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JM-20 Treatment After MCAO Reduced Astrocyte Reactivity and Neuronal Death on Peri-infarct Regions of the Rat Brain

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Abstract

Stroke is frequently associated with severe neurological decline and mortality, and its incidence is expected to increase due to aging population. The only available pharmacological treatment for cerebral ischemia is thrombolysis, with narrow therapeutic windows. Efforts aimed to identify new therapeutics are crucial. In this study, we look into plausible molecular and cellular targets for JM-20, a new hybrid molecule, against ischemic stroke in vivo. Male Wistar rats were subjected to 90 min middle cerebral artery occlusion (MCAO) following 23 h of reperfusion. Animals treated with 8 mg/kg JM-20 (p.o., 1 h after reperfusion) showed minimal neurological impairment and lower GABA and IL-1β levels in CSF when compared to damaged rats that received vehicle. Immunocontent of pro-survival, phosphorylated Akt protein decreased in the cortex after 24 h as result of the ischemic insult, accompanied by decreased number of NeuN+ cells in the peri-infarct cortex, cornu ammonis 1 (CA1) and dentate gyrus (DG) areas. Widespread reactive astrogliosis in both cortex and hippocampus (CA1, CA3, and DG areas) was observed 24 h post-ischemia. JM-20 prevented the activated Akt reduction, neuronal death, and astrocytes reactivity throughout the brain. Overall, the results reinforce the pharmacological potential of JM-20 as neuroprotective agent and provide important evidences about its molecular and cellular targets in this model of cerebral ischemia.

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Acknowledgements

This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-Brazil/Ministerio de Educación Superior (MES)-Cuba projects 140/11 and 092/10, Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção (INCTEN)/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), IBN.Net/CNPq, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), and the Non-Governmental Organization MEDICUBA-SPAIN. We would like to thank to Dr. Nancy Pavón Fuentes for the scientific advising.

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Authors and Affiliations

  1. Centro de Investigación y Desarrollo de Medicamentos, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600, Havana, Cuba

    Jeney Ramírez-Sánchez, Yanier Nuñez-Figueredo & René Delgado-Hernández

  2. Programa de Pós-graduação em Bioquímica, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil

    Elisa Nicoloso Simões Pires, André Meneghetti, Gisele Hansel, Christianne Salbego & Diogo O Souza

  3. Centro de Estudio para las Investigaciones y Evaluaciones Biológicas, Instituto de Farmacia y Alimentos, Universidad de La Habana, ave. 23 # 21425 e/214 y 222, La Coronela, La Lisa, CP 13600, Havana, Cuba

    Gilberto L. Pardo-Andreu

  4. Laboratorio de Síntesis Orgánica de La Facultad de Química, Universidad de La Habana, Zapata s/n entre G y Carlitos Aguirre, Vedado Plaza de la Revolución, CP 10400, Havana, Cuba

    Estael Ochoa-Rodríguez & Yamila Verdecia-Reyes

  5. Departamento de Bioquímica, PPG em Bioquímica, PPG em Educação em Ciência, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil

    Christianne Salbego & Diogo O Souza

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  1. Jeney Ramírez-Sánchez
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  2. Elisa Nicoloso Simões Pires
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  3. André Meneghetti
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Correspondence to Diogo O Souza.

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Ramírez-Sánchez, J., Pires, E.N.S., Meneghetti, A. et al. JM-20 Treatment After MCAO Reduced Astrocyte Reactivity and Neuronal Death on Peri-infarct Regions of the Rat Brain. Mol Neurobiol 56, 502–512 (2019). https://doi.org/10.1007/s12035-018-1087-8

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