Table I.
Evidence implicating protein kinase C (PKC) in the pathophysiology and treatment of bipolar disorder
| Study (y) | PKC-related evidence |
|---|---|
| Cultures, animals, humans | |
| Bitran et al.[32] (1990) | Chronic (but not acute) lithium treatment attenuates agonist- and phorbol ester- and phorbol-12- myristate-13-acetate-mediated stimulation of the Na+/H+ antiporter activity in HL-60 cells, suggesting an impairment of PKC activity |
| Giambalvo[33,34] (1992) | Increased particulate PKC activity in synaptosomes incubated with amphetamine 1–10 μmol/L |
| Friedman et al.[35] (1993) | Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in manic subjects. Also, serotonin-elicited platelet PKC translocation was enhanced in subjects with mania; lithium treatment resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin, which normalized with lithium treatment Increased membrane/cytosol PKC partitioning in platelets from manic subjects; normalized with lithium treatment |
| Gnegy et al.[36] (1993) | Amphetamine resulted in increased phosphorylation of the neural-specific calmodulin-binding protein GAP-43 (involved in neurotransmitter release) in purified synaptic plasma membrane of female rat striatum |
| Manji et al.[37] (1993) | Chronic lithium treatment for 5 wk resulted in a 30% reduction in [3H]PDbu-binding in the subiculum and in CA1 regions of the rat hippocampus as measured by quantitative autoradiography; immunoblot analysis of hippocampal PKC with isozyme-specific antibodies showed a 30% reduction in membrane-associated PKC α |
| Chen et al.[28] (1994) | Chronic exposure (6–7 d) of rat C6 glioma cells to ‘therapeutic’ concentrations (0.6 mmol/L) of valproate resulted in decreased PKC activity in both membrane and cytosolic fractions and increased the cytosol/membrane ratio of PKC activity; Western blot analysis revealed isozyme-selective decreases in the levels of PKC α and ε in both the membrane and cytosolic fractions after long-term valproate exposure |
| Manji et al.[38] (1996) | Chronic myoinositol administration attenuated lithium-induced decreased in PKC α, and levels of MARCKS and GAP-43 in rat hippocampus and frontal cortex |
| Cervo et al.[39] (1997) | In a balanced CPP in rats, PKC was found to be involved in the mechanism underlying consolidation of CPP |
| Birnbaum et al.[40] (2004) | High levels of PKC activity in prefrontal cortex, as seen during stress exposure, markedly impair behavioural and electrophysiological measures of working memory in rat; chronic treatment with lithium or valproate for 6 wk abolished exogenous activation of PKC signalling |
| Wang and Friedman[41] (1989) | Chronic treatment with lithium in rats resulted in a significantly decreased PKC stimulation-induced release with phorbol esters in cortex, hypothalamus and hippocampus; exposure of brain slices obtained from lithium-treated rats to depolarization and PKC stimulation resulted in marked reductions in translocation of PKC from the cytoplasma to the membrane compartment |
| Lenox et al.[42] (1992) | Immunoblot analysis revealed that chronic (but not acute) lithium treatment results in reduced in vivo levels of MARCKS in rat hippocampus – effects that were not immediately reversed following lithium discontinuation |
| Friedman et al.[35] (1993) | Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in 12 medication-free manic subjects. Also, serotonin-elicited platelet PKC translocation was enhanced in subjects with mania; lithium treatment resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin, which normalized with lithium treatment Increased membrane/cytosol PKC partitioning in platelets from manic subjects; normalized with lithium treatment |
| Steketee[27,43] (1993, 1994) | Intra-A10 administration of a PKC inhibitor, H7, inhibited cocaine-induced behavioural sensitization in rats |
| Wang and Friedman[44] (1996) | Brain membrane-associated PKC activity was higher in bipolar subjects vs controls; PKC isozymes in cortical homogenates showed that cytosolic α and membrane-associated γ PKC isozymes were elevated in cortices of subjects with bipolar affective disorder |
| Watson and Lenox[45] (1996) | Chronic lithium treatment produces a dose- and time-dependent downregulation of MARCKS protein in immortalized rat hippocampus cells |
| Browman et al.[29] (1998) | Behavioural and tissue studies indicate that injection of a PKC inhibitor, Ro31-8220, into the nucleus acumbens in rats attenuates the acute response to amphetamine |
| Wang et al.[46] (1999) | In basal state, manic subjects had higher membrane PKC activity than depressed subjects and controls; ratio of membrane to cytosol PKC activity was significantly higher in manic subjects compared with controls, depressed or schizophrenic subjects; stimulation of platelets with serotonin in vitro resulted in greater membrane-to-cytosol ratio in manic subjects compared with other groups |
| Hahn and Friedman[47] (1999) | Long-term lithium treatment significantly reduced PKC activation in rat brains, as measured by the translocation of cytoplasmic PKC to the membrane component, or by quantitative binding of the PKC ligand, PDBu. Alterations in platelet PKC were shown in bipolar patients during the manic states of the illness. Compared with patients with major depressive disorder, schizophrenia or healthy controls, PKC activity was significantly increased in manic patients and was suppressed following mood-stabilizer treatment |
| Soares et al.[48] (2000) | Lithium-treated euthymic bipolar patients had lower levels of cytosolic PKC α compared with healthy subjects |
| Wang et al.[49] (2001) | In slices of rat brain cortex, chronic (but not acute) lithium treatment reduced phorbol-induced PKC translocation from cytosol to membrane without affecting basal membrane or cytosolic PKC activity; immunoblotting revealed that chronic lithium treatment reduced cytosolic PKC α and δ |
| Wang and Friedman[50] (2001) | Increased association of RACK1 with membrane γPKC and ζPKC was increased under basal conditions in bipolar disorder relative to control brains; stimulation with phorbol esters increased the amount of RACK1 that co-immunoprecipitated with α, β, γ, δ, ε PKC isozymes in frontal cortex of subjects with bipolar disorder |
| Einat et al.[21] (2007) | The PKC inhibitor tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity, and normalized amphetamine-induced increase in visits to the centre of an open field (representing risk-taking behaviour); tamoxifen attenuated amphetamine- induced phosphorylation of GAP-43 |
| Kurita et al.[51] (2007) | Sodium valproate at therapeutic concentrations inhibited PKC in human astrocytoma cells |
| Kantor and Gnegy[30] (1998) | PKC inhibitors blocked amphetamine-mediated dopamine release in rat striatal slice |
| Pandey et al.[52] (2008) | PKC βI and PKC βII, but not PKC α or δ, were significantly decreased in both membrane as well as cytosol fractions of platelets obtained from medication-free patients with bipolar disorder compared with healthy controls; pharmacotherapy significantly increased PKC activity not PKC isozymes |
| Clinical trials | |
| Kulkarni et al.[53] (2006) | In a 28-d, three-arm, double-blind, lithium and/or valproate add-on study, the PKC inhibitor tamoxifen 40 mg/d (n = 5) was found to have antimanic effects superior to placebo (n = 4) |
| Bebchuk et al.[54] (2000) | Preliminary data from a single-blind, open-label, add-on (some patients were on no other medications) study suggest that tamoxifen may have efficacy in the treatment of acute mania |
| Zarate et al.[55] (2007) | In a 3-wk, double-blind, placebo-controlled study (n = 16), tamoxifen (up to 140 mg/d) was superior to placebo in acute mania; lorazepam up to 2 mg/d was permitted for the first 10 d of the blinded phase. Significant improvement was seen as early as d 5 in YMRS scores; no significant improvement was seen in MADRS scores |
| Yildiz et al.[56] (2008) | In a 3-wk, double-blind, placebo-controlled study (n = 66), tamoxifen (up to 80 mg/d) was superior to placebo in acute mania; lorazepam up to 5 mg/day was permitted for the entire duration of the study. Significant improvement in YMRS was reported at wk 3; significant improvement was also seen in CGI and PANSS total and positive subscale scores; no significant improvement was seen with HAMD-17 and MADRS scores; caregiver permitted as well as individualized food preferences and enriched recreational activities |
CGI = Clinical Global Impression scale; CPP = conditioned place preference; GAP-43 = growth-associated protein-43; HAMD-17 = 17-Item Hamilton Depression Rating Scale; MADRS = Montgomery-Åsberg Depression Rating Scale; MARCKS = myristoylated alanine-rich PKC substrate; PANSS = Positive and Negative Syndrome Scale; PDBu = [3H]phorbol 12,13-dibutyrate; RACK1 = receptor for activated C kinase-1; YMRS = Young Mania Rating Scale.