Neural network dysfunction in bipolar depression: clues from the efficacy of lamotrigine

2009 ◽  
Vol 37 (5) ◽  
pp. 1080-1084 ◽  
Author(s):  
Charles H. Large ◽  
Elena Di Daniel ◽  
Xingbao Li ◽  
Mark S. George
Keyword(s):  
Bipolar Disorder ◽  
Valproic Acid ◽  
Protein Kinase ◽  
Glycogen Synthase ◽  
Bipolar Depression ◽  
Inhibitory Effect ◽  
Mood Stabilizers ◽  
Mitogen Activated Protein Kinase ◽  
Facilitatory Effect

One strategy to understand bipolar disorder is to study the mechanism of action of mood-stabilizing drugs, such as valproic acid and lithium. This approach has implicated a number of intracellular signalling elements, such as GSK3β (glycogen synthase kinase 3β), ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) or protein kinase C. However, lamotrigine does not seem to modulate any of these targets, which is intriguing given that its profile in the clinic differs from that of valproic acid or lithium, with greater efficacy to prevent episodes of depression than mania. The primary target of lamotrigine is the voltage-gated sodium channel, but it is unclear why inhibition of these channels might confer antidepressant efficacy. In healthy volunteers, we found that lamotrigine had a facilitatory effect on the BOLD (blood-oxygen-level-dependent) response to TMS (transcranial magnetic stimulation) of the prefrontal cortex. This effect was in contrast with an inhibitory effect of lamotrigine when TMS was applied over the motor cortex. In a follow-up study, a similar prefrontal specific facilitatory effect was observed in a larger cohort of healthy subjects, whereas valproic acid inhibited motor and prefrontal cortical TMS-induced BOLD response. In vitro, we found that lamotrigine (3–10 μM) enhanced the power of gamma frequency network oscillations induced by kainic acid in the rat hippocampus, an effect that was not observed with valproic acid (100 μM). These data suggest that lamotrigine has a positive effect on corticolimbic network function that may differentiate it from other mood stabilizers. The results are also consistent with the notion of corticolimbic network dysfunction in bipolar disorder.

scholarly journals A Redox-Sensitive Thiol in Wis1 Modulates the Fission Yeast Mitogen-Activated Protein Kinase Response to H2O2 and Is the Target of a Small Molecule

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Johanna J. Sjölander ◽  
Agata Tarczykowska ◽  
Cecilia Picazo ◽  
Itziar Cossio ◽  
Itedale Namro Redwan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Fission Yeast ◽  
Inhibitory Effect ◽  
Mitogen Activated Protein Kinase ◽  
Activation Loop ◽  
Content Type ◽  
Kinase Activation ◽  
Mitogen Activated Protein

ABSTRACT Oxidation of a highly conserved cysteine (Cys) residue located in the kinase activation loop of mitogen-activated protein kinase kinases (MAPKK) inactivates mammalian MKK6. This residue is conserved in the fission yeast Schizosaccharomyces pombe MAPKK Wis1, which belongs to the H2O2-responsive MAPK Sty1 pathway. Here, we show that H2O2 reversibly inactivates Wis1 through this residue (C458) in vitro. We found that C458 is oxidized in vivo and that serine replacement of this residue significantly enhances Wis1 activation upon addition of H2O2. The allosteric MAPKK inhibitor INR119, which binds in a pocket next to the activation loop and C458, prevented the inhibition of Wis1 by H2O2 in vitro and significantly increased Wis1 activation by low levels of H2O2 in vivo. We propose that oxidation of C458 inhibits Wis1 and that INR119 cancels out this inhibitory effect by binding close to this residue. Kinase inhibition through the oxidation of a conserved Cys residue in MKK6 (C196) is thus conserved in the S. pombe MAPKK Wis1.

scholarly journals Pioglitazone Protected against Cardiac Hypertrophy via Inhibiting AKT/GSK3βand MAPK Signaling Pathways

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Wen-Ying Wei ◽  
Zhen-Guo Ma ◽  
Si-Chi Xu ◽  
Ning Zhang ◽  
Qi-Zhu Tang
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Glycogen Synthase ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Aortic Banding ◽  
Hypertrophic Response

Peroxisome proliferator activated receptorγ(PPARγ) has been closely involved in the process of cardiovascular diseases. This study was to investigate whether pioglitazone (PIO), a PPARγagonist, could protect against pressure overload-induced cardiac hypertrophy. Mice were orally given PIO (2.5 mg/kg) from 1 week after aortic banding and continuing for 7 weeks. The morphological examination and biochemical analysis were used to evaluate the effects of PIO. Neonatal rat ventricular cardiomyocytes were also used to verify the protection of PIO against hypertrophy in vitro. The results in our study demonstrated that PIO remarkably inhibited hypertrophic response induced by aortic banding in vivo. Besides, PIO also suppressed cardiac fibrosis in vivo. PIO treatment also inhibited the activation of protein kinase B (AKT)/glycogen synthase kinase-3β(GSK3β) and mitogen-activated protein kinase (MAPK) in the heart. In addition, PIO alleviated angiotensin II-induced hypertrophic response in vitro. In conclusion, PIO could inhibit cardiac hypertrophy via attenuation of AKT/GSK3βand MAPK pathways.

Is the brain arachidonic acid cascade a common target of drugs used to manage bipolar disorder?

2009 ◽  
Vol 37 (5) ◽  
pp. 1104-1109 ◽  
Author(s):  
Richard P. Bazinet
Keyword(s):  
Bipolar Disorder ◽  
Valproic Acid ◽  
Arachidonic Acid ◽  
Rat Brain ◽  
Bipolar Depression ◽  
Chronic Administration ◽  
Mood Stabilizers ◽  
Arachidonic Acid Cascade ◽  
Brain Phospholipids ◽  
The Brain

Although lithium has been used therapeutically to treat patients with bipolar disorder for over 50 years, its mechanism of action, as well as that of other drugs used to treat bipolar disorder, is not agreed upon. In the present paper, I review studies in unanaesthetized rats using a neuropharmacological approach, combined with kinetic, biochemical and molecular biology techniques, demonstrating that chronic administration of three commonly used mood stabilizers (lithium, valproic acid and carbamazepine), at therapeutically relevant doses, selectively target the brain arachidonic acid cascade. Upon chronic administration, lithium and carbamazepine decrease the binding activity of activator protein-2 and, in turn, the transcription, translation and activity of its arachidonic acid-selective calcium-dependent phospholipase A2 gene product, whereas chronic valproic acid non-competitively inhibits long-chain acyl-CoA synthetase. The net overlapping effects of the three mood stabilizers are decreased turnover of arachidonic acid, but not of docosahexaenoic acid, in rat brain phospholipids, as well as decreased brain cyclo-oxygenase-2 and prostaglandin E2. As an extension of this theory, drugs that are thought to induce switching to mania, especially when administered during bipolar depression (fluoxetine and imipramine), up-regulate enzymes of the arachidonic acid cascade and turnover of arachidonic acid in rat brain phospholipids. Future basic and clinical studies on the arachidonic acid hypothesis of bipolar disorder are warranted.

scholarly journals Carbon Dot Nanoparticles Exert Inhibitory Effects on Human Platelets and Reduce Mortality in Mice with Acute Pulmonary Thromboembolism

Nanomaterials ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1254
Author(s):  
Tzu-Yin Lee ◽  
Thanasekaran Jayakumar ◽  
Pounraj Thanasekaran ◽  
King-Chuen Lin ◽  
Hui-Min Chen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Platelet Activation ◽  
Pulmonary Thromboembolism ◽  
Antiplatelet Agent ◽  
Antiplatelet Agents ◽  
Inhibitory Effect ◽  
Mitogen Activated Protein Kinase ◽  
Carbon Dot ◽  
Acute Pulmonary Thromboembolism

The inhibition of platelet activation is considered a potential therapeutic strategy for the treatment of arterial thrombotic diseases; therefore, maintaining platelets in their inactive state has garnered much attention. In recent years, nanoparticles have emerged as important players in modern medicine, but potential interactions between them and platelets remain to be extensively investigated. Herein, we synthesized a new type of carbon dot (CDOT) nanoparticle and investigated its potential as a new antiplatelet agent. This nanoparticle exerted a potent inhibitory effect in collagen-stimulated human platelet aggregation. Further, it did not induce cytotoxic effects, as evidenced in a lactate dehydrogenase assay, and inhibited collagen-activated protein kinase C (PKC) activation and Akt (protein kinase B), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) phosphorylation. The bleeding time, a major side-effect of using antiplatelet agents, was unaffected in CDOT-treated mice. Moreover, our CDOT could reduce mortality in mice with ADP-induced acute pulmonary thromboembolism. Overall, CDOT is effective against platelet activation in vitro via reduction of the phospholipase C/PKC cascade, consequently suppressing the activation of MAPK. Accordingly, this study affords the validation that CDOT has the potential to serve as a therapeutic agent for the treatment of arterial thromboembolic disorders

Prescribing practices of Indian psychiatrists in the treatment of bipolar disorder

2019 ◽  
Vol 53 (5) ◽  
pp. 458-469 ◽  
Author(s):  
YC Janardhan Reddy ◽  
Venugopal Jhanwar ◽  
Rajesh Nagpal ◽  
MS Reddy ◽  
Nilesh Shah ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Maintenance Treatment ◽  
Bipolar Depression ◽  
Mood Stabilizer ◽  
Self Report ◽  
Mood Stabilizers ◽  
Prescribing Practices ◽  
Term Outcome ◽  
Cross Sectional ◽  
Long Term Outcome

Objective: The treatment of bipolar disorder is challenging because of its clinical complexity and availability of multiple treatment options, none of which are ideal mood stabilizers. This survey studies prescription practices of psychiatrists in India and their adherence to guidelines. Method: In total, 500 psychiatrists randomly selected from the Indian Psychiatric Society membership directory were administered a face-to-face 22-item questionnaire pertaining to the management of bipolar disorder. Results: For acute mania, most practitioners preferred a combination of a mood stabilizer and an atypical antipsychotic to monotherapy. For acute depression, there was a preference for a combination of an antidepressant and a mood stabilizer over other alternatives. Electroconvulsive therapy was preferred in the treatment of severe episodes and to hasten the process of recovery. Approximately, 50% of psychiatrists prescribe maintenance treatment after the first bipolar episode, but maintenance therapy was rarely offered lifelong. While the majority (85%) of psychiatrists acknowledged referring to various clinical guidelines, their ultimate choice of treatment was also significantly determined by personal experience and reference to textbooks. Limitations: The study did not study actual prescriptions. Hence, the responses to queries in the survey are indirect measures from which we have tried to understand the actual practices, and of course, these are susceptible to self-report and social-desirability biases. This was a cross-sectional study; therefore, temporal changes in responses could not be considered. Conclusion: Overall, Indian psychiatrists seemed to broadly adhere to recommendations of clinical practice guidelines, but with some notable exceptions. The preference for antidepressants in treating depression is contrary to general restraint recommended by most guidelines. Therefore, the efficacy of antidepressants in treating bipolar depression in the context of Indian psychiatrists’ practice needs to be studied systematically. Not initiating maintenance treatment early in the course of illness may have serious implications on the long-term outcome of bipolar disorder.

A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade

2012 ◽  
Vol 123 (3) ◽  
pp. 147-159 ◽  
Author(s):  
Ting-Hsing Chao ◽  
Shih-Ya Tseng ◽  
Yi-Heng Li ◽  
Ping-Yen Liu ◽  
Chung-Lung Cho ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
No Production ◽  
Angiogenic Effect

Cilostazol is an anti-platelet agent with vasodilatory activity that acts by increasing intracellular concentrations of cAMP. Recent reports have suggested that cilostazol may promote angiogenesis. In the present study, we have investigated the effect of cilostazol in promoting angiogenesis and vasculogenesis in a hindlimb ischaemia model and have also examined its potential mechanism of action in vitro and in vivo. We found that cilostazol treatment significantly increased colony formation by human early EPCs (endothelial progenitor cells) through a mechanism involving the activation of cAMP/PKA (protein kinase A), PI3K (phosphoinositide 3-kinase)/Akt/eNOS (endothelial NO synthase) and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) signalling pathways. Cilostazol also enhanced proliferation, chemotaxis, NO production and vascular tube formation in HUVECs (human umbilical vein endothelial cells) through activation of multiple signalling pathways downstream of PI3K/Akt/eNOS. Cilostazol up-regulated VEGF (vascular endothelial growth factor)-A165 expression and secretion of VEGF-A in HUVECs through activation of the PI3K/Akt/eNOS pathway. In a mouse hindlimb ischaemia model, recovery of blood flow ratio (ipsilateral/contralateral) 14 days after surgery was significantly improved in cilostazol-treated mice (10 mg/kg of body weight) compared with vehicle-treated controls (0.63±0.07 and 0.43±0.05 respectively, P<0.05). Circulating CD34+ cells were also increased in cilostazol-treated mice (3614±670 compared with 2151±608 cells/ml, P<0.05). Expression of VEGF and phosphorylation of PI3K/Akt/eNOS and ERK/p38 MAPK in ischaemic muscles were significantly enhanced by cilostazol. Our data suggest that cilostazol produces a vasculo-angiogenic effect by up-regulating a broad signalling network that includes the ERK/p38 MAPK, VEGF-A165, PI3K/Akt/eNOS and cAMP/PKA pathways.

scholarly journals Cross-talk between IRAK-4 and the NADPH oxidase1

2007 ◽  
Vol 403 (3) ◽  
pp. 451-461 ◽  
Author(s):  
Sandrine Pacquelet ◽  
Jennifer L. Johnson ◽  
Beverly A. Ellis ◽  
Agnieszka A. Brzezinska ◽  
William S. Lane ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
P38 Mapk ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Free System ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Tlr4 Activation

Exposure of neutrophils to LPS (lipopolysaccharide) triggers their oxidative response. However, the relationship between the signalling downstream of TLR4 (Toll-like receptor 4) after LPS stimulation and the activation of the oxidase remains elusive. Phosphorylation of the cytosolic factor p47phox is essential for activation of the NADPH oxidase. In the present study, we examined the hypothesis that IRAK-4 (interleukin-1 receptor-associated kinase-4), the main regulatory kinase downstream of TLR4 activation, regulates the NADPH oxidase through phosphorylation of p47phox. We show that p47phox is a substrate for IRAK-4. Unlike PKC (protein kinase C), IRAK-4 phosphorylates p47phox not only at serine residues, but also at threonine residues. Target residues were identified by tandem MS, revealing a novel threonine-rich regulatory domain. We also show that p47phox is phosphorylated in granulocytes in response to LPS stimulation. LPS-dependent phosphorylation of p47phox was enhanced by the inhibition of p38 MAPK (mitogen-activated protein kinase), confirming that the kinase operates upstream of p38 MAPK. IRAK-4-phosphorylated p47phox activated the NADPH oxidase in a cell-free system, and IRAK-4 overexpression increased NADPH oxidase activity in response to LPS. We have shown that endogenous IRAK-4 interacts with p47phox and they co-localize at the plasma membrane after LPS stimulation, using immunoprecipitation assays and immunofluorescence microscopy respectively. IRAK-4 was activated in neutrophils in response to LPS stimulation. We found that Thr133, Ser288 and Thr356, targets for IRAK-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after LPS stimulation. We conclude that IRAK-4 phosphorylates p47phox and regulates NADPH oxidase activation after LPS stimulation.

Far1 and Fus3 link the mating pheromone signal transduction pathway to three G1-phase Cdc28 kinase complexes

1993 ◽  
Vol 13 (9) ◽  
pp. 5659-5669 ◽  
Author(s):  
M Tyers ◽  
B Futcher
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
G1 Phase ◽  
Transduction Pathway ◽  
Yeast Saccharomyces Cerevisiae ◽  
Alpha Factor ◽  
Mitogen Activated Protein

In the yeast Saccharomyces cerevisiae, the Cdc28 protein kinase controls commitment to cell division at Start, but no biologically relevant G1-phase substrates have been identified. We have studied the kinase complexes formed between Cdc28 and each of the G1 cyclins Cln1, Cln2, and Cln3. Each complex has a specific array of coprecipitated in vitro substrates. We identify one of these as Far1, a protein required for pheromone-induced arrest at Start. Treatment with alpha-factor induces a preferential association and/or phosphorylation of Far1 by the Cln1, Cln2, and Cln3 kinase complexes. This induced interaction depends upon the Fus3 protein kinase, a mitogen-activated protein kinase homolog that functions near the bottom of the alpha-factor signal transduction pathway. Thus, we trace a path through which a mitogen-activated protein kinase regulates a Cdc2 kinase.

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