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

Molecular neurobiology 2021 Sep

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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. © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Citation

Andrezza Bond Vieira Furtado, Debora Farina Gonçalves, Diane Duarte Hartmann, Aline Alves Courtes, Gustavo Cassol, Yanier Nunez-Figueredo, Deivison Silva Argolo, Ravena Pereira do Nascimento, Silvia Lima Costa, Victor Diogenes Amaral da Silva, Luiz Fernando Freire Royes, Félix Alexandre Antunes Soares. JM-20 Treatment After Mild Traumatic Brain Injury Reduces Glial Cell Pro-inflammatory Signaling and Behavioral and Cognitive Deficits by Increasing Neurotrophin Expression. Molecular neurobiology. 2021 Sep;58(9):4615-4627