ | ″ | sg:pub.10.1007/s13300-020-00885-z |
23 | ″ | ″ | sg:pub.10.1038/nprot.2012.044 |
24 | ″ | ″ | sg:pub.10.1038/s41398-020-0808-8 |
25 | ″ | ″ | sg:pub.10.1038/s41596-018-0011-z |
26 | ″ | ″ | sg:pub.10.1038/s41598-017-02583-6 |
27 | ″ | ″ | sg:pub.10.1038/s41598-017-08055-1 |
28 | ″ | ″ | sg:pub.10.1038/s41598-019-53624-1 |
29 | ″ | ″ | sg:pub.10.1038/sj.npp.1301410 |
30 | ″ | ″ | sg:pub.10.1186/s12933-014-0148-1 |
31 | ″ | ″ | sg:pub.10.1186/s12974-017-0865-y |
32 | ″ | ″ | sg:pub.10.1186/s13046-019-1180-5 |
33 | ″ | schema:datePublished | 2021-10-18 |
34 | ″ | schema:datePublishedReg | 2021-10-18 |
35 | ″ | schema:description | Depression is an overwhelming health concern, and many patients fail to optimally respond to available standard therapies. Neuroplasticity and blood–brain barrier (BBB) integrity are the cornerstones of a well-functioning central nervous system, but they are vulnerable to an overly active NLRP3 inflammasome pathway that can also indirectly trigger the release of ET-1 and contribute to the ET system disturbance, which further damages stress resilience mechanisms. Here, the promising yet unexplored antidepressant potential of dapagliflozin (Dapa), a sodium–glucose co‐transporter‐2 inhibitor, was investigated by assessing its role in the modulation of the NLRP3 inflammasome pathway and ETBR signal transduction, and their impact on neuroplasticity and BBB integrity in an animal model of depression. Dapa (1 mg/kg/day; p.o.) with and without BQ-788 (1 mg/kg/day; i.p.), a specific ETBR blocker, were administered to adolescent male Wistar rats exposed to a 5-week chronic unpredictable stress protocol. The depressive animals demonstrated marked activation of the NLRP3 inflammasome pathway (NF-κB/NLRP3/caspase-1/IL/TNF-α), which was associated with both peripheral and central inflammatory responses. The ET system was disrupted, with noticeable reduction in miR-125a-5p and ETBR gene expression. Cortical ZO-1 expression was downregulated under the influence of NLRP3/TNF-α/miR-501-3p signaling, along with a prominent reduction in hippocampal BDNF and synapsin-1. With ETBR up-regulation being a cornerstone outcome, Dapa administration efficiently created an overall state of resilience, improved histopathological and behavioral variables, and preserved BBB function. These observations were further verified by the results obtained with BQ-788 co-administration. Thus, Dapa may exert its antidepressant action by reinforcing BBB integrity and promoting neuroplasticity through manipulation of the NLRP3/ET-1/ETBR/BDNF/ZO-1 axis, with a significant role for ETBR signaling.Graphical abstractGraphical illustration for the proposed mechanisms of the anti-depressant potential of Dapa. Dapa suppressed NLRP3 inflammasome activation and assembly with subsequent inhibition of pro-inflammatory ILs. This results in attenuation of neuro-inflammation, BBB disruption, glial cell activation, TNF-α and ET-1 release, and the enhanced production of neurotrophins. The role of ETBR signaling was emphasized; Dapa possibly augmented ETBR expression, which is thought to boost neurotrophins production. The ETBR blocker, BQ-788, suppressed most of the positive outcomes of Dapa. Finally, miR-125a-5p and miR-501-3p that played major roles in these pathological pathways were modulated by Dapa. It is not yet clear whether Dapa has a direct or rather indirect effect on their expression. BBB, blood–brain barrier; Dapa, dapagliflozin; ET-1, endothelin-1; ETBR, endothelin B receptor; IL, interleukin; NF-κB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; TNF-α, tumor necrosis factor-α. Created with BioRender.com. |
36 | ″ | schema:genre | article |
37 | ″ | schema:inLanguage | en |
38 | ″ | schema:isAccessibleForFree | false |
39 | ″ | schema:isPartOf | N4a41e9f99e0b4445b8e267b1440b74a0 |
40 | ″ | ″ | N5eb76ae91765412aaa74f84bf880a407 |
41 | ″ | ″ | sg:journal.1294839 |
42 | ″ | schema:keywords | B receptor |
43 | ″ | ″ | BBB |
44 | ″ | ″ | BBB disruption |
45 | ″ | ″ | BBB function |
46 | ″ | ″ | BBB integrity |
47 | ″ | ″ | BDNF |
48 | ″ | ″ | BQ-788 |
49 | ″ | ″ | DAPA |
50 | ″ | ″ | DAPA administration |
51 | ″ | ″ | ET system |
52 | ″ | ″ | ET-1 |
53 | ″ | ″ | ET-1 release |
54 | ″ | ″ | ETBR expression |
55 | ″ | ″ | EtBr |
56 | ″ | ″ | IL |
57 | ″ | ″ | NF-κB |
58 | ″ | ″ | NLRP3 |
59 | ″ | ″ | NLRP3 inflammasome activation |
60 | ″ | ″ | NLRP3 inflammasome pathway |
61 | ″ | ″ | SGLT2 inhibitors |
62 | ″ | ″ | TNF |
63 | ″ | ″ | Wistar rats |
64 | ″ | ″ | ZO |
65 | ″ | ″ | ZO-1 expression |
66 | ″ | ″ | action |
67 | ″ | ″ | activation |
68 | ″ | ″ | active NLRP3 |
69 | ″ | ″ | administration |
70 | ″ | ″ | adolescent male Wistar rats |
71 | ″ | ″ | animal models |
72 | ″ | ″ | animals |
73 | ″ | ″ | anti-depressant potential |
74 | ″ | ″ | antidepressant action |
75 | ″ | ″ | antidepressant potential |
76 | ″ | ″ | assembly |
77 | ″ | ″ | attenuation |
78 | ″ | ″ | available standard therapies |
79 | ″ | ″ | axis |
80 | ″ | ″ | barrier integrity |
81 | ″ | ″ | barriers |
82 | ″ | ″ | behavior |
83 | ″ | ″ | behavioral variables |
84 | ″ | ″ | blockers |
85 | ″ | ″ | blood-brain barrier |
86 | ″ | ″ | blood-brain barrier integrity |
87 | ″ | ″ | cell activation |
88 | ″ | ″ | central inflammatory response |
89 | ″ | ″ | central nervous system |
90 | ″ | ″ | chronic unpredictable stress protocol |
91 | ″ | ″ | concern |
92 | ″ | ″ | cornerstone |
93 | ″ | ″ | damage |
94 | ″ | ″ | dapagliflozin |
95 | ″ | ″ | depression |
96 | ″ | ″ | depression-like behavior |
97 | ″ | ″ | disruption |
98 | ″ | ″ | disturbances |
99 | ″ | ″ | domain |
100 | ″ | ″ | domain-containing protein 3 |
101 | ″ | ″ | effect |
102 | ″ | ″ | endothelin B receptor |
103 | ″ | ″ | endothelin-1 |
104 | ″ | ″ | enhanced production |
105 | ″ | ″ | et |
106 | ″ | ″ | expression |
107 | ″ | ″ | factor kappa B |
108 | ″ | ″ | factors |
109 | ″ | ″ | function |
110 | ″ | ″ | further damage |
111 | ″ | ″ | gene expression |
112 | ″ | ″ | glial cell activation |
113 | ″ | ″ | health concern |
114 | ″ | ″ | hippocampal BDNF |
115 | ″ | ″ | illustration |
116 | ″ | ″ | impact |
117 | ″ | ″ | indirect effects |
118 | ″ | ″ | inflammasome activation |
119 | ″ | ″ | inflammasome pathway |
120 | ″ | ″ | inflammatory response |
121 | ″ | ″ | influence |
122 | ″ | ″ | inhibition |
123 | ″ | ″ | inhibitors |
124 | ″ | ″ | integrity |
125 | ″ | ″ | interleukin |
126 | ″ | ″ | kappa B |
127 | ″ | ″ | leucine-rich repeats |
128 | ″ | ″ | major role |
129 | ″ | ″ | male Wistar rats |
130 | ″ | ″ | manipulation |
131 | ″ | ″ | marked activation |
132 | ″ | ″ | mechanism |
133 | ″ | ″ | miR |
134 | ″ | ″ | miRNAs |
135 | ″ | ″ | model |
136 | ″ | ″ | modulation |
137 | ″ | ″ | modulatory role |
138 | ″ | ″ | necrosis factor |
139 | ″ | ″ | nervous system |
140 | ″ | ″ | neuro-inflammation |
141 | ″ | ″ | neuroplasticity |
142 | ″ | ″ | neurotrophin production |
143 | ″ | ″ | neurotrophins |
144 | ″ | ″ | noticeable reduction |
145 | ″ | ″ | nuclear factor kappa B |
146 | ″ | ″ | observations |
147 | ″ | ″ | oligomerization domain |
148 | ″ | ″ | outcomes |
149 | ″ | ″ | overall state |
150 | ″ | ″ | pathological pathways |
151 | ″ | ″ | pathway |
152 | ″ | ″ | patients |
153 | ″ | ″ | positive outcomes |
154 | ″ | ″ | potential |
155 | ″ | ″ | pro-inflammatory IL |
156 | ″ | ″ | production |
157 | ″ | ″ | prominent reduction |
158 | ″ | ″ | promising |
159 | ″ | ″ | protein 3 |
160 | ″ | ″ | protocol |
161 | ″ | ″ | pyrin domain-containing protein 3 |
162 | ″ | ″ | rats |
163 | ″ | ″ | receptors |
164 | ″ | ″ | reduction |
165 | ″ | ″ | regulation |
166 | ″ | ″ | release |
167 | ″ | ″ | repeats |
168 | ″ | ″ | resilience |
169 | ″ | ″ | resilience mechanisms |
170 | ″ | ″ | response |
171 | ″ | ″ | results |
172 | ″ | ″ | role |
173 | ″ | ″ | signal transduction |
174 | ″ | ″ | signaling |
175 | ″ | ″ | significant role |
176 | ″ | ″ | sodium-glucose co-transporter-2 inhibitors |
177 | ″ | ″ | standard therapy |
178 | ″ | ″ | state |
179 | ″ | ″ | stress |
180 | ″ | ″ | stress protocol |
181 | ″ | ″ | subsequent inhibition |
182 | ″ | ″ | synapsin 1 |
183 | ″ | ″ | system |
184 | ″ | ″ | system disturbances |
185 | ″ | ″ | therapy |
186 | ″ | ″ | transduction |
187 | ″ | ″ | tumor necrosis factor |
188 | ″ | ″ | variables |
189 | ″ | schema:name | Crosstalk Among NLRP3 Inflammasome, ETBR Signaling, and miRNAs in Stress-Induced Depression-Like Behavior: a Modulatory Role for SGLT2 Inhibitors |
190 | ″ | schema:pagination | 2664-2681 |
191 | ″ | schema:productId | N6a860138334a4af1b1ab566022bd18b8 |
192 | ″ | ″ | Na733aa58fb2d44ae89518d9438eb9ef2 |
193 | ″ | ″ | Nd9fde430c8be497d9701cfdec5d3a16d |
194 | ″ | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1141985432 |
195 | ″ | ″ | https://doi.org/10.1007/s13311-021-01140-4 |
196 | ″ | schema:sdDatePublished | 2022-05-20T07:39 |
197 | ″ | schema:sdLicense | https://scigraph.springernature.com/explorer/license/ |
198 | ″ | schema:sdPublisher | N79e60fff965740fb946b6b800985d216 |
199 | ″ | schema:url | https://doi.org/10.1007/s13311-021-01140-4 |
200 | ″ | sgo:license | sg:explorer/license/ |
201 | ″ | sgo:sdDataset | articles |
202 | ″ | rdf:type | schema:ScholarlyArticle |
203 | N05be2426e0dc49b2a938640beeb1aa76 | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
204 | ″ | schema:name | Rats, Wistar |
205 | ″ | rdf:type | schema:DefinedTerm |
206 | N2388fdb397ae4c48b69385fcb4dfb52e | rdf:first | sg:person.01350034322.36 |
207 | ″ | rdf:rest | Nb7e8db52e562429daea815d3351e4a71 |
208 | N24982be31d5142ea8f5c163a59ae8bb5 | schema:affiliation | grid-institutes:None |
209 | ″ | schema:familyName | Abdul Salam |
210 | ″ | schema:givenName | Rania M. |
211 | ″ | rdf:type | schema:Person |
212 | N272f6ef94270488c8e5f6578a7c0d11b | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
213 | ″ | schema:name | Male |
214 | ″ | rdf:type | schema:DefinedTerm |
215 | N48af6f15654047fdac4d5be879cc49ba | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
216 | ″ | schema:name | Animals |
217 | ″ | rdf:type | schema:DefinedTerm |
218 | N4a41e9f99e0b4445b8e267b1440b74a0 | schema:volumeNumber | 18 |
219 | ″ | rdf:type | schema:PublicationVolume |
220 | N5868a8a7ba8d4a82b48715f3920697e6 | rdf:first | Ncf3e56830d2148bb80872f671c1dbe02 |
221 | ″ | rdf:rest | N612de3905bec4ee392841f63b620225f |
222 | N5c1da7e894fa489f806e0df41ebdc6f8 | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
223 | ″ | schema:name | Inflammasomes |
224 | ″ | rdf:type | schema:DefinedTerm |
225 | N5eb76ae91765412aaa74f84bf880a407 | schema:issueNumber | 4 |
226 | ″ | rdf:type | schema:PublicationIssue |
227 | N612de3905bec4ee392841f63b620225f | rdf:first | N24982be31d5142ea8f5c163a59ae8bb5 |
228 | ″ | rdf:rest | N2388fdb397ae4c48b69385fcb4dfb52e |
229 | N6a860138334a4af1b1ab566022bd18b8 | schema:name | pubmed_id |
230 | ″ | schema:value | 34664178 |
231 | ″ | rdf:type | schema:PropertyValue |
232 | N721bba2a069a48648019cedadf307caa | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
233 | ″ | schema:name | Signal Transduction |
234 | ″ | rdf:type | schema:DefinedTerm |
235 | N731bfe242c914aed9f21de0d11754347 | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
236 | ″ | schema:name | Depression |
237 | ″ | rdf:type | schema:DefinedTerm |
238 | N79e60fff965740fb946b6b800985d216 | schema:name | Springer Nature - SN SciGraph project |
239 | ″ | rdf:type | schema:Organization |
240 | Na7209c7dedb0483d96d9f4e95357243e | rdf:first | sg:person.010061330607.14 |
241 | ″ | rdf:rest | N5868a8a7ba8d4a82b48715f3920697e6 |
242 | Na733aa58fb2d44ae89518d9438eb9ef2 | schema:name | dimensions_id |
243 | ″ | schema:value | pub.1141985432 |
244 | ″ | rdf:type | schema:PropertyValue |
245 | Nac660a9dcfef4582b93c40b84d2a5d54 | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
246 | ″ | schema:name | Rats |
247 | ″ | rdf:type | schema:DefinedTerm |
248 | Nb79ba5ea56f8456babd88613415de399 | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
249 | ″ | schema:name | NF-kappa B |
250 | ″ | rdf:type | schema:DefinedTerm |
251 | Nb7e8db52e562429daea815d3351e4a71 | rdf:first | sg:person.0666621004.84 |
252 | ″ | rdf:rest | rdf:nil |
253 | Ncf3e56830d2148bb80872f671c1dbe02 | schema:affiliation | grid-institutes:grid.7776.1 |
254 | ″ | schema:familyName | Ahmed |
255 | ″ | schema:givenName | Lamiaa A. |
256 | ″ | rdf:type | schema:Person |
257 | Nd5205e3227e74c48abd1acc1ee69c045 | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
258 | ″ | schema:name | NLR Family, Pyrin Domain-Containing 3 Protein |
259 | ″ | rdf:type | schema:DefinedTerm |
260 | Nd9fde430c8be497d9701cfdec5d3a16d | schema:name | doi |
261 | ″ | schema:value | 10.1007/s13311-021-01140-4 |
262 | ″ | rdf:type | schema:PropertyValue |
263 | Nf77737a7dc364eef9cbb6fbbb777e50c | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
264 | ″ | schema:name | Sodium-Glucose Transporter 2 Inhibitors |
265 | ″ | rdf:type | schema:DefinedTerm |
266 | Nfd9bc18db7cc469e854eb774762f172d | schema:inDefinedTermSet | https://www.nlm.nih.gov/mesh/ |
267 | ″ | schema:name | MicroRNAs |
268 | ″ | rdf:type | schema:DefinedTerm |
269 | anzsrc-for:11 | schema:inDefinedTermSet | anzsrc-for: |
270 | ″ | schema:name | Medical and Health Sciences |
271 | ″ | rdf:type | schema:DefinedTerm |
272 | anzsrc-for:1109 | schema:inDefinedTermSet | anzsrc-for: |
273 | ″ | schema:name | Neurosciences |
274 | ″ | rdf:type | schema:DefinedTerm |
275 | sg:journal.1294839 | schema:issn | 1878-7479 |
276 | ″ | ″ | 1933-7213 |
277 | ″ | schema:name | Neurotherapeutics |
278 | ″ | schema:publisher | Springer Nature |
279 | ″ | rdf:type | schema:Periodical |
280 | sg:person.010061330607.14 | schema:affiliation | grid-institutes:grid.7776.1 |
281 | ″ | schema:familyName | Muhammad |
282 | ″ | schema:givenName | Radwa N. |
283 | ″ | schema:sameAs | https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010061330607.14 |
284 | ″ | rdf:type | schema:Person |
285 | sg:person.01350034322.36 | schema:affiliation | grid-institutes:grid.7776.1 |
286 | ″ | schema:familyName | Ahmed |
287 | ″ | schema:givenName | Kawkab A. |
288 | ″ | schema:sameAs | https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01350034322.36 |
289 | ″ | rdf:type | schema:Person |
290 | sg:person.0666621004.84 | schema:affiliation | grid-institutes:grid.7776.1 |
291 | ″ | schema:familyName | Attia |
292 | ″ | schema:givenName | Amina S. |
293 | ″ | schema:sameAs | https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0666621004.84 |
294 | ″ | rdf:type | schema:Person |
295 | sg:pub.10.1007/s00005-014-0310-1 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1025399559 |
296 | ″ | ″ | https://doi.org/10.1007/s00005-014-0310-1 |
297 | ″ | rdf:type | schema:CreativeWork |
298 | sg:pub.10.1007/s00005-019-00543-8 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1113796674 |
299 | ″ | ″ | https://doi.org/10.1007/s00005-019-00543-8 |
300 | ″ | rdf:type | schema:CreativeWork |
301 | sg:pub.10.1007/s00441-013-1581-2 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1028763041 |
302 | ″ | ″ | https://doi.org/10.1007/s00441-013-1581-2 |
303 | ″ | rdf:type | schema:CreativeWork |
304 | sg:pub.10.1007/s00702-019-02084-y | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1121501280 |
305 | ″ | ″ | https://doi.org/10.1007/s00702-019-02084-y |
306 | ″ | rdf:type | schema:CreativeWork |
307 | sg:pub.10.1007/s10557-017-6725-2 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1085063373 |
308 | ″ | ″ | https://doi.org/10.1007/s10557-017-6725-2 |
309 | ″ | rdf:type | schema:CreativeWork |
310 | sg:pub.10.1007/s11033-019-05129-3 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1121795414 |
311 | ″ | ″ | https://doi.org/10.1007/s11033-019-05129-3 |
312 | ″ | rdf:type | schema:CreativeWork |
313 | sg:pub.10.1007/s12031-020-01597-6 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1128097367 |
314 | ″ | ″ | https://doi.org/10.1007/s12031-020-01597-6 |
315 | ″ | rdf:type | schema:CreativeWork |
316 | sg:pub.10.1007/s13300-020-00885-z | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1129665002 |
317 | ″ | ″ | https://doi.org/10.1007/s13300-020-00885-z |
318 | ″ | rdf:type | schema:CreativeWork |
319 | sg:pub.10.1038/nprot.2012.044 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1020413118 |
320 | ″ | ″ | https://doi.org/10.1038/nprot.2012.044 |
321 | ″ | rdf:type | schema:CreativeWork |
322 | sg:pub.10.1038/s41398-020-0808-8 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1127347512 |
323 | ″ | ″ | https://doi.org/10.1038/s41398-020-0808-8 |
324 | ″ | rdf:type | schema:CreativeWork |
325 | sg:pub.10.1038/s41596-018-0011-z | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1105426012 |
326 | ″ | ″ | https://doi.org/10.1038/s41596-018-0011-z |
327 | ″ | rdf:type | schema:CreativeWork |
328 | sg:pub.10.1038/s41598-017-02583-6 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1085537757 |
329 | ″ | ″ | https://doi.org/10.1038/s41598-017-02583-6 |
330 | ″ | rdf:type | schema:CreativeWork |
331 | sg:pub.10.1038/s41598-017-08055-1 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1091033730 |
332 | ″ | ″ | https://doi.org/10.1038/s41598-017-08055-1 |
333 | ″ | rdf:type | schema:CreativeWork |
334 | sg:pub.10.1038/s41598-019-53624-1 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1122789257 |
335 | ″ | ″ | https://doi.org/10.1038/s41598-019-53624-1 |
336 | ″ | rdf:type | schema:CreativeWork |
337 | sg:pub.10.1038/sj.npp.1301410 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1046232699 |
338 | ″ | ″ | https://doi.org/10.1038/sj.npp.1301410 |
339 | ″ | rdf:type | schema:CreativeWork |
340 | sg:pub.10.1186/s12933-014-0148-1 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1022419393 |
341 | ″ | ″ | https://doi.org/10.1186/s12933-014-0148-1 |
342 | ″ | rdf:type | schema:CreativeWork |
343 | sg:pub.10.1186/s12974-017-0865-y | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1085376760 |
344 | ″ | ″ | https://doi.org/10.1186/s12974-017-0865-y |
345 | ″ | rdf:type | schema:CreativeWork |
346 | sg:pub.10.1186/s13046-019-1180-5 | schema:sameAs | https://app.dimensions.ai/details/publication/pub.1115975999 |
347 | ″ | ″ | https://doi.org/10.1186/s13046-019-1180-5 |
348 | ″ | rdf:type | schema:CreativeWork |
349 | grid-institutes:None | schema:alternateName | Department of Biology, School of Pharmacy, New Giza University, Giza, Egypt |
350 | ″ | schema:name | Department of Biology, School of Pharmacy, New Giza University, Giza, Egypt |
351 | ″ | ″ | Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt |
352 | ″ | rdf:type | schema:Organization |
353 | grid-institutes:grid.7776.1 | schema:alternateName | Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt |
354 | ″ | ″ | Pathology Department, Faculty of Veterinary Medicine, Cairo University, 12211, Giza, Egypt |
355 | ″ | schema:name | Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt |
356 | ″ | ″ | Pathology Department, Faculty of Veterinary Medicine, Cairo University, 12211, Giza, Egypt |
357 | ″ | rdf:type | schema:Organization |