Progress in Neuro-Psychopharmacology and Biological Psychiatry
Curcumin enhances neuronal survival in N-methyl-d-aspartic acid toxicity by inducing RANTES expression in astrocytes via PI-3K and MAPK signaling pathways
Research Highlights
► Curcumin enhances RANTES expression in primary astrocytes. ► Activation of PI-3K and MAPK augments RANTES expression in astrocytes. ► Curcumin inhibits iNOS expression in primary astrocytes. ► Curcumin-treated ACM protects neurons from NMDA toxicity.
Introduction
Neuroinflammation plays an important role in the pathogenesis of several neurodegenerative disorders, such as Alzheimer's disease (AD), multiple sclerosis, stroke, and Parkinson's disease (Cartier et al., 2005, Galimberti et al., 2006, Xia and Hyman, 1999). Astrocytes, the major non-neuronal cell type in the central nervous system (CNS), rapidly release chemokines and cytokines in response to inflammatory insults. Chemokines are a family of proinflammatory cytokines that are involved in the regulation of inflammation and the immune system (Mennicken et al., 1999). Chemokines are subdivided into four groups (CXC, CC, CX3C, and XC) based on the number and position of cysteine residues in their structures. The CXC subfamily includes interleukin (IL)-8, stromal cell-derived factor (SDF)-1alpha, and interferon-induced protein (IP)-10. The CC subfamily contains the largest number of chemokines, including regulated on activation normal T expressed and secreted (RANTES), and macrophage inflammatory protein (MIP)-1α. Chemokines interact with guanine-protein-coupled receptors (GPCRs) named CXCR, CCR, or CX3R.
There is increasing evidence that interactions between astrocytes and neurons play greatly important roles in brain function. Many pathological conditions of the CNS are accompanied by astrogliosis. The mechanisms that lead to astrogliosis remain unclear (Röhl et al., 2007). It has been postulated that activated microglia play a role in astrogliosis. It has been found that activated microglia increase the number of astrocytes but do not have a hypertrophic effect on astrocytes (Röhl et al., 2007).The interaction between astrocytes and neurons appears to be important for regulation of brain energy metabolism (Escartin et al., 2006). There is evidence from in vitro and in vivo studies in rodents that glutamate and Na+ uptake in astrocytes provides an important signal for glucose regulation in the brain (Escartin et al., 2006). The disturbance of the interactions between astrocytes and neurons is related to numerous neurologic disorders, including cerebral ischemia, neurodegeneration, cerebral edema, and hepatic encephalopathy (Lin et al., 2009). The role of astrocytes in protecting neurons has been an area of significant research interest and has emerged as a potential therapeutic target in the treatment of neurodegenerative diseases.
Numerous studies have found that the expression of RANTES and MIP-1α, among other chemokines and their GPCRs, are involved in neurodegenerative diseases, especially AD (Heneka and O'Banion, 2007, Huang et al., 2000, McGeer et al., 2006, Mennicken et al., 1999). However, the effects of such chemokines are diverse, and both neurotoxic and neuroprotective effects have been described. An increase in MIP-1α expression from Parkinson's disease-producing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), has been reported in vivo (Pattarini et al., 2007). There is also a correlation between MIP-1α level and cognitive dysfunction in patients with Down's syndrome and Alzheimer-like dementia (Carta et al., 2002). Both RANTES and MIP-1α have also been shown to be produced by astrocytes in vivo after challenge with amyloid-beta peptide, which mimics the neuroinflammation and cell death observed in AD (Smits et al., 2002). In contrast, a study using cDNA microarrays found that a large number of RANTES-responsive genes in cultured neurons appeared to be involved in neuronal survival and differentiation (Tripathy et al., 2010). More recently, Tripathy et al. (2010) demonstrated that treatment with RANTES in primary cultures of cortical neurons enhanced neuronal survival, and that pre-treatment with RANTES resulted in neuroprotection against toxicity of thrombin and sodium nitroprusside. Accordingly, any novel treatment that modulates the multifunctional mediator, RANTES, in augmenting neuroprotection and diminishing neuroinflammation would be a valuable therapeutic advancement in neurodegenerative disorder therapies.
Originally identified as a T-cell specific gene (Schall et al., 1988), RANTES has been shown to be involved in the ontogenetic development of the brain. RANTES is expressed by 5-week old human brains, and induces proliferation of astrocyte cultures (Bakhiet et al., 2001). RANTES has also been shown to protect mixed cortical cultures from human immunodeficiency virus (HIV)-tat or N-methyl-d-aspartic acid (NMDA)-induced apoptosis (Eugenin et al., 2003). Pretreatment with RANTES in the murine hippocampal cell line HT22 enhances HT22 cell viability in the presence of amyloid-beta peptide, via its GPCR, GPR75, which mediates the activation of the antiapoptotic mitogen activated protein kinase (MAPK) via the phospholipase-C (PLC)/phosphatidylinositol 3-kinase (PI-3K)/Akt signaling pathway (Ignatov et al., 2006). This enhanced survival of HT22 cells is explained by the activation of Akt and MAPK, which is known to promote cell proliferation, differentiation, growth, and survival (Li et al., 2003).
In AD, a complex array of mediators in the inflammatory cascade contributes to neurodegeneration and accumulation of beta-amyloid peptide. These include RANTES, MIP-1α, IL-8, reactive oxygen species (ROS), and inducible nitric-oxide synthase (iNOS)-mediated production of nitric oxide species (NOS) (Akiyama et al., 2000). Excitotoxic stimulation of the NMDA receptor by glutamate is implicated in neurodegenerative diseases including AD (Reisberg et al., 2003).
The curry spice, curcumin, from a plant (Curcuma longa) from the Ginger family, has been proposed as a potential therapeutic for neurodegenerative diseases such as AD, for its anti-inflammatory, antioxidant, and immunomodulatory activities (Menon and Sudheer, 2007). The effects of curcumin have been demonstrated to result from its modulation of important molecular targets that include transcription factors, enzymes, cell cycle proteins, receptors, and cell surface adhesion molecules (Shishodia et al., 2005). Curcumin inhibits aggregation of beta-amyloid and promotes its disaggregation (Garcia-Alloza et al., 2007), and antagonizes several mediators of the inflammatory cascade, including activation of nuclear factor-kB, and iNOS (Weber et al., 2006). Curcumin is also a superior scavenger of nitric oxide (NO) compared to vitamin E (Chan et al., 1998). Many of curcumin's protective effects are attainable at a dose of 1 μM or less (Cole et al., 2007). It has been recently demonstrated that curcumin exhibited neuroprotective effects via activation of brain-derived neutrophic factor/TrkB-dependent MAPK and PI-3K cascades in rodent cortical neurons (Wang et al., 2010). In the present study, we sought to investigate whether curcumin can induce RANTES expression and secretion in primary cultured astrocytes without stress, and if so, whether the PI-3K and MAPK signal pathways are involved, and whether RANTES has a protective effect with regard to NMDA-treated and aged neurons. We hypothesized that curcumin would upregulate RANTES expression via PI-3K and MAPK signaling pathways, and that this would contribute to enhanced neuronal survival in NMDA toxicity, representing neurodegenerative diseases, and long-term cultures, representing aging.
Section snippets
Chemicals and reagents
NMDA, curcumin, U0126 and MTT were purchased from Sigma-Aldrich (St. Louis, MO). AG490 and RO-318220 were obtained from Calbiochem (San Diego, CA). LY294002 was purchased from Calbiochem (Cambridge, MA). All common chemicals were from Sigma (St Louis, MO, USA) unless otherwise indicated.
Animals
Pregnant female Sprague–Dawley (SD) rats and neonatal 1- to 2-day-old SD rats, obtained from the National Institute of Experimental Animal Research, Taipei, Taiwan, were used in this study for the primary
Curcumin enhances RANTES mRNA expression and protein secretion in non-stimulated cultured astrocytes
To evaluate the effects of curcumin on RANTES expression by astrocytes, we treated primary cultured astrocytes with a low dose of 1 μΜ curcumin. We did not use a high-dose of curcumin because it was likely that a high concentration would have been excitotoxic to astrocytes. Real-time PCR analysis showed that treatment with curcumin in primary cultured astrocytes resulted in a 14-fold increase in RANTES mRNA expression (Fig. 1) when compared to control (P < 0.001). ACM from cultured astrocytes
Discussion
We found that in non-stressed conditions, curcumin enhanced RANTES mRNA expression in non-stimulated cultured astrocytes, and that this effect was blocked by PI-3K and MAPK inhibitors. RANTES mRNA expression by non-stimulated astrocytes was significantly elevated at doses greater than 1 μΜ, but decreased after treatment with 5 μΜ curcumin, presumably because of excitotoxic activity of curcumin at high doses. We next investigated whether curcumin would enhance neuronal survival in NMDA toxicity
Disclosure
Muh-Shi Lin: Conception and design; acquisition of data; analysis and interpretation of data; and drafting the article
Kuo-Sheng Hung: Conception and design; critically revising the article; approve it for submission; and study supervision
Wen-Ta Chiu: Conception and design; critically revising the article; reviewed final version of manuscript and approved it for submission; and study supervision
Yu-Yo Sun: Acquisition of data and statistical analysis
Shin-Han Tsai:
Acknowledgments
This work serves as the doctoral thesis of MS Lin. The authors acknowledge support for this work by Taipei Medical University-Wan Fang Hospital (grant no. 98-wf-phd-02 and 99-wf-phd-02) and DOH99-TD-B-111-003, Center of Excellence for Clinical Trial and Research in Neuroscience, NHRI-EX99-9940NI from National Health Research Institute, Aim for the Top University Plan 99ACB11-2 from Ministry of Education, NSC 99-2323-B-038 -003 and NSC 99-2323-B-038 -003 from National Science Council, Taiwan.
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