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Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo - PubMed

  • ️Wed Jan 01 2014

Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo

Joerg Hucklenbroich et al. Stem Cell Res Ther. 2014.

Abstract

Introduction: Aromatic (ar-) turmerone is a major bioactive compound of the herb Curcuma longa. It has been suggested that ar-turmerone inhibits microglia activation, a property that may be useful in treating neurodegenerative disease. Furthermore, the effects of ar-turmerone on neural stem cells (NSCs) remain to be investigated.

Methods: We exposed primary fetal rat NSCs to various concentrations of ar-turmerone. Thereafter, cell proliferation and differentiation potential were assessed. In vivo, naïve rats were treated with a single intracerebroventricular (i.c.v.) injection of ar-turmerone. Proliferative activity of endogenous NSCs was assessed in vivo, by using noninvasive positron emission tomography (PET) imaging and the tracer [(18)F]-fluoro-L-thymidine ([(18)F]FLT), as well as ex vivo.

Results: In vitro, ar-turmerone increased dose-dependently the number of cultured NSCs, because of an increase in NSC proliferation (P < 0.01). Proliferation data were supported by qPCR-data for Ki-67 mRNA. In vitro as well as in vivo, ar-turmerone promoted neuronal differentiation of NSCs. In vivo, after i.c.v. injection of ar-turmerone, proliferating NSCs were mobilized from the subventricular zone (SVZ) and the hippocampus of adult rats, as demonstrated by both [(18)F]FLT-PET and histology (P < 0.05).

Conclusions: Both in vitro and in vivo data suggest that ar-turmerone induces NSC proliferation. Ar-turmerone thus constitutes a promising candidate to support regeneration in neurologic disease.

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Figures

Figure 1
Figure 1

Ar-turmerone increases NSC proliferation in vitro. (A) Ar-turmerone significantly increased the numbers of fetal rat NSCs in primary monolayer culture (mean ± SEM; *P < 0.05, compared with control), dependent on its concentration; representative phase-contrast images are depicted of NSC-treated without (Aʹ) or with (Aʹʹ) 6.25 μg/ml ar-turmerone (bar represents 200 μm). (B) Ar-turmerone significantly increased the number of proliferating NSCs, as assessed by BrdU-incorporation (mean ± SEM; **P < 0.01, compared with control), dependent on its concentration; representative images are depicted of NSCs treated without (Bʹ) or with (Bʹʹ) 3.125 μg/ml ar-turmerone, stained for BrdU-incorporation (bar represents 200 μm). (C) Treating NSCs with 6.25 μg/ml ar-turmerone led to a significant increase in Ki67 mRNA; mRNA levels were normalized to endogenous RPL13a expression and calculated with the 2-ΔCt method; data are depicted as mean ± SEM; *P < 0.05. (D) In high concentrations, ar-turmerone significantly decreased ratio of surviving NSCs within 24 hours of treatment, wheres concentrations between 1.56 and 6.25 μg/ml had no effect (mean ± SEM; *P < 0.05, compared with control).

Figure 2
Figure 2

Ar-turmerone induces neurogenesis in vitro and in vivo. (A) NSCs were allowed to differentiate in the absence (control) or presence of 6.25 μg/ml ar-turmerone. Immunocytochemistry 10 days after growth-factor discontinuation revealed fewer undifferentiated (SOX2+) NSCs in the turmerone-treated group, but more young neurons. The generation of astrocytes and oligodendrocytes was not affected by ar-turmerone (mean ± SEM; **P < 0.01, compared with control). (B) Representative images of differentiated cells include CNPase-positive oligodendrocytes (left), TuJ1-positive young neurons (middle), and GFAP-positive astrocytes (right); bar represents 50 μm. (C) After i.c.v. injection of 3 mg (1 mg/μl) ar-turmerone, significantly more DCX-positive neuroblasts were observed in the SVZ compared with placebo-injected control animals (mean ± SEM; **P < 0.01). (D) Representative staining of DCX-positive neuroblasts in the SVZ (bar represents 50 μm).

Figure 3
Figure 3

Proliferation of endogenous NSC is induced by ar-turmerone in vivo. (A) Staining for proliferating NSCs with anti-BrdU demonstrates that the subventricular zone (SVZ) of rats treated with 3 mg (1 mg/μl) ar-turmerone i.c.v. (left) was wider than that of placebo-treated control animals (Aʹ, right); bar represents 100 μm. (B) Differences in the width of the SVZ were statistically significant (mean ± SEM; *P < 0.05, compared with control). (C) BrdU staining of the hippocampus did not reveal a statistically significant increase in the width of the dentate gyrus, although a trend was noted favoring ar-turmerone (mean ± SEM).

Figure 4
Figure 4

Endogenous NSCs in the neurogenic niches of the rat brain are mobilized by ar-turmerone in vivo. (A) [18F]FLT-PET of a rat brain 1 week after intracerebroventricular injection of ar-turmerone shows enhanced accumulation of [18F]FLT in the subventricular zone compared with (B) Saline-injected control brain, indicating an increase of proliferating endogenous NSCs caused by ar-turmerone. (C) Ar-turmerone-treated rats showed significantly more [18F]FLT accumulation in the SVZ and the hippocampus than did control animals (mean ± SEM; **P < 0.01).

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