Abstract
Aim:
To investigate the effects of bilobalide on the activation of NF-κB, and apoptosis of dopaminergic neurons induced by 6-hydroxydopamine (6-OHDA).
Methods:
A rat model of Parkinson's disease was produced with a unilateral infusion of 6-OHDA (8 μg) into the substantia nigra par compact. Bilobalide was administered 5, 10, and 20 mg/kg (ip) once a day for 7 d, starting 6 d prior to the 6-OHDA infusion. The rats were subjected to locomotor activity and rotational behavior testing 2 or 3 weeks after the 6-OHDA infusion. The expressions of tyrosine hydroxylase (TH) and NF-κB p65 were examined by immunofluorescence. The loss of dopaminergic neurons was detected by Nissl's staining. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling was used to identify apoptosis.
Results:
The behavioral changes due to 6-OHDA were significantly restored by bilobalide pretreatment. Bilobalide inhibited the 6-OHDA-induced loss of TH-positive neurons, decreased the activation of NF-κB, and protected dopaminergic neurons from apoptosis remarkably.
Conclusion:
NF-κB activation contributes to the 6-OHDA-induced loss of dopaminergic neurons, and the inhibition of the NF-κB pathway is likely to be involved in the neuroprotective effect of bilobalide.
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Chinta SJ, Andersen JK . Dopaminergic neurons. Int J Biochem Cell Biol 2005; 37: 942–6.
Ziv I, Barzilai A, Offen D, Nardi N, Melamed E . Nigrostriatal neuronal death in Parkinson's disease—a passive or an active genetically-controlled process? J Neural Transm Suppl 1997; 49: 69–76.
Barzilai A, Melamed E, Shirvan A . Is there a rationale for neuroprotection against dopamine toxicity in Parkinson's disease? Cell Mol Neurobiol 2001; 21: 215–35.
Qin ZH, Wang Y, Nakai M, Chase TN . Nuclear factor-κB contributes to excitotoxin-induced apoptosis in rat striatum. Mol Pharmacol 1998; 53: 33–42.
Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN . Nuclear factor κB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J Neurosci 1999; 19: 4023–33.
Liang ZQ, Li YL, Zhao XL, Han R, Wang XX, Wang Y, et al. NF-κB contributes to 6-hydroxydopamine-induced apoptosis of nigral dopaminergic neurons through p53. Brain Res 2007; 1145: 190–203.
Panet H, Barzilai A, Daily D, Melamed E, Offen D . Activation of nuclear transcription factor κB (NF-κB) is essential for dopam-ine-induced apoptosis in PC12 cells. J Neurochem 2001; 77: 391–8.
DeFeudis FV, Drieu K . Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Current Drug Targets 2000; 1: 25–58.
Ahlemeyer B, Krieglstein J . Neuroprotective effects of Ginkgo biloba extract. Cell Mol Life Sci 2003; 60: 1779–92.
Ahlemeyer B, Krieglstein J . Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease. Pharmacopsychiatry 2003; 36 ( Suppl 1): S8–14.
Grundman M, Grundman M, Delaney P . Antioxidant strategies for Alzheimer's disease. Proc Nutr Soc 2002; 61: 191–202.
DeFeudis FV . Ginkgo biloba extract (EGb761): Pharmacological activities and clinical applications. Paris: Elsevier; 1991.
Zhang J, Fu S, Liu S, Mao T, Xiu R . The therapeutic effect of Ginkgo biloba extract in SHR rats and its possible mechanisms based on cerebral microvascular flow and vasomotion. Clin Hemorheol Microcirc 2000; 23: 133–8.
Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y . EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease. FASEB J 2007; 21: 2400–8.
Brunetti L, Orlando G, Menghini L, Ferrante C, Chiavaroli A . Ginkgo biloba leaf extract reverses amyloid beta-peptide-induced isoprostane production in rat brain in vitro. Planta Med 2006; 72: 1296–9.
Pardon MC, Joubert C, Perez-Diaz F, Christen Y, Launay JM, Cohen-Salmon C . In vivo regulation of cerebral monoamine oxidase activity in senescent controls and chronically stressed mice by long-term treatment with Ginkgo biloba extract (EGb 761). Mech Ageing Dev 2000; 113: 157–68.
Wu WR, Zhu XZ . Involvement of monoamine oxidase inhibition in neuroprotective and neurorestorative effects of Ginkgo biloba extract against MPTP-induced nigrostriatal dopaminer-gic toxicity in C57 mice. Life Sci 1999; 65: 157–64.
Ahmad M, Saleem S, Ahmad AS, Yousuf S, Ansari MA, Khan MB, et al. Ginkgo biloba affords dose-dependent protection against 6-hydroxydopamine-induced parkinsonism in rats: neurobehavioural, neurochemical and immunohistochemical evidences. J Neurochem 2005; 93: 94–104.
Cao F, Sun S, Tong ET . Experimental study on inhibition of neuronal toxical effect of levodopa by Ginkgo biloba extract on Parkinson's disease in rats. J Huazhong Univ Sci Tech Med Sci 2003; 23: 151–3.
Otani M, Chatterjee SS, Gabard B, Kreutzberg GW . Effect of an extract of Ginkgo biloba on triethyltin-induced cerebral edema. Acta Neuropathol 1986; 69: 54–65.
Chandrasekaran K, Mehrabian Z, Spinnewyn B, Drieu K, Fiskum G . Neuroprotective effects of bilobalide, a component of the Ginkgo biloba extract (EGb 761), in gerbil global brain ischemia. Brain Res 2001; 922: 282–92.
Chandrasekaran K, Mehrabian Z, Spinnewyn B, Chinopoulos C, Drieu K, Fiskum G . Bilobalide, a component of the Ginkgo biloba extract (EGb 761), protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity. Cell Mol Biol 2002; 48: 663–9.
Chandrasekaran K, Mehrabian Z, Spinnewyn B, Chinopoulos C, Drieu K, Fiskum G . Neuroprotective effects of bilobalide, a component of Ginkgo biloba extract (EGb 761) in global brain ischemia and in excitotoxicity-induced neuronal death. Pharmacopsychiatry 2003; 36 ( Suppl 1): S89–94.
Ahlemeyer B, Krieglstein J . Neuroprotective effects of Ginkgo biloba extract. Cell Mol Life Sci 2003; 60: 1779–92.
Zhou LJ, Zhu XZ . Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide. J Pharmacol Exp Ther 2000; 293: 982–8.
Weichel O, Hilgert M, Chatterjee SS, Lehr M, Klein J . Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phos-pholipase A2 activation and phospholipid breakdown in rat hippocampus. Naunyn Schmiedebergs Arch Pharmacol 1999; 360: 609–15.
Carman LS, Gage FH, Shults CW . Partial lesion of the substantia nigra: relation between extent of lesion and rotational behavior. Brain Res 1991; 553: 275–83.
West MJ, Slomianka L, Gundersen HJ . Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 1991; 231: 482–97.
Sarikcioglu SB, Oner G, Tercan E . Antioxidant effect of EGb 761 on hydrogen peroxide-induced lipoperoxidation of G-6-PD deficient erythrocytes. Phytother Res 2004; 8: 837–40.
Biddlestone L, Corbett AD, Dolan S . Oral administration of Ginkgo biloba extract, EGb-761 inhibits thermal hyperalgesia in rodent models of inflammatory and post-surgical pain. Br J Pharmacol 2007; 151: 285–91.
Han Y . Ginkgo terpene component has an anti-inflammatory effect on Candida albicans-caused arthritic inflammation. Int Immunopharmacol 2005; 5: 1049–56.
Sharma HS, Drieu K, Westman J . Antioxidant compounds EGb-761 and BN-52021 attenuate brain edema formation and hemeoxygenase expression following hyperthermic brain injury in the rat. Acta Neurochir Suppl 2003; 86: 313–9.
Smith JV, Luo Y . Elevation of oxidative free radicals in Alzheimer's disease models can be attenuated by Ginkgo biloba extract EGb 761. J Alzheimers Dis 2003; 5: 287–300.
Wettstein A . Cholinesterase inhibitors and Gingko extracts—are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months' duration. Phytomedicine 2000; 6: 393–401.
Mdzinarishvili A, Kiewert C, Kumar V, Hillert M, Klein J . Bilobalide prevents ischemia-induced edema formation in vitro and in vivo. Neuroscience 2007; 144: 217–22.
Janssens D, Delaive E, Remacle J, Michiels C . Protection by bilobalide of the ischaemia-induced alterations of the mitochon-drial respiratory activity. Fundam Clin Pharmacol 2000; 14: 193–201.
Bouaziz N, Redon M, Quere L, Remacle J, Michiels C . Mito-chondrial respiratory chain as a new target for anti-ischemic molecules. Eur J Pharmacol 2002; 441: 35–45.
Ahlemeyer B, Möwes A, Krieglstein J . Inhibition of serum deprivation- and staurosporine-induced neuronal apoptosis by Ginkgo biloba extract and some of its constituents. Eur J Pharmacol 1999; 367: 423–30.
Klein J, Chatterjee SS, Loffelholz K . Phospholipid breakdown and choline release under hypoxic conditions: inhibition by bilobalide, a constituent of Ginkgo biloba. Brain Res 1997; 755: 347–50.
Hunot S, Brugg B, Ricard D, Michel PP, Muriel MP, Ruberg M, et al. Nuclear translocation of NF-κB is increased in dopaminergic neurons of patients with Parkinson disease. Proc Natl Acad Sci USA 1997; 94: 7531–6.
Soos J, Engelhardt JI, Siklos L, Havas L, Majtenyi K . The expression of PARP, NF-κB and parvalbumin is increased in Parkinson's disease. Neuroreport 2004; 15: 1715–8.
Tarabin V, Schwaninger M . The role of NF-κB in 6-hydroxydopamine- and TNFα-induced apoptosis of PC12 cells. Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 563–9.
Lou Y, Hattori A, Munoz J, Qin ZH, Roth GS . Intrastriatal dopamine injection induces apoptosis through oxidation-involved activation of transcription factors AP-1 and NF-κB in rats. Mol Pharmacol 1999; 56: 254–64.
Panet H, Barzilai A, Daily D, Melamed E, Offen D . Activation of nuclear transcription factor κB (NF-κB) is essential for dopam-ine-induced apoptosis in PC12 cells. J Neurochem 2001; 77: 391–8.
Park SH, Choi WS, Yoon SY, Ahn YS, Oh YJ . Activation of NF-κB is involved in 6-hydroxydopamine- but not MPP+-induced dopaminergic neuronal cell death: its potential role as a survival determinant. Biochem Biophys Res Commun 2004; 322: 727–33.
Dehmer T, Heneka MT, Sastre M, Dichgans J . Protection by pioglitazone in the model of Parkinson's disease correlates with IκBα induction and block of NF-κB and iNOS activation. J Neurochem 2004; 88: 494–501.
Levites Y, Youdim BH, Maor G, Mandel S . Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-κB) activation and cell death by tea extracts in neuronal cultures. Biochem Pharmacol 2002; 63: 21–9.
Youdim MB, Grunblatt E, Mandel S . The pivotal role of iron in NF-κB activation and nigrostriatal dopaminergic neurodegeneration. Prospects for neuroprotection in Parkinson's disease with iron chelators. Ann N Y Acad Sci 1999; 890: 7–25.
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Project supported by grants from the National Natural Science Foundation of China (No 30672452), the Natural Science Foundation of Jiangsu Province (No BK2006051), and the Natural Science Foundation of Jiangsu High Education Bureau (No 05KJB310117).
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Li, Ly., Zhao, Xl., Fei, Xf. et al. Bilobalide inhibits 6-OHDA-induced activation of NF-κB and loss of dopaminergic neurons in rat substantia nigra. Acta Pharmacol Sin 29, 539–547 (2008). https://doi.org/10.1111/j.1745-7254.2008.00787.x
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DOI: https://doi.org/10.1111/j.1745-7254.2008.00787.x
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