Bipolar research paper

Bipolar research paper

We would like to show you a description here but the site won’t allow blogger.com more Jul 17,  · Sometimes it seems like coming up with a good idea for a paper is more challenging than the actual research and writing. Fortunately, there are plenty of great places to find inspiration and the following list contains just a few ideas to help get you started. Finding a solid topic is one of the most important steps when writing any type of paper Bipolar disorder (BD) is one of the most severe of the major mental illnesses, and recent estimates place its lifetime prevalence (including BD spectrum) at about % in the U.S. population ().Several pathophysiological findings in BD associated with loss of neurotrophic effects and consequent cellular injury have been widely described in different targets regulated by a wide range of

Try out PMC Labs and tell us what you think, bipolar research paper. Learn More. a Experimental Therapeutics, Mood and Anxiety Disorders Research Program, bipolar research paper, NIMH-NIH, Department of Health and Human Services, bipolar research paper, Bethesda, MD. Lithium has been and continues to be the mainstay of bipolar disorder BD pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention.

Lithium is also the definitive proof-of-concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders.

Enhancing neuroprotection which directly involves neurotrophic effects is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long-term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. Bipolar disorder BD is one of the most severe of the major mental illnesses, and recent estimates place its lifetime prevalence including BD spectrum at about 4.

population 1. Several pathophysiological findings in BD associated with loss of neurotrophic effects and consequent cellular injury have been widely described in different targets regulated by a wide range of specific mechanisms [reviewed in 23 ]. The mood stabilizer lithium has been the standard pharmacological treatment for BD for over 60 years. Its introduction led to an immediate improvement in outcome for many patients suffering from this illness whose treatment options had, until that point, been quite bleak.

Lithium was found be effective in treating acute manic and depressive episodes, as well as in reducing the recurrence of mood episodes and minimizing the risk of suicidal behaviors 45.

Lithium is the lightest of all metals, with a density only half that of water. These bipolar research paper have been widely associated with the activation bipolar research paper neurotrophic pathways involved in the pathophysiology of BD. Briefly, enhancing neuroprotection which directly involves neurotrophic effects is a therapeutic strategy intended to slow or halt the progression of neuronal loss 8 or pharmacological interventions that produce long-term benefits by favorably influencing underlying etiology or pathogenesis, and thereby preventing onset of disease or clinical decline 9, bipolar research paper.

In other words, a neurotrophic therapy is expected to act on the pathophysiological mechanisms underlying the clinical presentation of the disease, thus altering its natural course and outcome, bipolar research paper. It is also logical to assume that a neurotrophic therapy capable of concomitantly preventing and reversing dysfunctional cellular and molecular effects in diverse targets may represent the standard treatment for the illness.

Lithium would act by limiting or reversing disease progression directly associated with the activation of neurotrophic effects; these have been widely described in studies evaluating targets such as neurotransmitters, second messengers, signaling pathways, hormones, neurotrophic factors, ion channels, organelles, genes, and others. It is important to emphasize that lithium has already demonstrated diverse molecular effects reversing well-described pathophysiological changes such as increased oxidative stress, programmed cell death apoptosisinflammation, environmental stress, glial dysfunction, neurotrophic factor dysfunction, excitotoxicity, mitochondrial and endoplasmic reticulum ER dysfunction, and disruption in epigenetic mechanisms.

All these changes strongly suggest molecular imbalances that trigger the cellular stress, atrophy, and death described over the course of BD. Yucel et al. showed increased bilateral hippocampal volume after 2—4 years of lithium treatment in previously drug-naïve BD subjects Also, a recent study using high-resolution volumetric MRI showed a direct therapeutic relevance of lithium neurotrophic effects in BD.

It was observed that only lithium-responders showed increases in gray matter in the prefrontal areas Bipolar research paper instance, Öngur and colleagues 14 described a significant decrease Changes in brain volume and structure, as well as altered energy parameters in specific brain areas related to mood regulation, have been described in neuroimaging studies evaluating individuals with BD. In addition, MRS studies showed regional abnormalities of N-acetyl-aspartate NAAcholine, and myoinositol in BD, especially in the prefrontal and anterior cingulate cortices, hippocampus, and basal ganglia [reviewed in 18 ].

These markers are related to the regulation of neurotrophic pathways described elsewhere and responded to lithium treatment see next sectionmaking them potential state-dependent markers.

For instance, BD subjects showed abnormally high myoinositol levels in diverse brain areas during manic and depressive episodes; such levels were not observed during euthymia, in healthy controls, or after lithium treatment in BD subjects [reviewed in 19 ]. Notably, bipolar research paper, while BD is not considered a classic neurodegenerative disorder based on the absence of gliosis a marker of neurdegenerationit has bipolar research paper patterns of glial loss possibly associated with the decreased NAA and elevated choline levels described above in BD subjects 1820 Furthermore, NAA synthesis occurs in the mitochondria, which are implicated in the altered cell energy regulation e.

The most replicated finding from structural neuroimaging studies is an association between lithium treatment and increased gray matter volume in brain areas implicated in emotional processing and cognitive control, such as the anterior cingulate gyrus, amygdala, and hippocampus, which suggests that lithium has considerable neurotrophic effects 24bipolar research paper, One study found that patients with BD who were not treated with lithium had significantly reduced left anterior cingulate volumes compared to healthy volunteers and lithium-treated patients Additional magnetic resonance imaging MRI studies examined the gray and white matter volumes of 12 untreated and 17 lithium-treated patients with BD and 46 healthy controls and found that total gray matter volumes were significantly increased in lithium-treated relative to untreated patients and healthy controls Another study found bipolar research paper gray matter density was significantly greater in patients with BD relative to healthy controls in diffuse cortical regions Increased NAA levels were observed after four weeks of lithium treatment in different brain areas 3031and decreased choline and myoinositol were reported after chronic lithium treatment in individuals with BD [ 32reviewed in 19 ].

Interest in GSK-3 as a target for BD drug development arose from findings that it is key to a number of central functions, such as glycogen synthesis, gene transcription, bipolar research paper, synaptic plasticity, apoptosis cell deathcellular structure and resilience, and the circadian cycle 33 ; notably, all of these functions are significantly implicated in the pathophysiology of severe recurrent mood disorders.

Indeed, Benedetti and colleagues 34 bipolar research paper that a polymorphism in the GSK-3 gene was associated with earlier onset of Bipolar research paper. Activation of GSK-3β functionally inhibits cyclic AMP response element binding protein CREBβ-catenin, and other survival-promoting transcription factors, bipolar research paper.

GSK-3 is also directly regulated by signals originating from a number of different signaling pathways including the Wnt pathway, the PI-3kinase PI3K pathway, protein kinase A PKAand protein kinase C PKC see Fig. For instance, certain PKC isoforms have been shown to phosphorylate and inactivate GSK-3β in vitro Modulation of GSK-3 by these and other signaling pathways fine-tunes the activity of this critical enzyme, bipolar research paper.

The downstream targets of GSK-3 are many, and the resulting functional consequences of GSK-3 activation or inhibition often depend on the signaling pathway targeted. For example, GSK inhibition by the Wnt pathway activates the transcription factor β -catenin an important component of memory consolidation. Other targets of GSK-3 include transcription factors like c-Jun, proteins bound to microtubules [Tau, microtubule-associated protein MAP -1B, kinesin light chain], cell cycle mediators cyclin Dbipolar research paper, and regulators of metabolism glycogen synthase, pyruvate dehydrogenase GSK-3 also directly regulates different neurotransmitter systems involved in the pathophysiology of BD, such as the dopaminergic, glutamatergic, and serotonergic systems [reviewed in 3738 ].

Anti-apoptotic proteins are showed in blue. Activation of brain neurotransmitter-coupled G-proteins induces PLC hydrolysis of PIP 2 to IP 3 and DAG not shownbipolar research paper, which activates PKC. IP 3 binds to the IP 3 R, thus inducing the release of ER calcium stores. Increased intracellular calcium levels have been described in bipolar disorder and may increase the bipolar research paper of apoptosis.

The neuroprotective protein Bcl-2 downregulates ER calcium release through an IP 3 R-dependent mechanism. The same effect is induced by lithium treatment, which also increases Bipolar research paper levels. Cellular signaling through Wnt glycoproteins and frizzled receptors result in GSK-3β inhibition, a critical cellular target and effector for diverse proteins. Inhibition of GSK-3β prevents β-catenin phosphorylation and stimulates its translocation to the nucleus, thus targeting transcription of specific genes activating neurotrophic effects and synaptogenesis.

BDNF also activates the PI3K pathway, which indirectly inhibits GSK-3β and BAD. Mitochondrial Bcl-2 and Bcl-xl also inhibit pro-apoptotic activation bipolar research paper BAD, as well as consequent mitochondrial increase of calcium influx and cytochrome C release. GSK-3 inhibition is commonly associated with the neurotrophic effects of different survival factors. GSK-3 inhibition directly influences gene transcription, leading to anti-apoptotic effects and improved cell structural stability Indeed, GSK-3 is potently inhibited by chronic administration of lithium 42 — 44 ; specifically, lithium inhibits GSK-3 with an enzyme inhibition constant K i of 1—2 mM serum therapeutic range 0.

More recently, bipolar research paper, lithium was found to modulate GSK-3 transcription in vitro and in vivo Bipolar research paper activation and indirect inhibition of GSK-3 by lithium have also been demonstrated after acute or chronic treatment with therapeutically relevant levels of lithium [reviewed in 50 ].

In addition, GSK-3 modulation is either the direct or downstream target of action for other mood stabilizers Also, peripheral administration of a GSK-3 inhibitor decreased amphetamine-induced hyperactivity in rats More recently, transgenic mice overexpressing β-catenin demonstrated changes comparable to those observed following the administration of lithium, including decreased immobility time in the forced swim test and the inhibition of d-amphetamine-induced hyperlocomotion.

These findings are consistent with the hypothesis that the behavioral effects of lithium are mediated through its direct inhibition of GSK-3 and the consequent increase in β-catenin However, because isozymes of GSK-3 are a target in several organ systems more than 40 proteins are phosphorylated by GSK-3, including over a dozen transcription factors 33caution bipolar research paper needed when developing such bipolar research paper due to bipolar research paper possibility of congenital defects 36 Phospholipids are precursors for many signaling molecules.

Inositol phospholipids play a key role in receptor-mediated signal-transduction pathways, and are implicated in a variety of responses such as cell division, secretion, neuronal excitability, and responsiveness. The PI pathway is initiated by the activation of G-protein-coupled receptors, which couple neurotransmitter receptors to multiple types of intracellular effector proteins. PKC comprises a family of 12 structurally related isozymes subspecies with a heterogeneous distribution throughout the body 65 PKC isoforms differ in structure, subcellular localization, tissue specificity, mode of activation, and substrate specificity PKC is a primary target of DAG, and as such has been the object of intense research.

PKC is a ubiquitous enzyme, bipolar research paper, highly enriched in the brain, where it plays a significant role in regulating both pre- and postsynaptic aspects of neurotransmission In addition, PKC is active in many other cellular processes, including transmembrane glucose transport, secretion, exocytosis, long-term alterations in gene expression and plasticity, modulation of ion conductance, cell proliferation, bipolar research paper, and desensitization of extracellular receptors The ratios of platelet membrane bound to cytosolic PKC activities were found to be elevated in subjects experiencing a manic episode In addition, serotonin-elicited platelet PKC translocation, as well as PKC isozyme levels, activity, and translocation, were found to be enhanced in postmortem brain tissue of patients with BD Certain PKC isoforms have been also shown to phosphorylate and inactivate GSK-3 in vitro Indeed, activation of PKC results in the post-translational phosphorylation of various proteins, but MARCKS is its major substrate in the brain In the PI cycle, bipolar research paper, lithium blocks inositol monophosphatase IMPasepreventing conversion of inositolphosphate IP 1 to myoinositol, bipolar research paper.

This leads to accumulation of inositol monophosphates and depletion of myoinositol, which reduces PIP 2 and its cleavage products—IP 3 and DAG. Dampening the PI cycle with lithium treatment downregulates PKC isozymes. Among PKC substrates, MARCKS is particularly relevant Fig.

MARCKS is an actin-binding protein expressed in neurites and implicated in cytoskeletal restructuring; its expression is downregulated by lithium, thereby stabilizing the neuronal membrane and representing an important target for its neurotrophic effects.

It has been proposed that lithium induces its therapeutic effects in BD by reducing cellular levels of myoinositol and PIP 2 concentrations see Fig. IMPase is the final, common step for conversion of monophosphorylated inositols into myoinositol, and thus inhibition of IMPase can decrease myoinositol levels.

A significant decrease in myoinositol levels in the right frontal lobe induced by lithium in BD subjects prior to clinical response was described using MRS Inhibition of IMPase and the consequent reduction of myoinositol levels have been observed after lithium treatment.

Also, lithium-induced reductions of myoinositol levels were found in children and adults with BD in brain regions previously implicated in this disorder 3281 Another recent study using lithium-7 and proton magnetic resonance spectroscopy 1H-MRS evaluated the effects of brain lithium on NAA and myoinositol levels in older bipolar research paper with BD treated with lithium. In this cross-sectional study, lithium treatment was associated with higher NAA levels and higher myoinositol levels, bipolar research paper.

Notably, lithium was also found to reduce free inositol levels in brain sections and in the brains of rodents However, at least one recent study challenges this hypothesis; investigators found that the reduced intracellular inositol associated with brain sodium—myoinositol transporter SMIT1 knockout in mice had no effect on PI levels Lithium has been shown to alter signaling pathways that also directly regulate neurotrophic effects 36987 — In particular, chronic treatment with lithium in rats significantly decreased PKC stimulation-induced release with phorbol esters in cortex, hypothalamus, and hippocampus.

In addition, chronic lithium administration resulted in reduced isoforms of PKC α and ε Interestingly, addition of inositol reverses the lithium-induced downregulation of MARCKS, suggesting that MARCKS downregulation was regulated by the PI pathway Further support for the involvement of the PKC signaling pathway in the pathophysiology of BD comes from two independent genome-wide association studies that identified diacylglycerol kinase eta DGKH as a risk gene for BD DGKH is a major regulator of DAG, which activates all known conventional and novel isoforms of PKC, but may also involve non-PKC targets.

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Bipolar disorder (BD) is one of the most severe of the major mental illnesses, and recent estimates place its lifetime prevalence (including BD spectrum) at about % in the U.S. population ().Several pathophysiological findings in BD associated with loss of neurotrophic effects and consequent cellular injury have been widely described in different targets regulated by a wide range of We would like to show you a description here but the site won’t allow blogger.com more Jul 17,  · Sometimes it seems like coming up with a good idea for a paper is more challenging than the actual research and writing. Fortunately, there are plenty of great places to find inspiration and the following list contains just a few ideas to help get you started. Finding a solid topic is one of the most important steps when writing any type of paper