Abstract
Using primary rat mesencephalic neuron-glia cultures as an in vitro model of Parkinson’s disease (PD), we tested the effect of curcumin, a natural dietary pigment with well-known anti-inflammation effects, on dopaminergic (DA) degeneration. Curcumin pretreatment mitigated LPS-induced DA neurotoxicity in a concentration-dependent manner and curcumin post-treatment also showed protective effect. Microglia depletion abolished this protective effect of curcumin, indicating that microglia play an important role in this effect. Supportively, observation by immunocytochemistry staining using OX-42 antibody showed that curcumin treatment inhibited LPS-induced morphological change of microglia. Besides, LPS-induced production of many proinflammatory factors and their gene expressions decreased dramatically after curcumin treatment. Results also revealed that curcumin treatment decreased LPS-induced activation of two transcription factors—nuclear factors κB (NF-κB) and activator protein-1 (AP-1). Taken together, our study implicated that curcumin might be a potential preventive and therapeutic strategy for inflammation-related neurodegenerative diseases.
Similar content being viewed by others
References
Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015
McGeer EG, Klegeris A, McGeer PL (2005) Inflammation, the complement system and the diseases of aging. Neurobiol Aging 26(Suppl 1):94–97
Bruck W, Stadelmann C (2003) Inflammation and degeneration in multiple sclerosis. Neurol Sci 24(Suppl 5):S265–S267
Barouch FC, Miller JW (2007) The role of inflammation and infection in age-related macular degeneration. Int Ophthalmol Clin 47:185–197
Hald A, Van Beek J, Lotharius J (2007) Inflammation in Parkinson’s disease: causative or epiphenomenal? Subcell Biochem 42:249–279
Wilms H, Zecca L, Rosenstiel P, Sievers J, Deuschl G, Lucius R (2007) Inflammation in Parkinson’s diseases and other neurodegenerative diseases: cause and therapeutic implications. Curr Pharm Des 13:1925–1928
McGeer PL, Itagaki S, Akiyama H, McGeer EG (1988) Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24:574–576
Brown DR (2001) Microglia and prion disease. Microsc Res Tech 54:71–80
Brown DR, Kretzschmar HA (1997) Microglia and prion disease: a review. Histol Histopathol 12:883–892
Giese A, Brown DR, Groschup MH, Feldmann C, Haist I, Kretzschmar HA (1998) Role of microglia in neuronal cell death in prion disease. Brain Pathol 8:449–457
Akiyama H, McGeer PL (1989) Microglial response to 6-hydroxydopamine-induced substantia nigra lesions. Brain Res 489:247–253
Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease. J Neurochem 81:1285–1297
Gao HM, Hong JS, Zhang W, Liu B (2003) Synergistic dopaminergic neurotoxicity of the pesticide rotenone and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson’s disease. J Neurosci 23:1228–1236
Daniel S, Limson JL, Dairam A, Watkins GM, Daya S (2004) Through metal binding, curcumin protects against lead- and cadmium-induced lipid peroxidation in rat brain homogenates and against lead-induced tissue damage in rat brain. J Inorg Biochem 98:266–275
Shih PC, Lee HH, Lai SC, Chen KM, Jiang ST, Chen YF, Shiow SJ (2007) Efficacy of curcumin therapy against Angiostrongylus cantonensis-induced eosinophilic meningitis. J Helminthol 81:1–5
Suzuki M, Nakamura T, Iyoki S, Fujiwara A, Watanabe Y, Mohri K, Isobe K, Ono K, Yano S (2005) Elucidation of anti-allergic activities of curcumin-related compounds with a special reference to their anti-oxidative activities. Biol Pharm Bull 28:1438–1443
Chan MM, Huang HI, Fenton MR, Fong D (1998) In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties. Biochem Pharmacol 55:1955–1962
Chen HW, Kuo HT, Chai CY, Ou JL, Yang RC (2007) Pretreatment of curcumin attenuates coagulopathy and renal injury in LPS-induced endotoxemia. J Endotoxin Res 13:15–23
Ferguson LR, Philpott M (2007) Cancer prevention by dietary bioactive components that target the immune response. Curr Cancer Drug Targets 7:459–464
Kuhad A, Pilkhwal S, Sharma S, Tirkey N, Chopra K (2007) Effect of curcumin on inflammation and oxidative stress in cisplatin-induced experimental nephrotoxicity. J Agric Food Chem 55:10150–10155
Sawada H, Ibi M, Kihara T, Honda K, Nakamizo T, Kanki R, Nakanishi M, Sakka N, Akaike A, Shimohama S (2002) Estradiol protects dopaminergic neurons in a MPP+ Parkinson’s disease model. Neuropharmacology 42:1056–1064
Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT (2005) 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 39:1119–1125
Rajeswari A (2006) Curcumin protects mouse brain from oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Eur Rev Med Pharmacol Sci 10:157–161
Liu B, Du L, Hong JS (2000) Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther 293:607–617
Gao HM, Hong JS, Zhang W, Liu B (2002) Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 22:782–790
Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS (2004) NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 279:1415–1421
Yang S, Yang J, Yang Z, Chen P, Fraser A, Zhang W, Pang H, Gao X, Wilson B, Hong JS, Block ML (2006) Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 and PACAP4-6 are neuroprotective through inhibition of NADPH oxidase: potent regulators of microglia-mediated oxidative stress. J Pharmacol Exp Ther 319:595–603
Shimamura T, Fujimura Y, Ukeda H (2007) Electron spin resonance analysis of superoxide anion radical scavenging activity with spin trapping agent, Diphenyl-PMPO. Anal Sci 23:1233–1235
Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318
Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98
Gao HM, Liu B, Zhang W, Hong JS (2003) Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson’s disease. Faseb J 17:1954–1956
Aloisi F (1999) The role of microglia and astrocytes in CNS immune surveillance and immunopathology. Adv Exp Med Biol 468:123–133
Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577
Gao HM, Liu B, Zhang W, Hong JS (2003) Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson’s disease. Faseb J 17:1957–1959
Jeohn GH, Kim WG, Hong JS (2000) Time dependency of the action of nitric oxide in lipopolysaccharide-interferon-gamma-induced neuronal cell death in murine primary neuron-glia co-cultures. Brain Res 880:173–177
Estevez AG, Jordan J (2002) Nitric oxide and superoxide, a deadly cocktail. Ann N Y Acad Sci 962:207–211
Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD (2002) Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia. J Neurosci 22:3484–3492
Nagatsu T, Sawada M (2005) Inflammatory process in Parkinson’s disease: role for cytokines. Curr Pharm Des 11:999–1016
Sawada M, Imamura K, Nagatsu T (2006) Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm Suppl:373–381
Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M (1999) NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med 5:554–559
O’Neill LA, Kaltschmidt C (1997) NF-kappaB: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci 20:252–258
Grilli M, Memo M (1999) Possible role of NF-kappaB and p53 in the glutamate-induced pro-apoptotic neuronal pathway. Cell Death Differ 6:22–27
Bethea JR, Castro M, Keane RW, Lee TT, Dietrich WD, Yezierski RP (1998) Traumatic spinal cord injury induces nuclear factor-kappaB activation. J Neurosci 18:3251–3260
Clemens JA, Stephenson DT, Dixon EP, Smalstig EB, Mincy RE, Rash KS, Little SP (1997) Global cerebral ischemia activates nuclear factor-kappa B prior to evidence of DNA fragmentation. Brain Res Mol Brain Res 48:187–196
Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, Weih F, Frank N, Schwaninger M, Koistinaho J (2004) Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke 35:987–991
Hunot S, Brugg B, Ricard D, Michel PP, Muriel MP, Ruberg M, Faucheux BA, Agid Y, Hirsch EC (1997) Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with Parkinson disease. Proc Natl Acad Sci USA 94:7531–7536
Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C (1997) Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc Natl Acad Sci USA 94:2642–2647
Terai K, Matsuo A, McGeer PL (1996) Enhancement of immunoreactivity for NF-kappaB in the hippocampal formation and cerebral cortex of Alzheimer’s disease. Brain Res 735:159–168
Gius D, Botero A, Shah S, Curry HA (1999) Intracellular oxidation/reduction status in the regulation of transcription factors NF-kappaB and AP-1. Toxicol Lett 106:93–106
Li G, Cui G, Tzeng NS, Wei SJ, Wang T, Block ML, Hong JS (2005) Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage. Faseb J 19:489–496
Liu B, Qin L, Yang SN, Wilson BC, Liu Y, Hong JS (2001) Femtomolar concentrations of dynorphins protect rat mesencephalic dopaminergic neurons against inflammatory damage. J Pharmacol Exp Ther 298:1133–1141
Liu Y, Qin L, Li G, Zhang W, An L, Liu B, Hong JS (2003) Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther 305:212–218
Peng GS, Li G, Tzeng NS, Chen PS, Chuang DM, Hsu YD, Yang S, Hong JS (2005) Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Res Mol Brain Res 134:162–169
Author information
Authors and Affiliations
Corresponding author
Additional information
Special issue article in honor of Dr. Ji-Sheng Han.
Rights and permissions
About this article
Cite this article
Yang, S., Zhang, D., Yang, Z. et al. Curcumin Protects Dopaminergic Neuron Against LPS Induced Neurotoxicity in Primary Rat Neuron/Glia Culture. Neurochem Res 33, 2044–2053 (2008). https://doi.org/10.1007/s11064-008-9675-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-008-9675-z