Protein Kinase C Inhibitors

Rationale for Use and Potential in the Treatment of Bipolar Disorder

Abstract

Bipolar disorder is one of the most severely debilitating of all medical illnesses. For a large number of patients, outcomes are quite poor. The illness results in tremendous suffering for patients and their families and commonly impairs functioning and workplace productivity. Risks of increased morbidity and mortality, unfortunately, are frequent occurrences as well.

Until recently, little has been known about the specific molecular and cellular underpinnings of bipolar disorder. Such knowledge is crucial for the prospect of developing specific targeted therapies that are more effective and that have a more rapid onset of action than currently available treatments. Exciting recent data suggest that regulation of certain signalling pathways may be involved in the aetiology of bipolar disorder and that these pathways may be profitably targeted to treat the disorder. In particular, mania is associated with overactive protein kinase C (PKC) intracellular signalling, and recent genome-wide association studies of bipolar disorder have implicated an enzyme that reduces the activation of PKC. Importantly, the current mainstays in the treatment of mania, lithium (a monovalent cation) and valproate (a small fatty acid) indirectly inhibit PKC. In addition, recent clinical studies with the relatively selective PKC inhibitor tamoxifen add support to the relevance of the PKC target in bipolar disorder.

Overall, a growing body of work both on a preclinical and clinical level indicates that PKC signalling may play an important role in the pathophysiology and treatment of bipolar disorder. The development of CNS-penetrant PKC inhibitors may have considerable benefit for this devastating illness.

This is a preview of subscription content, access via your institution.

Table I
Fig. 1
Fig. 2
Fig. 3
Table II

References

  1. 1.

    Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 2007; 64(5): 543–52

    PubMed  Article  Google Scholar 

  2. 2.

    Gitlin M. Treatment-resistant bipolar disorder. Mol Psychiatry 2006; 11(3): 227–40

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Manji HK, Zarate CA. Molecular and cellular mechanisms underlying mood stabilization in bipolar disorder: implications for the development of improved therapeutics. Mol Psychiatry 2002; 7Suppl. 1: S1–7

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Zarate Jr CA, Singh J, Manji HK. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 2006; 59(11): 1006–20

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Casabona G. Intracellular signal modulation: a pivotal role for protein kinase C. Prog Neuropsychopharmacol Biol Psychiatry 1997; 21(3): 407–25

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Tanaka C, Nishizuka Y. The protein kinase C family for neuronal signaling. Annu Rev Neurosci 1994; 17: 551–67

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Serova M, Ghoul A, Benhadji KA, et al. Preclinical and clinical development of novel agents that target the protein kinase C family. Semin Oncol 2006; 33(4): 466–78

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Toker A. Signaling through protein kinase C. Front Biosci 1998; 3: D1134–47

    PubMed  CAS  Google Scholar 

  9. 9.

    Mellor H, Parker PJ. The extended protein kinase C super-family. Biochem J 1998; 332 (Pt 2): 281–92

    PubMed  CAS  Google Scholar 

  10. 10.

    Takai Y, Kishimoto A, Inoue M, et al. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues I: purification and characterization of an active enzyme from bovine cerebellum. J Biol Chem 1977; 252(21): 7603–9

    PubMed  CAS  Google Scholar 

  11. 11.

    Huang KP, Nakabayashi H, Huang FL. Isozymic forms of rat brain Ca2+-activated and phospholipid-dependent protein kinase. Proc Natl Acad Sci U S A 1986; 83(22): 8535–9

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Mackay HJ, Twelves CJ. Targeting the protein kinase C family: are we there yet? Natl Rev Cancer 2007; 7(7): 554–62

    Article  CAS  Google Scholar 

  13. 13.

    Churchill E, Budas G, Vallentin A, et al. PKC Isozymes in chronic cardiac disease: possible therapeutic targets? Annu Rev Pharmacol Toxicol 2008; 48: 569–99

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Dempsey EC, Cool CD, Littler CM. Lung disease and PKCs. Pharmacol Res 2007; 55(6): 545–59

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Aksoy E, Goldman M, Willems F. Protein kinase C epsilon: a new target to control inflammation and immune-mediated disorders. Int J Biochem Cell Biol 2004; 36(2): 183–8

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Das Evcimen N, King GL. The role of protein kinase C activation and the vascular complications of diabetes. Pharmacol Res 2007; 55(6): 498–510

    PubMed  Article  Google Scholar 

  17. 17.

    Calabrese B, Halpain S. Essential role for the PKC target MARCKS in maintaining dendritic spine morphology. Neuron 2005; 48(1): 77–90

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Craske ML, Fivaz M, Batada NN, et al. Spines and neurite branches function as geometric attractors that enhance protein kinase C action. J Cell Biol 2005; 170(7): 1147–58

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Hongpaisan J, Alkon DL. A structural basis for enhancement of long-term associative memory in single dendritic spines regulated by PKC. Proc Natl Acad Sci U S A 2007; 104(49): 19571–6

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Manji HK, Lenox RH. Ziskind-Somerfeld Research Award. Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol Psychiatry 1999; 46(10): 1328–51

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Einat H, Yuan P, Szabo ST, et al. Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology 2007; 55(3–4): 123–31

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Finlay JM, Zigmond MJ, Abercrombie ED. Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam. Neuroscience 1995; 64: 619–28

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Birnbaum SG, Yuan PX, Wang M, et al. Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 2004; 306: 882–4

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Runyan JD, Moore AN, Dash PK. A role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory. Learn Mem 2005; 12: 103–10

    PubMed  Article  Google Scholar 

  25. 25.

    Arnsten AFT, Manji HK. Mania: a rational neurobiology. Future Neurol 2008; 3(2): 125–31

    Article  Google Scholar 

  26. 26.

    Coyle JT, Duman RS. Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 2003; 38(2): 157–60

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Steketee JD. Injection of the protein kinase inhibitor H7 into the A10 dopamine region blocks the acute responses to cocaine: behavioral and in vivo microdialysis studies. Neuropharmacology 1993; 32(12): 1289–97

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Chen G, Manji HK, Hawver DB, et al. Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. J Neurochem 1994; 63(6): 2361–4

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Browman KE, Kantor L, Richardson S, et al. Injection of the protein kinase C inhibitor Ro31-8220 into the nucleus accumbens attenuates the acute response to amphetamine: tissue and behavioral studies. Brain Res 1998; 814(1–2): 112–9

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Kantor L, Gnegy ME. Protein kinase C inhibitors block amphetamine-mediated dopamine release in rat striatal slices. J Pharmacol Exp Ther 1998; 284(2): 592–8

    PubMed  CAS  Google Scholar 

  31. 31.

    Jope RS. Anti-bipolar therapy: mechanism of action of lithium. Mol Psychiatry 1999; 4(2): 117–28

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Bitran JA, Potter WZ, Manji HK, et al. Chronic Li+ attenuates agonist- and phorbol ester-mediated Na+/H+ antiporter activity in HL-60 cells. Eur J Pharmacol 1990; 188(4–5): 193–202

    PubMed  CAS  Google Scholar 

  33. 33.

    Giambalvo CT. Protein kinase C and dopamine transport: 2. Effects of amphetamine in vitro. Neuropharmacology 1992; 31(12): 1211–22

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Giambalvo CT. Protein kinase C and dopamine transport: 1. Effects of amphetamine in vivo. Neuropharmacology 1992; 31(12): 1201–10

    CAS  Google Scholar 

  35. 35.

    Friedman E, Hoau-Yan-Wang, Levinson D, et al. Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry 1993; 33(7): 520–5

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Gnegy ME, Hong P, Ferrell ST. Phosphorylation of neuromodulin in rat striatum after acute and repeated, intermittent amphetamine. Brain Res Mol Brain Res 1993; 20(4): 289–98

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Manji HK, Etcheberrigaray R, Chen G, et al. Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the alpha isozyme. J Neurochem 1993; 61(6): 2303–10

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Manji HK, Bersudsky Y, Chen G, et al. Modulation of protein kinase C isozymes and substrates by lithium: the role of myo-inositol. Neuropsychopharmacology 1996; 15(4): 370–81

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Cervo L, Mukherjee S, Bertaglia A, et al. Protein kinases A and C are involved in the mechanisms underlying consolidation of cocaine place conditioning. Brain Res 1997; 775(1–2): 30–6

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Birnbaum SG, Yuan PX, Wang M, et al. Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 2004; 306(5697): 882–4

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Wang HY, Friedman E. Lithium inhibition of protein kinase C activation-induced serotonin release. Psychopharmacology (Berl) 1989; 99(2): 213–8

    Article  CAS  Google Scholar 

  42. 42.

    Lenox RH, Watson DG, Patel J, et al. Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res 1992; 570(1–2): 333–40

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Steketee JD. Intra-A10 injection of H7 blocks the development of sensitization to cocaine. Neuroreport 1994; 6(1): 69–72

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Wang HY, Friedman E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol Psychiatry 1996; 40(7): 568–75

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Watson DG, Lenox RH. Chronic lithium-induced down-regulation of MARCKS in immortalized hippocampal cells: potentiation by muscarinic receptor activation. J Neurochem 1996; 67(2): 767–77

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Wang HY, Markowitz P, Levinson D, et al. Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients. J Psychiatr Res 1999; 33(2): 171–9

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Hahn CG, Friedman E. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord 1999; 1(2): 81–6

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Soares JC, Chen G, Dippold CS, et al. Concurrent measures of protein kinase C and phosphoinositides in lithium-treated bipolar patients and healthy individuals: a preliminary study. Psychiatry Res 2000; 95(2): 109–18

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Wang HY, Johnson GP, Friedman E. Lithium treatment inhibits protein kinase C translocation in rat brain cortex. Psychopharmacology (Berl) 2001; 158(1): 80–6

    Article  CAS  Google Scholar 

  50. 50.

    Wang H, Friedman E. Increased association of brain protein kinase C with the receptor for activated C kinase-1 (RACK1) in bipolar affective disorder. Biol Psychiatry 2001; 50(5): 364–70

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Kurita M, Nishino S, Ohtomo K, et al. Sodium valproate at therapeutic concentrations changes Ca2+ response accompanied with its weak inhibition of protein kinase C in human astrocytoma cells. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31(3): 600–4

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Pandey GN, Ren X, Dwivedi Y, et al. Decreased protein kinase C (PKC) in platelets of pediatric bipolar patients: effect of treatment with mood stabilizing drugs. J Psychiatr Res 2008; 42(2): 106–16

    PubMed  Article  Google Scholar 

  53. 53.

    Kulkarni J, Garland KA, Scaffidi A, et al. A pilot study of hormone modulation as a new treatment for mania in women with bipolar affective disorder. Psychoneuroendocrinology 2006; 31(4): 543–7

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Bebchuk JM, Arfken CL, Dolan-Manji S, et al. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch Gen Psychiatry 2000; 57(1): 95–7

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Zarate Jr CA, Singh JB, Carlson PJ, et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord 2007; 9(6): 561–70

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Yildiz A, Guleryuz S, Ankerst DP, et al. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry 2008; 65(3): 255–63

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Seelan RS, Khalyfa A, Lakshmanan J, et al. Deciphering the lithium transcriptome: microarray profiling of lithium-modulated gene expression in human neuronal cells. Neuroscience 2008; 151(4): 1184–97

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Lenox RH, et al. Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain? J Clin Psychiatry 1996; 57Suppl. 13:23–31

    PubMed  CAS  Google Scholar 

  59. 59.

    Iwata S, Hewlett GH, Gnegy ME. Amphetamine increases the phosphorylation of neuromodulin and synapsin I in rat striatal synaptosomes. Synapse 1997; 26(3): 281–91

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Iwata SI, Hewlett GH, Ferrell ST, et al. Enhanced dopamine release and phosphorylation of synapsin I and neuromodulin in striatal synaptosomes after repeated amphetamine. J Pharmacol Exp Ther 1997; 283(3): 1445–52

    PubMed  CAS  Google Scholar 

  61. 61.

    Johnson DN. Effect of diazepam on food consumption in rats. Psychopharmacology (Berl) 1978; 56(1): 111–2

    Article  CAS  Google Scholar 

  62. 62.

    Papp M, Willner P, Muscat R. An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology (Berl) 1991; 104(2): 255–9

    Article  CAS  Google Scholar 

  63. 63.

    Aujla H, Beninger RJ. Intra-accumbens protein kinase C inhibitor NPC 15437 blocks amphetamine-produced conditioned place preference in rats. Behav Brain Res 2003; 147(1–2): 41–8

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Baum AE, Akula N, Cabanero M, et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 2008; 13(2): 197–207

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Wellcome Trust Case Control Consortium. Genomewide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447(7145): 661–78

    Article  Google Scholar 

  66. 66.

    Jordan VC. Molecular mechanisms of antiestrogen action in breast cancer. Breast Cancer Res Treat 1994; 31(1): 41–52

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Horgan K, Cooke E, Hallett MB, et al. Inhibition of protein kinase C mediated signal transduction by tamoxifen: importance for antitumour activity. Biochem Pharmacol 1986; 35(24): 4463–5

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Couldwell WT, Weiss MH, DeGiorgio CM, et al. Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen. Neurosurgery 1993; 32(3): 485–9

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Tang P, Roldan G, Brasher PM, et al. A phase II study of carboplatin and chronic high-dose tamoxifen in patients with recurrent malignant glioma. J Neurooncol 2006; 78(3): 311–6

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994

    Google Scholar 

  71. 71.

    Young RC, Biggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429–35

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Goldstein JA. Danazol and the rapid-cycling patient. J Clin Psychiatry 1986; 47(3): 153–4

    PubMed  CAS  Google Scholar 

  73. 73.

    Lopez M, Lelliott CJ, Tovar S, et al. Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes 2006; 55(5): 1327–36

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Cathcart CK, Jones SE, Pumroy CS, et al. Clinical recognition and management of depression in node negative breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 1993; 27(3): 277–81

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med 1988; 109(3): 219–28

    PubMed  CAS  Google Scholar 

  76. 76.

    Costanzo ES, Lutgendorf SK, Mattes ML, et al. Adjusting to life after treatment: distress and quality of life following treatment for breast cancer. Br J Cancer 2007; 97(12): 1625–31

    PubMed  Article  CAS  Google Scholar 

  77. 77.

    Gould TD, Quiroz JA, Singh J, et al. Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers. Mol Psychiatry 2004; 9(8): 734–55

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Catapano L, Manji H. Kinases as drug targets in the treatment of bipolar disorder. Drug Development Today 2008; 13: 295–302

    Article  CAS  Google Scholar 

  79. 79.

    Podar K, Raab MS, Chauhan D, et al. The therapeutic role of targeting protein kinase C in solid and hematologic malignancies. Expert Opin Investig Drugs 2007; 16(10): 1693–707

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Martinez A, Castro A, Medina M. Glycogen synthase kinase 3 (GSK-3) and its inhibitors. Hoboken (NJ): John Wiley & Sons, Inc., 2006

    Google Scholar 

  81. 81.

    Tohen M. Clinical trials in bipolar mania: implications in study design and drug development. Arch Gen Psychiatry 2008; 65(3): 252–3

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the support of the Intramural Research Program of the National Institute of Mental Heath, the Stanley Medical Research Institute. The authors have no conflicts of interest that are directly relevant to the content of this review. Husseini K. Manji is currently employed by Johnson & Johnson Pharmaceuticals Research and Development.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Carlos A. Zarate.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zarate, C.A., Manji, H.K. Protein Kinase C Inhibitors. CNS Drugs 23, 569–582 (2009). https://doi.org/10.2165/00023210-200923070-00003

Download citation

Keywords

  • Tamoxifen
  • Bipolar Disorder
  • Valproate
  • Conditioned Place Preference
  • Young Mania Rate Scale