JM-20 Treatment After Mild Traumatic Brain Injury Reduces Glial Cell Pro-inflammatory Signaling and Behavioral and Cognitive Deficits by Increasing Neurotrophin Expression
Traumatic brain injury (TBI) is considered a public health problem and is often related to motor and cognitive disabilities, besides behavioral and emotional changes that may remain for the rest of the subject’s life. Resident astrocytes and microglia are the first cell types to start the inflammato...
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| Veröffentlicht in: | Molecular neurobiology 2021-09, Vol.58 (9), p.4615-4627 |
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| creator | Furtado, Andrezza Bond Vieira Gonçalves, Debora Farina Hartmann, Diane Duarte Courtes, Aline Alves Cassol, Gustavo Nunez-Figueredo, Yanier Argolo, Deivison Silva do Nascimento, Ravena Pereira Costa, Silvia Lima da Silva, Victor Diogenes Amaral Royes, Luiz Fernando Freire Soares, Félix Alexandre Antunes |
| description | Traumatic brain injury (TBI) is considered a public health problem and is often related to motor and cognitive disabilities, besides behavioral and emotional changes that may remain for the rest of the subject’s life. Resident astrocytes and microglia are the first cell types to start the inflammatory cascades following TBI. It is widely known that continuous or excessive neuroinflammation may trigger many neuropathologies. Despite the large numbers of TBI cases, there is no effective pharmacological treatment available. This study aimed to investigate the effects of the new hybrid molecule 3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro1H-pyrido[2,3-b][1,5]benzodiazepine (JM-20) on TBI outcomes. Male Wistar rats were submitted to a weight drop model of mild TBI and treated with a single dose of JM-20 (8 mg/kg). Twenty-four hours after TBI, JM-20–treated animals showed improvements on locomotor and exploratory activities, and short-term memory deficits induced by TBI improved as well. Brain edema was present in TBI animals and the JM-20 treatment was able to prevent this change. JM-20 was also able to attenuate neuroinflammation cascades by preventing glial cells—microglia and astrocytes—from exacerbated activation, consequently reducing pro-inflammatory cytokine levels (TNF-α and IL-1β). BDNF mRNA level was decreased 24 h after TBI because of neuroinflammation cascades; however, JM-20 restored the levels. JM-20 also increased GDNF and NGF levels. These results support the JM-20 neuroprotective role to treat mild TBI by reducing the initial damage and limiting long-term secondary degeneration after TBI. |
| doi_str_mv | 10.1007/s12035-021-02436-4 |
| format | Article |
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Resident astrocytes and microglia are the first cell types to start the inflammatory cascades following TBI. It is widely known that continuous or excessive neuroinflammation may trigger many neuropathologies. Despite the large numbers of TBI cases, there is no effective pharmacological treatment available. This study aimed to investigate the effects of the new hybrid molecule 3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro1H-pyrido[2,3-b][1,5]benzodiazepine (JM-20) on TBI outcomes. Male Wistar rats were submitted to a weight drop model of mild TBI and treated with a single dose of JM-20 (8 mg/kg). Twenty-four hours after TBI, JM-20–treated animals showed improvements on locomotor and exploratory activities, and short-term memory deficits induced by TBI improved as well. Brain edema was present in TBI animals and the JM-20 treatment was able to prevent this change. JM-20 was also able to attenuate neuroinflammation cascades by preventing glial cells—microglia and astrocytes—from exacerbated activation, consequently reducing pro-inflammatory cytokine levels (TNF-α and IL-1β). BDNF mRNA level was decreased 24 h after TBI because of neuroinflammation cascades; however, JM-20 restored the levels. JM-20 also increased GDNF and NGF levels. These results support the JM-20 neuroprotective role to treat mild TBI by reducing the initial damage and limiting long-term secondary degeneration after TBI.</description><identifier>ISSN: 0893-7648</identifier><identifier>EISSN: 1559-1182</identifier><identifier>DOI: 10.1007/s12035-021-02436-4</identifier><identifier>PMID: 34148214</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Animal models ; Animals ; Anti-Inflammatory Agents - pharmacology ; Anti-Inflammatory Agents - therapeutic use ; Astrocytes ; Behavior, Animal - drug effects ; Benzodiazepines ; Benzodiazepines - pharmacology ; Benzodiazepines - therapeutic use ; Biomedical and Life Sciences ; Biomedicine ; Brain Concussion - metabolism ; Brain-derived neurotrophic factor ; Cell Biology ; Cognition - drug effects ; Cognitive ability ; Cognitive Dysfunction - drug therapy ; Disease Models, Animal ; Drug therapy ; Edema ; Emotional behavior ; Glial cell line-derived neurotrophic factor ; Glial cells ; IL-1β ; Inflammation ; Male ; Microglia ; Microglia - metabolism ; mRNA ; Nerve growth factor ; Nerve Growth Factors - metabolism ; Neurobiology ; Neurodegeneration ; Neuroglia - drug effects ; Neurology ; Neuronal-glial interactions ; Neuroprotection ; Neuroprotective Agents - pharmacology ; Neuroprotective Agents - therapeutic use ; Neurosciences ; Niacin - analogs & derivatives ; Niacin - pharmacology ; Niacin - therapeutic use ; Public health ; Rats ; Rats, Wistar ; Short term memory ; Signal Transduction - drug effects ; Traumatic brain injury ; Tumor necrosis factor-α</subject><ispartof>Molecular neurobiology, 2021-09, Vol.58 (9), p.4615-4627</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-cd336ad8f4a13e137982cf5178941f507e829a78b235ed0d626d212d2bdb1e003</citedby><cites>FETCH-LOGICAL-c441t-cd336ad8f4a13e137982cf5178941f507e829a78b235ed0d626d212d2bdb1e003</cites><orcidid>0000-0002-3948-1273</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12035-021-02436-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12035-021-02436-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34148214$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Furtado, Andrezza Bond Vieira</creatorcontrib><creatorcontrib>Gonçalves, Debora Farina</creatorcontrib><creatorcontrib>Hartmann, Diane Duarte</creatorcontrib><creatorcontrib>Courtes, Aline Alves</creatorcontrib><creatorcontrib>Cassol, Gustavo</creatorcontrib><creatorcontrib>Nunez-Figueredo, Yanier</creatorcontrib><creatorcontrib>Argolo, Deivison Silva</creatorcontrib><creatorcontrib>do Nascimento, Ravena Pereira</creatorcontrib><creatorcontrib>Costa, Silvia Lima</creatorcontrib><creatorcontrib>da Silva, Victor Diogenes Amaral</creatorcontrib><creatorcontrib>Royes, Luiz Fernando Freire</creatorcontrib><creatorcontrib>Soares, Félix Alexandre Antunes</creatorcontrib><title>JM-20 Treatment After Mild Traumatic Brain Injury Reduces Glial Cell Pro-inflammatory Signaling and Behavioral and Cognitive Deficits by Increasing Neurotrophin Expression</title><title>Molecular neurobiology</title><addtitle>Mol Neurobiol</addtitle><addtitle>Mol Neurobiol</addtitle><description>Traumatic brain injury (TBI) is considered a public health problem and is often related to motor and cognitive disabilities, besides behavioral and emotional changes that may remain for the rest of the subject’s life. Resident astrocytes and microglia are the first cell types to start the inflammatory cascades following TBI. It is widely known that continuous or excessive neuroinflammation may trigger many neuropathologies. Despite the large numbers of TBI cases, there is no effective pharmacological treatment available. This study aimed to investigate the effects of the new hybrid molecule 3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro1H-pyrido[2,3-b][1,5]benzodiazepine (JM-20) on TBI outcomes. Male Wistar rats were submitted to a weight drop model of mild TBI and treated with a single dose of JM-20 (8 mg/kg). Twenty-four hours after TBI, JM-20–treated animals showed improvements on locomotor and exploratory activities, and short-term memory deficits induced by TBI improved as well. Brain edema was present in TBI animals and the JM-20 treatment was able to prevent this change. JM-20 was also able to attenuate neuroinflammation cascades by preventing glial cells—microglia and astrocytes—from exacerbated activation, consequently reducing pro-inflammatory cytokine levels (TNF-α and IL-1β). BDNF mRNA level was decreased 24 h after TBI because of neuroinflammation cascades; however, JM-20 restored the levels. JM-20 also increased GDNF and NGF levels. These results support the JM-20 neuroprotective role to treat mild TBI by reducing the initial damage and limiting long-term secondary degeneration after TBI.</description><subject>Animal models</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>Astrocytes</subject><subject>Behavior, Animal - drug effects</subject><subject>Benzodiazepines</subject><subject>Benzodiazepines - pharmacology</subject><subject>Benzodiazepines - therapeutic use</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain Concussion - metabolism</subject><subject>Brain-derived neurotrophic factor</subject><subject>Cell Biology</subject><subject>Cognition - drug effects</subject><subject>Cognitive ability</subject><subject>Cognitive Dysfunction - drug therapy</subject><subject>Disease Models, Animal</subject><subject>Drug therapy</subject><subject>Edema</subject><subject>Emotional behavior</subject><subject>Glial cell line-derived neurotrophic factor</subject><subject>Glial cells</subject><subject>IL-1β</subject><subject>Inflammation</subject><subject>Male</subject><subject>Microglia</subject><subject>Microglia - 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pharmacology</topic><topic>Anti-Inflammatory Agents - therapeutic use</topic><topic>Astrocytes</topic><topic>Behavior, Animal - drug effects</topic><topic>Benzodiazepines</topic><topic>Benzodiazepines - pharmacology</topic><topic>Benzodiazepines - therapeutic use</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain Concussion - metabolism</topic><topic>Brain-derived neurotrophic factor</topic><topic>Cell Biology</topic><topic>Cognition - drug effects</topic><topic>Cognitive ability</topic><topic>Cognitive Dysfunction - drug therapy</topic><topic>Disease Models, Animal</topic><topic>Drug therapy</topic><topic>Edema</topic><topic>Emotional behavior</topic><topic>Glial cell line-derived neurotrophic factor</topic><topic>Glial cells</topic><topic>IL-1β</topic><topic>Inflammation</topic><topic>Male</topic><topic>Microglia</topic><topic>Microglia - metabolism</topic><topic>mRNA</topic><topic>Nerve growth factor</topic><topic>Nerve Growth Factors - metabolism</topic><topic>Neurobiology</topic><topic>Neurodegeneration</topic><topic>Neuroglia - 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Resident astrocytes and microglia are the first cell types to start the inflammatory cascades following TBI. It is widely known that continuous or excessive neuroinflammation may trigger many neuropathologies. Despite the large numbers of TBI cases, there is no effective pharmacological treatment available. This study aimed to investigate the effects of the new hybrid molecule 3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro1H-pyrido[2,3-b][1,5]benzodiazepine (JM-20) on TBI outcomes. Male Wistar rats were submitted to a weight drop model of mild TBI and treated with a single dose of JM-20 (8 mg/kg). Twenty-four hours after TBI, JM-20–treated animals showed improvements on locomotor and exploratory activities, and short-term memory deficits induced by TBI improved as well. Brain edema was present in TBI animals and the JM-20 treatment was able to prevent this change. JM-20 was also able to attenuate neuroinflammation cascades by preventing glial cells—microglia and astrocytes—from exacerbated activation, consequently reducing pro-inflammatory cytokine levels (TNF-α and IL-1β). BDNF mRNA level was decreased 24 h after TBI because of neuroinflammation cascades; however, JM-20 restored the levels. JM-20 also increased GDNF and NGF levels. These results support the JM-20 neuroprotective role to treat mild TBI by reducing the initial damage and limiting long-term secondary degeneration after TBI.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>34148214</pmid><doi>10.1007/s12035-021-02436-4</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-3948-1273</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0893-7648 |
| ispartof | Molecular neurobiology, 2021-09, Vol.58 (9), p.4615-4627 |
| issn | 0893-7648 1559-1182 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2543706557 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Animal models Animals Anti-Inflammatory Agents - pharmacology Anti-Inflammatory Agents - therapeutic use Astrocytes Behavior, Animal - drug effects Benzodiazepines Benzodiazepines - pharmacology Benzodiazepines - therapeutic use Biomedical and Life Sciences Biomedicine Brain Concussion - metabolism Brain-derived neurotrophic factor Cell Biology Cognition - drug effects Cognitive ability Cognitive Dysfunction - drug therapy Disease Models, Animal Drug therapy Edema Emotional behavior Glial cell line-derived neurotrophic factor Glial cells IL-1β Inflammation Male Microglia Microglia - metabolism mRNA Nerve growth factor Nerve Growth Factors - metabolism Neurobiology Neurodegeneration Neuroglia - drug effects Neurology Neuronal-glial interactions Neuroprotection Neuroprotective Agents - pharmacology Neuroprotective Agents - therapeutic use Neurosciences Niacin - analogs & derivatives Niacin - pharmacology Niacin - therapeutic use Public health Rats Rats, Wistar Short term memory Signal Transduction - drug effects Traumatic brain injury Tumor necrosis factor-α |
| title | JM-20 Treatment After Mild Traumatic Brain Injury Reduces Glial Cell Pro-inflammatory Signaling and Behavioral and Cognitive Deficits by Increasing Neurotrophin Expression |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T06%3A52%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=JM-20%20Treatment%20After%20Mild%20Traumatic%20Brain%20Injury%20Reduces%20Glial%20Cell%20Pro-inflammatory%20Signaling%20and%20Behavioral%20and%20Cognitive%20Deficits%20by%20Increasing%20Neurotrophin%20Expression&rft.jtitle=Molecular%20neurobiology&rft.au=Furtado,%20Andrezza%20Bond%20Vieira&rft.date=2021-09-01&rft.volume=58&rft.issue=9&rft.spage=4615&rft.epage=4627&rft.pages=4615-4627&rft.issn=0893-7648&rft.eissn=1559-1182&rft_id=info:doi/10.1007/s12035-021-02436-4&rft_dat=%3Cproquest_cross%3E2578529683%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2578529683&rft_id=info:pmid/34148214&rfr_iscdi=true |