Action of β-amyloid peptide1-40 on IHVA and its modulation by ginkgolide B

( views:77, downloads:0 )
CHEN Lei()
LIU Chang-Jin()
TANG Ming()
LI Ai()
HU Xin-Wu()
Zhou Ying()
Jürgen Hescheler()
Journal Title:
Volume 58, Issue 01, 2006
Key Word:
hippocampus;β-amyloid peptide;voltage-dependent calcium channel current;ginkgolide B;patch-clamp technique

Abstract: Whole-cell patch clamp recording was used to investigate the action of β-amyloid peptide1-40 (Aβ1-40) on high voltageactivated calcium channel current (IHVA) in acutely isolated hippocampal CA1 pyramidal neurons in rats and observe its modulation by ginkgolide B (GB). Drug was applied by extracellular bath or adding in the pipette solution, and its effect was determined by comparing the amplitude of IHVA before and after the drug application. Bath application of aggregated Aβ1-40 at concentrations of 0.01 ~30 μmol/L increased the amplitude of IHVA in a dose-dependent manner by (5.43+3.01)% (n=8, P>0.05), (10.49+4.13)% (n=11, P>0.05), (40.69+8.01)% (n=16, P<0.01), (58.32+4.85)% (n=12, P<0.01), and (75.45+5.81)% (n=6, P<0.01), respectively, but had no effect on the I-V curve of IHVA; fresh Aβ1-40 almost had no effect on IHVA (n=5, P>0.05). L-type calcium channel antagonist nifedipine abolished the increase of IHVA by Aβ1-40. The increase of IHVA by Aβ1-40 (1.0 μmol/L) was enhanced to (66.19+5.74)% (P<0.05) by 8-Br-cAMP (membrane permeable analogue of cAMP) and to (73.21 +6.90)% (P<0.05) by forskolin, an adenylyl cyclase (AC) agonist, and reduced to (20.08+2.18)% (P<0.05) by H-89, cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) antagonist. GB effectively inhibited the increase of IHVA by Aβ1-40. The results indicate that Aβ1-40 leads to an intracellular calcium overload by increasing IHVA via AC-cAMP-PKA. This may be one of the mechanisms for its neurotoxicity. GB can prevent neurons from neurotoxicity by inhibiting abnormal calcium influx caused by Aβ1-40.

  • [1]Stéphan A,Laroche S,Davis S.Generation of aggregated β-amyloid in the rat hippocampus impairs synaptic transmission and plasticity and causes memory deficits.J Neurosci 2001; 21(15):5703-5714.
  • [2]Trubetskaya VV,Stepanichev MY,Onufriev MV,Lazareva NA,Markevich VA,Gulyaeva NV.Administration of aggregated betaamyloid peptide induces changes in long-term potentiation in the hippocampus in vivo.Neurosci Behav Physiol 2003; 33(2):95-98.
  • [3]Walsh DM,Klyubin I,Fadeeva JV,Cullen WK,Anwyl R,Wolfe MS,Rowan M J,Selkoe DJ.Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo.Nature 2002; 416:535-539.
  • [4]Rovira C,Arbez N,Mariani J.Aβ (25-35) and Aβ (1-40) act on different calcium channels in CA 1 hippocampal neurons.Biochem Biophys Res Commun 2002; 296:1317-1321.
  • [5]MacManus A,Ramsden M,Murray M,Henderson Z,Pearson HA,Campbell VA.Enhancement of 45 Ca2+ influx and voltage-dependent Ca2+ channel activity by β-amyloid-(1-40) in rat cortical synaptosomes and cultured cortical neurons,modulation by the proinflammatory cytokine interleukin-1 β.J Biol Chem 2000; 275(7):4713-4718.
  • [6]Whitson JS,Appel SH.Neurotoxicity of Aβ-amyloid protein in vitro is not altered by calcium channels blockade.Neurobiol Aging 1995; 16(1):5-10.
  • [7]Bastianetto S,Quirion R.EGb 761 is a neuroprotective agent against beta-amyloid toxicity.Cell Mol Bioll (Noisy-le-grand)2002; 48(6):693-697.
  • [8]Wu XF (吴雪丰),Wang QJ,Lou FC.Protective effect of ginkgolides on rat focal brain ischemia.J China Pharm Univ (中国药科大学学报) 2001; 32(2):141-145 (Chinese,English abstract).
  • [9]Chen L,Liu CJ,Tang M,Li A,HU XW,Du YM,Shen JJ,Lu YL,Heschler J.Action of aluminum on high voltage-dependent calcium current and its modulation by ginkgolide B.Acta Pharmacol Sin 2005; 26(5):539-545.
  • [10]He LM,Chen LY,Lou XL,Qu AL,Zhou Z,Xu T.Evaluation of β-amyloid peptide 25-35 on calcium homeostasis in cultured rat dorsal root ganglion neurons.Brain Res 2002; 939(1-2):65-75.
  • [11]Liu H (刘辉),Chen JP,Tian SY,Gao QW,Han Y.Intrahippocampal injection of β amyloid 1-40 induces neurotoxicity in rats in vivo.Chin J Neurol (中华神经科杂志) 2000; 33(3):150-152 (Chinese,English abstract).
  • [12]Harkany T,Abraham I,Konya C,Nyakas C,Zarandi M,Penke B,Luiten PG.Mechanisms of beta-amyloid neurotoxicity:perspective of pharmacotheray.Rev Neurosci 2000; 11(4):329-382.
  • [13]Kavalali ET,Hwang KS,Plummer MR.cAMP-dependent enhancement of digydropyridein-sensitive calcium channels availability in hippocampal neurons.J Neurosci 1997; 17(4):5334-5348.
  • [14]Ekinci FJ,Malik KU,Shea TB.Activation of the L voltagesensitive calcium channel by mitogen-activated protein (MAP)kinase following exposure of neuronal cells to beta-amyloid.MAP kinase mediates beta-amyloid-induced neurodegeneration.J Biol Chem 1999; 274(42):30322-30327.
  • [15]Ahlemeyer B,Krieglstein J.Neuroprotective effects of Ginkgo biloba constituents.Cell Mol Life Sci 2003; 60(9):1779-1792.
  • [16]Nin YH,Yang XY,Bao WS.Protective effects of Ginkgo biloba extract on cultured rat cardiomyocytes damaged by H2O2.Acta Pharmcol Sin 1999; 20:635-638.
  • [17]Lenoir M,Pedruzzi E,Rais S,Drieu K,Perianin A.Sensitization of human neutrophil defense activities through activation of platelet-activating factor receptors by ginkgolide B,a bioactive component of the Ginkgo biloba extract EGB 761.Biochem Pharmacol 2002; 63(7):1241-1249.
  • [18]Bastianetto S,Zheng WH,Quirion R.The Ginkgo biloba extract(EGb 761) protects and rescues hippocampal cells nitric oxideinduced toxicity:involvement of its flavonoid constituents and protein kinase C.J Neurochem 2000; 74(6):2268-2277.
WanfangData CO.,Ltd All Rights Reserved
About WanfangData | Contact US
Healthcare Department, Fuxing Road NO.15, Haidian District Beijing, 100038 P.R.China
Tel:+86-010-58882616 Fax:+86-010-58882615