Although these responses are very rapid, they also bring about more sOrder Lamictal Dispersible online US changes via regulation of gene transcription. One pathway gaining increasing recent attention in adult mammalian neurobiology is the Wnt signaling pathway. Wnts are a group of glycoproteins active in development, but now known to play important roles in the mature brain. Binding of Wnts to the Wnt receptor (WntR) activates an intermediary protein, Disheveled, which regulates a glycogen synthase kinase (GSKSfi). GSK-3P exerts many cellular effects; it regulates cytoskeletal proteins, including tau, and also plays an important role in determining cell survival/cell death decisions. GSK-3P has recently been identified as a target for Li+’s actions. GSK-3P also regulates phosphorylation of fi-catenin, a protein that when dephosphorylated acts as a transcription factor at lymphoid enhancer factor (LEF) sites. CREB, cAMP response element binding protein; R^ and Rs, extracellular GPCRs coupled to stimulation or inhibition of adenylyl cyclases (ACs), respectively; Rq/11, GPCR coupled to activation of phospholipase C (PLC); MARCKS, myristoylated alanine-rich C kinase substrate, a protein associated with several neuroplastic events. Source: Modified and reproduced with permission from Ref. 302.
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To date, there have only been a limited number of studies directly examining PKC in bipolar disorder. Although undoubtedly an over-simplification, parti-culate (or membrane) PKC is sometimes seen as the more active form of PKC, and thus examining the sub-cellular partitioning of this enzyme can be used as an index of the degree of activation. Friedman investigated PKC activity and PKC translocation in response to serotonin in platelets obtained from bipolar disorder patients before and during lithium treatment, and reported that the ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Wang and Friedman measured PKC isozyme levels, activity, and translocation in post-mortem brain tissue from bipolar disorder patients, and reported increased PKC activity and translocation in bipolar disorder brains compared with controls, effects which were accompanied by elevated levels of selected PKC isozymes in the cortices of the bipolar disorder patients.
Accumulated evidence from several investigative groups has clearly demonstrated that lithium, at therapeutically relevant concentrations, exerts significant effects on the PKC signaling cascade. Data suggest that chronic lithium attenuates PKC activity, and downregulate the expression of PKC isozymes a and s in the frontal cortex and hippocampus of patients with bipolar disorder. Chronic lithium has also been demonstrated to dramatically reduce the hippocampal levels of a major PKC substrate, myristoylated alanine-rich C kinase substrate (MARCKS), which has a role in regulating long-term neuroplastic events.
Although these effects of lithium on PKC isozymes and MARCKS are striking, a major problem inherent in neuropharmacologic research is the difficulty in attributing therapeutic relevance to any observed biochemical finding. It is thus noteworthy that the structurally dissimilar antimanic agent valproate (VPA) produces very similar effects as lithium on PKC a and s isozymes and MARCKS protein. Lithium and VPA appear to bring about their effects on the PKC signaling pathway by distinct mechanisms, consistent with clinical observations that some patients show preferential response to one or other of the agents, and that one often observes additive therapeutic effects in patients when the two agents are co-administered.
In view of the pivotal role of the PKC signaling pathway in the regulation of neuronal excitability, neurotransmitter release, and long-term synaptic events, we postulated that the attenuation of PKC activity may play a role in the antimanic effects of lithium and VPA. To test this idea, we piloted a study in seven bipolar manic patients treated with tamoxifen, a non-steroidal antiestrogen known to be a PKC inhibitor at higher concentrations; tamoxifen was found to possess antimanic efficacy in this study. Due to the small sample size, however, these study results have to be considered preliminary. In view of the preliminary data suggesting the involvement of the PKC signaling system in the pathophysiology of bipolar disorder, these results suggest that PKC inhibitors may be very useful agents in the treatment of mania, and warrant larger double-blind, placebo-controlled studies of tamoxifen and of novel selective PKC inhibitors.
Glycogen Synthase Kinase
The enzyme GSK-3 is a crucial kinase that functions as an intermediary in numerous intracellular signaling pathways, and recent research suggests the importance of this enzyme in bipolar disorder research. GSK-3 — a constitutively active and a highly conserved enzyme in evolution — is found in two nearly identical isoforms
Recent Advances in the Neurobiology of Bipolar Disorder 129
(slight variations) in mammals, the a and (3 isoforms. This enzyme was first discovered (and named) based upon its ability to phosphorylate and thereby inactivate the enzyme glucogen synthase, which leads to a decrease in the synthesis of glycogen. GSK-3 is unique among kinases because it is generally constitutively active, and therefore most intracellular signals to GSK-3 inactivate this enzyme. Signals deactivating GSK-3 arise from insulin stimulation, numerous growth factors [e. g., phophoinositide (PI) 3-kinase], and developmental signals. A number of endogenous growth factors (e. g., nerve growth factor and BDNF) use the PI 3-kinase signaling cascade as a major effector system. Thus, growth factors may bring about many of their neurotrophic and neuroprotective effects at least partly by inhibiting GSK-3. GSK-3 phosphorylates — and thereby inactivates — many transcription factors, and modulates the function of cytoskeletal proteins such as the Alzheimer’s disease protein tau (a previous name for GSK-3 was tau kinase). Inhibition of GSK-3 thus results in the release of this inhibition and the activation generic-celexa-citalopram-hydrobromide-10-20mg-pharmacy “>of multiple cellular targets.
Growing evidence suggests that GSK-3 plays an important role in regulating neuroplasticity and cellular resilience. Studies have suggested that changes in GSK-3 mediated mitogen-activated protein (MAP)-IB (a cytoskeletal protein) phos-phorylation are associated with the loss and/or unbundling of sOrder Lamictal Dispersible online US axonal micro-tubules. Furthermore, GSK-3(3 inhibition results in generic-paxil-pexep-paroxetine-10-20-30-40mg/cheapest-generic-paxil-pexep-paroxetine-10-20-30-40mg-online-review “>the accumulation of synapsin I, a protein involved in synaptic vesicle docking and release of growth cone-like areas.
In addition to its putative role in regulating synapse formation and axonal growth, there is considerable excitement in the field regarding the role of GSK-3 in regulating cell death (apoptosis) in mature neuronal tissue, and regarding the development of GSK-3 inhibitors as novel therapeutic agents for bipolar disorder and classical neurodegenerative diseases. Although it was initially reported in Lamictal Dispersible that GSK-3 activity was required for (3-amyloid-induced neurotoxicity in primary hippocampal neurons, this observation was not fully appreciated until further recent studies were done. These recent studies have demonstrated that GSK-3 may regulate cell death beyond its role in (3-amyloid-induced toxicity. In one study, GSK-3 over-expression induced apoptosis in cultured cells, which was prevented by dominant negative mutants. Furthermore, the expression of FRAT-1, a protein that inhibits GSK-3, also rescued primary sympathetic neurons from PI 3-kinase inhibition-induced cell death.
Fatty Acids and Bipolar Disorder