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JM-20 Treatment After Mild Traumatic Brain Injury Reduces Glial Cell Pro-inflammatory Signaling and Behavioral and Cognitive Deficits by Increasing Neurotrophin Expression

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Abstract

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.

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All data generated or analyzed during this study are included in this published article.

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Acknowledgements

We gratefully acknowledge the Universidade Federal de Santa Maria (UFSM), Universidade Federal da Bahia (UFBA), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) on 09/2018 Process 307539/2018-0, PI Fellowship to SLC; Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção—INCTEN); Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Programa de Apoio a Núcleos Emergentes (PRONEM) for the financial support. S.L.C, F.A.A.S and L.F.F.R is grateful to CNPQ for the fellowship.

Funding

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (PROEX Process Number: 88882.182135/2018–01 financial support number: 0737/2018), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Programa de Apoio a Núcleos Emergentes (PRONEM) [grant number16/2551–0000248-7], Foundation for Research Support of the State of Bahia (FAPESB, Process number INT 0016/2016).

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Authors and Affiliations

  1. Centro de Ciências Naturais E Exatas, Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Andrezza Bond Vieira Furtado, Debora Farina Gonçalves, Diane Duarte Hartmann, Aline Alves Courtes, Luiz Fernando Freire Royes & Félix Alexandre Antunes Soares

  2. Departamento de fisioterapia, Universidade Regional do Noroeste do Estado do Rio Grande do Sul., Ijuí, RS, Brazil

    Diane Duarte Hartmann

  3. Laboratório de Bioquímica Do Exercício, Centro de Educação Física E Desportos, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Gustavo Cassol

  4. Centro de Investigación Y Desarrollo de Medicamentos, Havana City, Cuba

    Yanier Nunez-Figueredo

  5. Laboratório de Neuroquímica E Biologia Celular, Departamento de Bioquímica E Biofísica, Universidade Federal Bahia, Salvador, BA, Brazil

    Deivison Silva Argolo, Ravena Pereira do Nascimento, Silvia Lima Costa & Victor Diogenes Amaral da Silva

  6. Departamento de Bioquímica E Biologia Molecular, CCNE, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Félix Alexandre Antunes Soares

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  1. Andrezza Bond Vieira Furtado
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  2. Debora Farina Gonçalves
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  9. Silvia Lima Costa
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  10. Victor Diogenes Amaral da Silva
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  11. Luiz Fernando Freire Royes
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  12. Félix Alexandre Antunes Soares
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Contributions

All the authors contributed to carrying out and designing this study. The first manuscript draft was written by Andrezza Bond Vieira Furtado and all the authors commented on the previous versions. All the authors read and approved the final manuscript version.

Corresponding author

Correspondence to Félix Alexandre Antunes Soares.

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All procedures with animals followed the Committee on Care and Use of Experimental Animal Resources Guidelines of the Federal University of Santa Maria, Brazil (9426190418).

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Furtado, A.B.V., Gonçalves, D.F., Hartmann, D.D. et al. JM-20 Treatment After Mild Traumatic Brain Injury Reduces Glial Cell Pro-inflammatory Signaling and Behavioral and Cognitive Deficits by Increasing Neurotrophin Expression. Mol Neurobiol 58, 4615–4627 (2021). https://doi.org/10.1007/s12035-021-02436-4

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