Modulation of Ion Channels in Rat Neurons by the Constituents of Hypericum Perforatum

Despite almost forty years of widespread use of antidepressant drugs, their mode of action is still unknown. Hyperforin, a phloroglucinol derivative, is a major pharmacologically and therapeutically active constituent of Hypericum perforatum extract that is widely used as an herbal antidepressant drug. However, the mechanism or mechanisms of action of these naturally abundant, non-toxic extracts remain unclear. Enzymatically isolated patch-clamped rat central and peripheral neurons exposed to rapid changes in the composition of external medium (concentration clamp) were used in our experiments to investigate the modulation of the various voltage- and ligand-gated channels by hyperforin, as well as by other constituents of Hypericum perforatum. At nanomolar concentrations, hyperforin induced significant inhibition of various ion channels. In the case of P-type Ca²⁺ channels, we established that hyperforin acts via interaction with calmodulin or through calmodulin-activated pathways involving at least one second messenger. The results presented here indicate that multiple mechanisms and extract constituents may be involved in the antidepressant action of Hypericum extracts, and that they could also possess neuroprotective and analgesic effects.

References

• 1 Arborelius L, Owens M J, Plotsky P M, C. B. Nemeroff CB. The role of corticotropin-releasing factor in depression and anxiety disorders. J.  Endocrinol.. 1999;  160 1-12
• 2 Barritt G J, Gregory R B. An evaluation of strategies available for the identification of GTP-binding proteins required in intracellular signalling pathways.  Cell Signal. 1997;  9 207-218
• 3 Bean B P. Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence.  Nature. 1989;  340 153-156
• 4 Brorson J R, Manzolillo P A, Gibbons S J, Miller R J. AMPA receptor desensitization predicts the selective vulnerability of cerebellar Purkinje cells to excitotoxicity.  J Neurosci. 1995;  15 4515-4524
• 5 Brorson J R, Manzolillo P A,. Miller RJ. Ca²⁺ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells.  J Neurosci. 1994;  14 187-197
• 6 Burnstock G. A unifying purinergic hypothesis for the initiation of pain.  Lancet. 1996;  347 1604-1605
• 7 Carter A J. The importance of voltage-dependent sodium channels in cerebral ischaemia.  Amino Acids. 1998;  14 159-169
• 8 Chatterjee S, Filippov V, Lishko P, Maximyuk O, Noldner M, Krishtal O. Hyperforin attenuates various ionic conductance mechanisms in the isolated hippocampal neurons of rat.  Life Sci. 1999;  65 2395-2405
• 9 Chatterjee S S, Bhattacharya S K, Wonnemann M, Singer A, Muller W E. Hyperforin as a possible antidepressant component of Hypericum extracts.  Life Sci. 1998a;  63 499-510
• 10 Chatterjee S S, Noldner M, Koch E, Erdelmeier C. Antidepressant activity of Hypericum perforatum and hyperforin: the neglected possibility.  Pharmacopsychiatry.. 1998b;  31 ((Suppl. 1)) 7-15
• 11 Chizhmakov I V, Kiskin N I, Krishtal O A. Two types of steady-state desensitization of N-methyl-D-aspartate receptor in isolated hippocampal neurones of rat.  J Physiol (Lond.). 1992;  448 453-472
• 12 Choi D W. Excitotoxic cell death.  J Neurobiol. 1992;  23 1261-1276
• 13 Choi D W. Calcium: still center-stage in hypoxic-ischemic neuronal death.  Trends Neurosci. 1995;  18 58-60
• 14 Ding Y, Cesare P, Drew L, Nikitaki D, Wood J N. ATP, P2X receptors and pain pathways.  J Auton Nerv Syst. 2000;  81 289-294
• 15 Doble A. Excitatory amino acid receptors and neurodegeneration.  Therapie. 1995;  50 319-337
• 16 el-Mallakh R S. The Na,K-ATPase hypothesis for manic-depression. II. The mechanism of action of lithium.  Med Hypotheses. 1983;  12 269-282
• 17 Elmslie K S, Zhou W, Jones S W. LHRH and GTP-gamma-S modify calcium current activation in bullfrog sympathetic neurons.  Neuron. 1990;  5 75-80
• 18 Evans R J, Lewis C, Virginio C, Lundstrom K, Buell G, Surprenant A, North R A. Ionic permeability of, and divalent cation effects on, two ATP-gated cation channels (P2X receptors) expressed in mammalian cells.  J Physiol (Lond). 1996;  497 413-422
• 19 Fisunov A, Lozovaya N, Tsintsadze T, Chatterjee S, Noldner M, Krishtal O. Hyperforin modulates gating of P-type Ca2+ current in cerebellar Purkinje neurons.  Pflugers Arch. 2000;  440 427-434
• 20 Grassi F, Lux H D. Voltage-dependent GABA-induced modulation of calcium currents in chick sensory neurons.  Neurosci Lett. 1989;  105 113-119
• 21 Iino M, Ozawa S, Tsuzuki K. Permeation of calcium through excitatory amino acid receptor channels in cultured rat hippocampal neurones.  J Physiol (Lond). 1990;  424 151-165
• 22 James P, Vorherr T, Carafoli E. Calmodulin-binding domains: just two faced or multi-faceted?.  Trends Biochem Sci. 1995;  20 38-42
• 23 Jurado L A, Chockalingam P S, Jarrett H W. Apocalmodulin.  Physiol Rev. 1999;  79 661-682
• 24 Kasai H, Aosaki T. Modulation of Ca-channel current by an adenosine analog mediated by a GTP-binding protein in chick sensory neurons.  Pflugers Arch. 1989;  414 145-149
• 25 Kopanitsa M V, Panchenko V A, Magura E I, Lishko P V, Krishtal O A. Capsaicin blocks Ca²⁺ channels in isolated rat trigeminal and hippocampal neurones.  Neuroreport. 1995;  6 2338-2340
• 26 Lee A, Wong S T, Gallagher D, Li B, Storm D R, Scheuer T, Catterall W A. Ca²⁺/calmodulin binds to and modulates P/Q-type calcium channels.  Nature. 1999;  399 155-159
• 27 Lin C T, Dedman J R, Brinkley BR,Means A R. Localization of calmodulin in rat cerebellum by immunoelectron microscopy.  J Cell Biol. 1980;  85 473-480
• 28 Linde K, Ramirez G, Mulrow C D, Pauls A, Weidenhammer W, Melchart D. St John’s wort for depression - an overview and meta-analysis of randomised clinical trials.  BMJ. 1996;  313 253-258
• 29 Maubach K A, Rupniak N M, Kramer M S, Hill R G. Novel strategies for pharmacotherapy of depression.  Curr Opin Chem Biol. 1999;  3 481-488
• 30 McEwen B S, Sapolsky R M. Stress and cognitive function.  Curr Opin Neurobiol. 1995;  5 205-216
• 31 Means A R, VanBerkum M F, Bagchi I, Lu K P, Rasmussen C D. Regulatory functions of calmodulin.  Pharmacol Ther. 1991;  50 255-270
• 32 Mintz I M, Bean B P. GABA_B receptor inhibition of P-type Ca²⁺ channels in central neurons.  Neuron. 1993;  10 889-898
• 33 Mintz I M, Venema M J, Swiderek K M, Lee T D, Bean B P, Adams M E. P-type calcium channels blocked by the spider toxin ω-Aga-IVA.  Nature. 1992;  355 827-829
• 34 Müller W E, Singer A, Wonneman M, Hafner U, Rolli M, Schäfer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of Hypericum extract.  Pharmacopsychiatry. 1998;  31 ((Suppl. 1)) 16-21
• 35 Nahrstedt A, Butterweck V. Biologically active and other chemical constituents of the herb of Hypericum perforatum L.  Pharmacopsychiatry. 1997;  30 ((Suppl. 2)) 129-134
• 36 Nixon R A, Saito K I, Grynspan F, Griffin W R, Katayama S, Honda T, Mohan P S, Shea T B, Beermann M. Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer’s disease.  Ann N Y Acad Sci. 1994;  74 77-91
• 37 Ortolano G A, Swonger A K, Kaiser E A, Hammond R P. A calcium hypothesis of antidepressant action.  Med Hypotheses. 1983;  10 207-221
• 38 Panchenko V A, Krishtal O A, Tegtmeier F, Tsyndrenko A Y. R56865 as Ca²⁺-channel blocker in Purkinje neurons of rat: comparison with flunarizine and nimodipine.  Neuroscience. 1993;  54 587-594
• 39 Patel S, Morris S A, Adkins C E, O’Beirne G, Taylor C W. Ca²⁺-independent inhibition of inositol trisphosphate receptors by calmodulin: redistribution of calmodulin as a possible means of regulating Ca²⁺ mobilization.  Proc Natl Acad Sci USA. 1997;  94 11 627-11 632
• 40 Regan L J. Voltage-dependent calcium currents in Purkinje cells from rat cerebellar vermis.  J Neurosci. 1991;  11 2259-2269
• 41 Scolnick P. Antidepressants for the new millenium.  Eur J Pharmacol. 1999;  375 31-40
• 42 Siggins G R, Gruol D, Aldenhoff J, Pittman Q. Electrophysiological actions of corticotropin-releasing factor in the central nervous system.  Fed Proc. 1985;  44 237-242
• 43 Sprang S R. G protein mechanisms: insights from structural analysis.  Annu Rev Biochem. 1997;  66 639-678
• 44 Urenjak J, Obrenovitch T P. Pharmacological modulation of voltage-gated Na⁺ channels: a rational and effective strategy against ischemic brain damage.  Pharmacol Rev. 1996;  48 21-67
• 45 Virginio C, North R A, Surprenant A. Calcium permeability and block at homomeric and heteromeric P2X2 and P2X3 receptors, and P2X receptors in rat nodose neurones.  J Physiol (Lond). 1998;  510 27-35
• 46 Vogel H J. The Merck Frosst Award Lecture 1994. Calmodulin: a versatile calcium mediator protein.  Biochem Cell Biol. 1994;  72 357-376
• 47 Weiss J H, Sensi S L. Ca²⁺-Zn²⁺ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration.  Trends Neurosci. 2000;  23 365-371
• 48 Yamaki T, Hidaka H. Ca²⁺-independent stimulation of cyclic GMP-dependent protein kinase by calmodulin.  Biochem Biophys Res Commun. 1980;  94 727-733
• 49 Yuan T, Vogel H J, Sutherland C, Walsh M P. Characterization of the Ca²⁺ -dependent and -independent interactions between calmodulin and its binding domain of inducible nitric oxide synthase.  FEBS Lett. 1998;  431 210-214
• 50 Yuan T, Walsh M P, Sutherland C, Fabian H, Vogel H J. Calcium-dependent and -independent interactions of the calmodulin-binding domain of cyclic nucleotide phosphodiesterase with calmodulin.  Biochemistry. 1999;  38 1446-1455