Effects of the flavonoid casticin from Brazilian Croton betulaster in cerebral cortical progenitors in vitro: Direct and indirect action through astrocytes

Abstract

Neurodegenerative diseases are a major constraint on the social and economic development of many countries. Evidence has suggested that phytochemicals have an impact on brain pathology; however, both their mechanisms of action and their cell targets are incompletely known. Here, we investigated the effects of the flavonoid casticin, extracted from Croton betulaster, a common plant in the state of Bahia in Brazil, on rat cerebral cortex neurons in vitro. Treatment of neural progenitors with 10 microM casticin increased the neuronal population positive for the neuronal marker beta-tubulin III and the neuronal transcriptional factor Tbr2 by approximately 20%. This event was followed by a 50% decrease in neuronal death. Pools of astrocyte (GFAP and S100beta), neural (nestin), and oligodendrocyte (Olig2 and NG2) progenitors were not affected by casticin. Neither neuronal commitment nor proliferation of progenitors was affected by casticin, suggesting a neuroprotective effect of this compound. Culture of neural progenitors on casticin-treated astrocyte monolayers increased the neuronal population by 40%. This effect was reproduced by conditioned medium derived from casticin-treated astrocytes, suggesting the involvement of a soluble factor. ELISA assays of the conditioned medium revealed a 20% increase in interleukin-6 level in response to casticin. In contrast to the direct effect, neuronal death was unaffected, but a 52% decrease in the death of nestin-positive progenitors was observed. Together our data suggest that casticin influences the neuronal population by two mechanisms: 1) directly, by decreasing neuronal death, and 2) indirectly, via astrocytes, by modulating the pool of neuronal progenitors.

Agathisflavone Enhances Retinoic Acid-Induced Neurogenesis and Its Receptors α and β in Pluripotent Stem Cells

“…This biflavonoid did not change proliferation or neural differentiation rates in those cells, but it was able to reduce cell death, which was about 35% in 0.1% of DMSO (vehicle) group. The reduction of cell death by FAB is consistent with previous results that show that flavonoids can reduce cell death [10,20]. The exact mechanism by which flavonoids protect against cell death may be vast, as those compounds are widely known not only as antioxidant, but also as activators of PI3 kinase, tyrosine kinase and MAP kinase pathway [4,31,32], enhancers of proteasome activity [33], and modulators of protein assembly and oligomerization [11].…”

“…The exact mechanism by which flavonoids protect against cell death may be vast, as those compounds are widely known not only as antioxidant, but also as activators of PI3 kinase, tyrosine kinase and MAP kinase pathway [4,31,32], enhancers of proteasome activity [33], and modulators of protein assembly and oligomerization [11]. Since DMSO is the solvent most suitable for maintaining the stability of RA and FAB [5,6,9,20,23,28], side effects induced by the vehicle might be an inevitable feature of the protocol. In this context, the association of FAB to the protocol becomes applicable in order to reduce inevitably cell death induced by the DMSO and RA.…”

“…As some flavonoids, such as casticin, are able to increase the survival of neuronal progenitor cells in vitro [20], we investigated whether FAB could reduce cell death in EBs undergoing neurogenesis. FAB was able to decrease the amount of TUNEL-positive cells in all experimental groups (Fig.…”

Flavonoids and Astrocytes Crosstalking: Implications for Brain Development and Pathology

“…The high responsiveness of astrocytes to several flavonoids supports the hypothesis that these cells might be mediators of flavonoid actions in the mature brain. Recently, it has been shown that resveratrol counteracts oxidative damage caused by H 2 O 2 , not only by its antioxidant properties, but also through the modulation of important glial functions, particularly improving glutamate uptake activity, increasing glutathione content and stimulating S100b secretion, thus contributing to functional recovery after brain injury [106,107]. Recently, our group investigated the neuroprotective properties of the flavonoid casticin, extracted from Croton betulaster, a common plant of the state of Bahia in Brazil, on rat cerebral cortex neurons in vitro.…”

Molecular Mechanisms of Casticin Action: an Update on its Antitumor Functions

“…As shown in Figure 1, accumulated data indicate that casticin was isolated from many plant species such as, namely Vitex agnus castus (Choudhary et al, 2009;Mesaik et al, 2009;Webster et al, 2011;Righeschi et al, 2012;Hogner et al, 2013), Daphne genkwa (Xie et al, 2011), Achillea millefolium (Haidara et al, 2006;Csupor-Loffler et al, 2009), Ficus microcarpa , Vitex rotundifolia (Ono et al, 2002;Hu et al, 2007b;Shen et al, 2009;Ye et al, 2010;Koh et al, 2011), Fructus viticis (Hu et al, 2007b;Guan et al, 2010;Chen et al, 2011b;Yang et al, 2011;Zeng et al, 2012;Zhou et al, 2013a), Vitex negundo (Diaz et al, 2003;Kunwar et al, 2010;Velpandian et al, 2013), Crataegus pinnatifida (Kao et al, 2005), Pavetta crassipes (Mali and Dhake, 2011), Nelsonia canescens, Butea frondosa Koen , Dalbergia odorifera (Mali and Dhake, 2011), Bryonia laciniosa (Aggarwal et al, 2011), Citrus unshu (Mali and Dhake, 2011;Nagoor et al, 2011), Centipeda minima (Mali and Dhake, 2011), Clausena excavate (Manosroi et al, 2005), Croton betulaster (de Sampaio e Spohr et al, 2010;Freitas et al, 2011), Dimorphandra mollis (Freitas et al, 2011), Artemisia abrotanum L. (Hernandez et al, 1999), Artemisia annua L …”