2. Academic Validation
  3. Geissoschizoline, a promising alkaloid for Alzheimer's disease: Inhibition of human cholinesterases, anti-inflammatory effects and molecular docking

Geissoschizoline, a promising alkaloid for Alzheimer's disease: Inhibition of human cholinesterases, anti-inflammatory effects and molecular docking

  • Bioorg Chem. 2020 Nov;104:104215. doi: 10.1016/j.bioorg.2020.104215.
Josélia A Lima 1,  Thiago Wilson R Costa 2,  Anna C C da Fonseca 3,  Rackele F do Amaral 3,  Maria do Desterro S B Nascimento 4,  Osvaldo A Santos-Filho 5,  Ana Luísa P de Miranda 6,  Denise Cristian Ferreira Neto 7,  Flavia R S Lima 3,  Lidilhone Hamerski 5,  Luzineide W Tinoco 5
Affiliations

Affiliations

  • 1 Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, 21941-909 Rio de Janeiro, RJ, Brazil; Programa de Pós-graduação em Saúde do Adulto, Universidade Federal do Maranhão, 65080-805, São Luís, MA, Brazil. Electronic address: joselialima@terra.com.br.
  • 2 Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
  • 3 Laboratório de Biologia das Células Gliais, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
  • 4 Programa de Pós-graduação em Saúde do Adulto, Universidade Federal do Maranhão, 65080-805, São Luís, MA, Brazil.
  • 5 Instituto de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil.
  • 6 Laboratório de Estudos em Farmacologia Experimental, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil.
  • 7 Grupo de Química medicinal, Instituto Militar de Engenharia, Praia Vermelha, Rio de Janeiro 22290-270, Brazil; Departamento de Química, Universidade Federal de Roraima, Boa Vista, Roraima 69310-000, Brazil.
PMID: 32920358 DOI: 10.1016/j.bioorg.2020.104215
Abstract

Due to the lack of effective pharmacotherapy options to treats Alzheimer's disease, new strategies have been approached in the search for multi-target molecules as therapeutic options. In this work, four Indole Alkaloids, geissoschizoline, geissoschizone, geissospermine, and 3',4',5',6'-tetradehydrogeissospermine were isolated from Geissospermum vellosii (Pao pereira) and evaluated for their anticholinesterase activities. While geissospermine inhibited only butyrylcholinesterase (BChE), the Other Alkaloids behaved as non-selective inhibitors of acetylcholinesterase (AChE) and BChE. In cell viability tests, only geissoschizoline was not cytotoxic. Therefore, geissoschizoline actions were also evaluated in human cholinesterases, where it was twice as potent inhibitor of hBChE (IC50 = 10.21 ± 0.01 µM) than hAChE (IC50 = 20.40 ± 0.93 µM). On Enzyme kinetic studies, geissoschizoline presented a mixed-type inhibition mechanism for both enzymes. Molecular docking studies pointed interactions of geissoschizoline with active site and peripheral anionic site of hAChE and hBChE, indicating a dual site inhibitor profile. Moreover, geissoschizoline also played a promising anti-inflammatory role, reducing microglial release of NO and TNF-α at a concentration (1 μM) ten and twenty times lower than the IC50 values of hBChE and hAChE inhibition, respectively. These actions give geissoschizoline a strong neuroprotective character. In addition, the ability to inhibit hAChE and hBChE, with approximate inhibitory potencies, accredits this alkaloid for therapeutic use in the moderate to severe phase of AD. Thus, geissoschizoline emerges as a possible multi-target prototype that can be very useful in preventing neurodegeneration and restore neurotransmission.

Keywords

Alzheimer’s disease; Cholinesterase inhibitor; Geissospermum vellosii; Indole alkaloids; Neuroinflammation; Pao pereira.

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