Curcumin, one of the major constituents of Curcuma longa, has been shown to inhibit depolarization-evoked glutamate release from rat prefrontocortical nerve terminals by reducing voltage-dependent Ca 2+ entry. This study showed that curcumin inhibited ionomycin-induced glutamate release and KCl-evoked FM1-43 release, suggesting that some steps after Ca 2+ entry are regulated by curcumin. Furthermore, disrupting the cytoskeleton organization using cytochalasin D abolished the inhibitory action of curcumin on ionomycin-induced glutamate release. Mitogen-activated protein kinase kinase (MEK) inhibition also prevented the inhibitory effect of curcumin on ionomycin-induced glutamate release. Western blot analyses showed that curcumin decreased the ionomycin-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and synaptic vesicle-associated protein synapsin I, the main presynaptic target of ERK. These results show that curcumin-mediated inhibition of glutamate release involves modulating downstream events by controlling synaptic vesicle recruitment and exocytosis, possibly through a decrease of MAPK/ERK activation and synapsin I phosphorylation, thereby decreasing synaptic vesicle availability for exocytosis.
References
[1]
Di Santo, R.; Costi, R.; Artico, M.; Ragno, R.; Greco, G.; Novellino, E.; Marchand, C.; Pommier, Y. Design, synthesis and biological evaluation of heteroaryl diketohexenoic and diketobutanoic acids as HIV-1 integrase inhibitors endowed with antiretroviral activity. Il Farmaco 2005, 60, 409–417.
[2]
Schaffer, M.; Schaffer, P.M.; Zidan, J.; Bar Sela, G. Curcuma as a functional food in the control of cancer and inflammation. Curr. Opin. Clin. Nutr. Metab. Care 2011, 14, 588–597.
[3]
Motterlini, R.; Foresti, R.; Bassi, R.; Green, C.J. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radic. Biol. Med 2000, 28, 1303–1312.
[4]
Thiyagarajan, M.; Sharma, S.S. Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci 2004, 74, 969–985.
[5]
Mizushina, Y.; Hirota, M.; Murakami, C.; Ishidoh, T.; Kamisuki, S.; Shimazaki, N.; Takemura, M.; Perpelescu, M.; Suzuki, M.; Yoshida, H.; et al. Some anti-chronic inflammatory compounds are DNA polymerase l-specific inhibitors. Biochem. Pharmacol 2003, 66, 1935–1944.
[6]
Park, S.Y.; Kim, H.S.; Cho, E.K.; Kwon, B.Y.; Phark, S.; Hwang, K.W.; Sul, D. Curcumin protected PC12 cells against beta-amyloid-induced toxicity through the inhibition of oxidative damage and tau hyperphosphorylation. Food Chem. Toxicol 2008, 46, 2881–2887.
[7]
Vajragupta, O.; Boonchoong, P.; Watanabe, H.; Tohda, M.; Kummasud, N.; Sumanont, Y. Manganese complexes of curcumin and its derivatives: Evaluation for the radical scavenging ability and neuroprotective activity. Free Radic. Biol. Med 2003, 35, 1632–1644.
Pan, R.; Qiu, S.; Lu, D.X.; Dong, J. Curcumin improves learning and memory ability and its neuroprotective mechanism in mice. Chin. Med. J 2008, 121, 832–839.
[10]
Ghoneim, A.I.; Abdel-Naim, A.B.; Khalifa, A.E.; El-Denshary, E.S. Protective effects of curcumin against ischaemia/reperfusion insult in rat forebrain. Pharmacol. Res 2002, 46, 273–279.
Rajeswari, A. Curcumin protects mouse brain from oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Eur. Rev. Med. Pharmacol. Sci 2006, 10, 157–161.
[13]
Zbarsky, V.; Datla, K.P.; Parkar, S.; Rai, D.K.; Aruoma, O.I.; Dexter, D.T. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease. Free Radic. Res 2005, 39, 1119–1125.
[14]
Fonnum, F. Glutamate: A neurotransmitter in mammalian brain. J. Neurochem 1984, 42, 1–11.
[15]
Greenamyre, J.T.; Porter, R.H. Anatomy and physiology of glutamate in the CNS. Neurology 1994, 44, S7–S13.
[16]
Meldrum, B.S. Glutamate as a neurotransmitter in the brain: Review of physiology and pathology. J. Nutr 2000, 130, 1007S–1015S.
[17]
Obrenovitch, T.P.; Urenjak, J. Altered glutamatergic transmission in neurological disorders: From high extracellular glutamate to excessive synaptic efficacy. Prog. Neurobiol 1997, 51, 39–87.
[18]
Raiteri, L.; Raiteri, M. Synaptosomes still viable after 25 years of superfusion. Neurochem. Res 2000, 25, 1265–1274.
[19]
Lin, T.Y.; Lu, C.W.; Wang, C.C.; Wang, Y.C.; Wang, S.J. Curcumin inhibits glutamate release in nerve terminals from rat prefrontal cortex: Possible relevance to its antidepressant mechanism. Prog. Neuropsychopharmacol. Biol. Psychiatry 2011, 35, 1785–1793.
[20]
Sihra, T.S.; Bogonez, E.; Nicholls, D.G. Localized Ca2+ entry preferentially effects protein dephosphorylation, phosphorylation, and glutamate release. J. Biol. Chem 1992, 267, 1983–1989.
[21]
Baldwin, M.L.; Rostas, J.A.; Sim, A.T. Two models of exocytosis from synaptosomes are differentially regulated by protein phosphatase types 2A and 2B. J. Neurochem 2003, 85, 1190–1199.
[22]
Greengard, P.; Valtorta, F.; Czernik, A.J.; Benfenati, F. Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 1993, 259, 780–785.
[23]
Pereira, D.B.; Carvalho, A.P.; Duarte, C.B. Non-specific effects of the MEK inhibitors PD098,059 and U0126 on glutamate release from hippocampal synaptosomes. Neuropharmacology 2002, 42, 9–19.
[24]
Lin, T.Y.; Lu, C.W.; Wang, S.J. Astaxanthin inhibits glutamate release in rat cerebral cortex nerve terminals via suppression of voltage-dependent Ca(2+) entry and mitogen-activated protein kinase signaling pathway. J. Agric. Food Chem 2010, 58, 8271–8278.
[25]
Alessi, D.R.; Cuenda, A.; Cohen, P.; Dudley, D.T.; Saltiel, A.R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol. Chem 1995, 270, 27489–27494.
[26]
Terrian, D.M.; Ways, D.K. Persistent enhancement of sustained calcium-dependent glutamate release by phorbol esters: Role of calmodulin-independent serine/threonine phosphorylation and actin disassembly. J. Neurochem 1995, 64, 181–190.
[27]
Cooper, J.A. Effects of cytochalasin and phalloidin on actin. J. Cell Biol 1987, 105, 1473–1478.
[28]
Zhang, L.; Ruehr, M.L.; Dorman, R.V. Arachidonic acid and oleoylacetylglycerol induce a synergistic facilitation of Ca21-dependent glutamate release from hippocampal mossy fiber nerve endings. J. Neurochem 1996, 66, 177–185.
[29]
Grewal, S.; York, R.; Stork, P. Extracellular-signal-regulated kinase signaling in neurons. Curr. Opin. Neurobiol 1999, 9, 544–553.
[30]
Chi, P.; Greengard, P.; Pyan, T.A. Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies. Neuron 2003, 38, 69–78.
[31]
Jovabovic, J.N.; Benfenati, F.; Siow, Y.L.; Sihra, T.S.; Sanghera, J.S.; Pelech, S.L.; Greengard, P.; Czernicj, A.J. Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions. Proc. Natl. Acad. Sci. USA 1996, 93, 3679–3683.
[32]
Chi, P.; Greengard, P.; Pyan, T.A. Synapsin dispersion and reclustering during synaptic activity. Nat. Neurosci 2001, 4, 1187–1193.
[33]
Hilfiker, F.E. Vesicle pools and synapsins: New insights into old enigmas. Brain Cell Biol 2006, 35, 107–115.
[34]
Jovanovic, J.N.; Czernik, A.J.; Fienberg, A.A.; Greengard, P.; Sihra, T.S. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat. Neurosci 2000, 3, 323–329.
[35]
Wang, R.; Li, Y.B.; Li, Y.H.; Xu, Y.; Wu, H.L.; Li, X.J. Curcumin protects against glutamate excitotoxicity in rat cerebral cortical neurons by increasing brain-derived neurotrophic factor level and activating TrkB. Brain Res 2008, 1210, 84–91.
[36]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem 1976, 72, 248–254.
[37]
Dunkley, P.R.; Jarvie, P.E.; Heath, J.W.; Kidd, G.J.; Rostas, J.A. A rapid method for isolation of synaptosomes on Percoll gradients. Brain Res 1986, 372, 115–129.
[38]
Dunkley, P.R.; Jarvie, P.E.; Robinson, P.J. A rapid Percoll gradient procedure for preparation of synaptosomes. Nat. Protoc 2008, 3, 1718–1728.
[39]
Nicholls, D.G. The glutamatergic nerve terminal. Eur. J. Biochem 1993, 212, 613–631.
