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Baccharin from Brazilian green propolis induces neurotrophic signaling pathways in PC12 cells: potential for axonal and synaptic regeneration

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Abstract

Neurodegenerative diseases are characterized by progressive loss of the structure and function of specific neuronal populations, and have been associated with reduced neurotrophic support. Neurotrophins, like NGF (nerve growth factor), are endogenous proteins that induce neuritogenesis and modulate axonal growth, branching, and synapsis; however, their therapeutic application is limited mainly by low stability, short half-life, and inability to cross the blood–brain barrier (BBB). Small neurotrophic molecules that have suitable pharmacokinetics and are able to cross the BBB are potential candidates for neuroprotection. Baccharin is a bioactive small molecule isolated from Brazilian green propolis. In the present study, we investigated the neurotrophic and neuroprotective potential of baccharin in the PC12 cell neuronal model. We used pharmacological inhibitors (K252a, LY294002, and U0126), and ELISA (phospho-trkA, phospho-Akt, and phospho-MEK) to investigate the involvement of trkA receptor, PI3k/Akt pathway, and MAPK/Erk pathway, respectively. Additionally, we evaluated the expression of axonal (GAP-43) and synaptic (synapsin I) proteins by western blot. The results showed that baccharin induces neuritogenesis in NGF-deprived PC12 cells, through activation of trkA receptor and the downstream signaling cascades (PI3K/Akt and MAPK/ERK), which is the same neurotrophic pathway activated by NGF in PC12 cells and neurons. Baccharin also induced the expression of GAP-43 and synapsin I, which mediate axonal and synaptic plasticity, respectively. Additionally, in silico predictions of baccharin showed favorable physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness. Altogether, these findings suggest that baccharin is a promising neurotrophic agent whose therapeutic application in neurodegeneration should be further investigated.

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Data availability

Original source data presented in figures and full-length immunoblot membranes are presented in Supplementary Material (S2).

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Funding

This work received financial support from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, process number 2017/04138–8), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, code 001), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq grant number 305823/2019–1).

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Authors and Affiliations

  1. Faculdade de Ciências Farmacêuticas de Ribeirão Preto – USP, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Lilian do Amaral, Gabriel Rocha Caldas, Neife Aparecida Guinaim dos Santos & Jairo Kennup Bastos

  2. Núcleo de Pesquisa Em Ciências Exatas E Tecnológicas, Universidade de Franca, Franca, SP, Brazil

    Renato Luis Tame Parreira

  3. Departamento de Análises Clínicas, Toxicológicas E Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, USP, Avenida do Café s/n, Ribeirão Preto, SP, 14040-903, Brazil

    Antonio Cardozo dos Santos

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ACS, NS, and JB conceived and designed research. LA and GC conducted experiments. RP performed in silico studies. LA and NS analyzed data and wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Antonio Cardozo dos Santos.

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do Amaral, L., Caldas, G.R., dos Santos, N.A.G. et al. Baccharin from Brazilian green propolis induces neurotrophic signaling pathways in PC12 cells: potential for axonal and synaptic regeneration. Naunyn-Schmiedeberg's Arch Pharmacol 395, 659–672 (2022). https://doi.org/10.1007/s00210-022-02224-4

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