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Vidar M. Steen - One of the best experts on this subject based on the ideXlab platform.
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a human myo inositol monophosphatase gene impa2 localized in a putative susceptibility region for bipolar disorder on chromosome 18p11 2 genomic structure and polymorphism screening in manic Depressive patients
Molecular Psychiatry, 2000Co-Authors: Gry Sjøholt, Anders Molven, Roger Løvlie, A K Gulbrandsen, Jan Oystein Berle, Vidar M. SteenAbstract:For several decades, lithium has been the drug of choice in the long-term treatment of manic-Depressive Illness, but the molecular mechanism(s) mediating its therapeutic effects remain to be determined. The enzyme myo-inositol monophosphatase (IMPase) in the phospholipase C signaling system is inhibited by lithium at therapeutically relevant concentrations, and is a candidate target of lithium's mood-stabilizing action. Two genes encoding human IMPases have so far been isolated, namely IMPA1 on chromosome 8q21.13–21.3 and IMPA2 on chromosome 18p11.2. Interestingly, several studies have indicated the presence of a susceptibility locus for bipolar disorder on chromosome 18p11.2. IMPA2 is therefore a candidate for genetic studies on both etiology and lithium treatment of manic-Depressive Illness. Here we report that the genomic structure of IMPA2 is composed of eight exons, ranging in size from 46 bp to 535 bp. the promoter region contains several sp1 elements and lacks a tata-box, features typical for housekeeping genes. by a preliminary polymorphism screening of exons 2–8 in a sample of 23 norwegian bipolar patients, we have identified nine single nucleotide polymorphisms (snps). seven of the polymorphisms were located in the introns, one was a silent transition in exon 2 (159t>c) and one was a transition in exon 5 (443g>A) resulting in a predicted amino acid substitution (R148Q). Our data show that even in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified. IMPA2 is therefore an intriguing candidate gene for future association studies of manic-Depressive Illness.
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Genomic structure and chromosomal localization of a human myo-inositol monophosphatase gene (IMPA).
Genomics, 1997Co-Authors: Gry Sjøholt, Anders Molven, Roger Løvlie, Andrea S. Wilcox, James M. Sikela, Vidar M. SteenAbstract:Manic-Depressive Illness is a serious psychiatric disorder that in many, but far from all, patients can be treated with lithium. The main causes for discontinuation of lithium therapy are unpleasant or serious side effects and lack of response. The reason for the striking variation in clinical efficacy of lithium treatment among bipolar patients is not known. The enzyme myo-inositol monophosphatase (IMPase) has been postulated as a target for the mood-stabilizing effects of lithium, but variation in the coding region of the human IMPA gene encoding IMPase activity has not been observed in manic-Depressive patients (Steen et al., Pharmacogenetics, 1996, 6, 113-116). It is nevertheless conceivable that polymorphisms or mutations in the noncoding regions of this gene could influence the lithium response in psychiatric patients. As a first step in investigating this possibility, we here report the genomic structure of the human IMPA gene. The gene is composed of at least nine exons and covers more than 20 kb of sequence on chromosome 8q21.13-q21.3. In the 3'-untranslated part of the gene, we observed a polymorphism (a G to A transition) and also two short sequences similar to the inositol/cholin-responsive element consensus. Finally, we postulate that two additional IMPA-like transcripts originate from the human genome, one from a position close to IMPA itself on chromosome 8 and the other from chromosome 18p. Our data may contribute to the identification of genetic factors involved in the pathogenesis and determination of treatment response in manic-Depressive Illness.
Bruce S Mcewen - One of the best experts on this subject based on the ideXlab platform.
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Mood disorders and allostatic load.
Biological Psychiatry, 2003Co-Authors: Bruce S McewenAbstract:The brain controls both the physiologic and the behavioral coping responses to daily events as well as major stressors, and the nervous system is itself a target of the mediators of those responses through circulating hormones. The amygdala and hippocampus interpret what is stressful and regulate appropriate responses. The amygdala becomes hyperactive in posttraumatic stress disorder (PTSD) and Depressive Illness, and hypertrophy of amygdala nerve cells is reported after repeated stress in an animal model. The hippocampus expresses adrenal steroid receptors. It undergoes atrophy in several psychiatric disorders and responds to repeated stressors with decreased dendritic branching and reduction in number of neurons in the dentate gyrus. Stress promotes adaptation ("allostasis"), but a perturbed diurnal rhythm or failed shutoff of mediators after stress ("allostatic state") leads, over time, to wear and tear on the body ("allostatic load"). Neural changes mirror the pattern seen in the cardiovascular, metabolic, and immune systems, that is, short-term adaptation versus long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesity, bone demineralization, and atrophy of nerve cells in brain. Allostatic load is seen in major Depressive Illness and may also be expressed in other chronic anxiety disorders such as PTSD and should be documented.
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Allostasis and Allostatic Load: Implications for Neuropsychopharmacology
Neuropsychopharmacology, 2000Co-Authors: Bruce S McewenAbstract:The primary hormonal mediators of the stress response, glucocorticoids and catecholamines, have both protective and damaging effects on the body. In the short run, they are essential for adaptation, maintenance of homeostasis, and survival (allostasis). Yet, over longer time intervals, they exact a cost (allostatic load) that can accelerate disease processes. The concepts of allostasis and allostatic load center around the brain as interpreter and responder to environmental challenges and as a target of those challenges. In anxiety disorders, Depressive Illness, hostile and aggressive states, substance abuse, and post-traumatic stress disorder (PTSD), allostatic load takes the form of chemical imbalances as well as perturbations in the diurnal rhythm, and, in some cases, atrophy of brain structures. In addition, growing evidence indicates that Depressive Illness and hostility are both associated with cardiovascular disease (CVD) and other systemic disorders. A major risk factor for these conditions is early childhood experiences of abuse and neglect that increase allostatic load later in life and lead individuals into social isolation, hostility, depression, and conditions like extreme obesity and CVD. Animal models support the notion of lifelong influences of early experience on stress hormone reactivity. Whereas, depression and childhood abuse and neglect tend to be more prevalent in individuals at the lower end of the socioeconomic ladder, cardiovascular and other diseases follow a gradient across the full range of socioeconomic status (SES). An SES gradient is also evident for measures of allostatic load. Wide-ranging SES gradients have also been described for substance abuse and affective and anxiety disorders as a function of education. These aspects are discussed as important, emerging public health issues where the brain plays a key role.
Mangala Lahkar - One of the best experts on this subject based on the ideXlab platform.
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lipopolysaccharide induced behavioral alterations are alleviated by sodium phenylbutyrate via attenuation of oxidative stress and neuroinflammatory cascade
Inflammation, 2016Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Mangala LahkarAbstract:Oxido-nitrosative stress, neuroinflammation, and reduced level of neurotrophins are implicated in the pathophysiology of anxiety and Depressive Illness. A few recent studies have revealed the role of endoplasmic reticulum (ER) stress in the pathophysiology of stress and depression. The aim of the present study is to investigate the neuroprotective potential of sodium phenylbutyrate (SPB), an ER stress inhibitor against lipopolysaccharide (LPS)-induced anxiety and Depressive-like behavior in Swiss albino mice. Anxiety and Depressive-like behavior was induced by LPS (0.83 mg/kg; i.p.) administration. Various behavioral tests were conducted to evaluate the anxiety and Depressive-like behavior in mice. Real-time PCR was employed for the detection and expression of ER stress markers (78-kDa glucose-regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Pretreatment with SPB significantly ameliorated the LPS-induced anxiety and Depressive-like behavior as revealed by behavioral paradigm results. LPS-induced oxidative stress was ameliorated by SPB pretreatment in hippocampus (HC) and prefrontal cortex (PFC) region. Neuroinflammation was significantly reduced by SPB pretreatment in LPS-treated mice as evident from reduction in proinflammatory cytokines (IL-1β and TNF-α). Importantly, LPS administration significantly up-regulated the GRP78 mRNA expression level in the HC which suggests the involvement of unfolded protein response (UPR) in LPS-evoked behavioral anomalies. These results highlight the neuroprotective potential of SPB in LPS-induced anxiety and Depressive Illness model which may be partially due to inhibition of oxidative stress-neuroinflammatory cascade.
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lipopolysaccharide induced behavioral alterations are alleviated by sodium phenylbutyrate via attenuation of oxidative stress and neuroinflammatory cascade
Inflammation, 2016Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Mangala LahkarAbstract:Oxido-nitrosative stress, neuroinflammation, and reduced level of neurotrophins are implicated in the pathophysiology of anxiety and Depressive Illness. A few recent studies have revealed the role of endoplasmic reticulum (ER) stress in the pathophysiology of stress and depression. The aim of the present study is to investigate the neuroprotective potential of sodium phenylbutyrate (SPB), an ER stress inhibitor against lipopolysaccharide (LPS)-induced anxiety and Depressive-like behavior in Swiss albino mice. Anxiety and Depressive-like behavior was induced by LPS (0.83 mg/kg; i.p.) administration. Various behavioral tests were conducted to evaluate the anxiety and Depressive-like behavior in mice. Real-time PCR was employed for the detection and expression of ER stress markers (78-kDa glucose-regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Pretreatment with SPB significantly ameliorated the LPS-induced anxiety and Depressive-like behavior as revealed by behavioral paradigm results. LPS-induced oxidative stress was ameliorated by SPB pretreatment in hippocampus (HC) and prefrontal cortex (PFC) region. Neuroinflammation was significantly reduced by SPB pretreatment in LPS-treated mice as evident from reduction in proinflammatory cytokines (IL-1β and TNF-α). Importantly, LPS administration significantly up-regulated the GRP78 mRNA expression level in the HC which suggests the involvement of unfolded protein response (UPR) in LPS-evoked behavioral anomalies. These results highlight the neuroprotective potential of SPB in LPS-induced anxiety and Depressive Illness model which may be partially due to inhibition of oxidative stress-neuroinflammatory cascade.
Gry Sjøholt - One of the best experts on this subject based on the ideXlab platform.
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a human myo inositol monophosphatase gene impa2 localized in a putative susceptibility region for bipolar disorder on chromosome 18p11 2 genomic structure and polymorphism screening in manic Depressive patients
Molecular Psychiatry, 2000Co-Authors: Gry Sjøholt, Anders Molven, Roger Løvlie, A K Gulbrandsen, Jan Oystein Berle, Vidar M. SteenAbstract:For several decades, lithium has been the drug of choice in the long-term treatment of manic-Depressive Illness, but the molecular mechanism(s) mediating its therapeutic effects remain to be determined. The enzyme myo-inositol monophosphatase (IMPase) in the phospholipase C signaling system is inhibited by lithium at therapeutically relevant concentrations, and is a candidate target of lithium's mood-stabilizing action. Two genes encoding human IMPases have so far been isolated, namely IMPA1 on chromosome 8q21.13–21.3 and IMPA2 on chromosome 18p11.2. Interestingly, several studies have indicated the presence of a susceptibility locus for bipolar disorder on chromosome 18p11.2. IMPA2 is therefore a candidate for genetic studies on both etiology and lithium treatment of manic-Depressive Illness. Here we report that the genomic structure of IMPA2 is composed of eight exons, ranging in size from 46 bp to 535 bp. the promoter region contains several sp1 elements and lacks a tata-box, features typical for housekeeping genes. by a preliminary polymorphism screening of exons 2–8 in a sample of 23 norwegian bipolar patients, we have identified nine single nucleotide polymorphisms (snps). seven of the polymorphisms were located in the introns, one was a silent transition in exon 2 (159t>c) and one was a transition in exon 5 (443g>A) resulting in a predicted amino acid substitution (R148Q). Our data show that even in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified. IMPA2 is therefore an intriguing candidate gene for future association studies of manic-Depressive Illness.
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Genomic structure and chromosomal localization of a human myo-inositol monophosphatase gene (IMPA).
Genomics, 1997Co-Authors: Gry Sjøholt, Anders Molven, Roger Løvlie, Andrea S. Wilcox, James M. Sikela, Vidar M. SteenAbstract:Manic-Depressive Illness is a serious psychiatric disorder that in many, but far from all, patients can be treated with lithium. The main causes for discontinuation of lithium therapy are unpleasant or serious side effects and lack of response. The reason for the striking variation in clinical efficacy of lithium treatment among bipolar patients is not known. The enzyme myo-inositol monophosphatase (IMPase) has been postulated as a target for the mood-stabilizing effects of lithium, but variation in the coding region of the human IMPA gene encoding IMPase activity has not been observed in manic-Depressive patients (Steen et al., Pharmacogenetics, 1996, 6, 113-116). It is nevertheless conceivable that polymorphisms or mutations in the noncoding regions of this gene could influence the lithium response in psychiatric patients. As a first step in investigating this possibility, we here report the genomic structure of the human IMPA gene. The gene is composed of at least nine exons and covers more than 20 kb of sequence on chromosome 8q21.13-q21.3. In the 3'-untranslated part of the gene, we observed a polymorphism (a G to A transition) and also two short sequences similar to the inositol/cholin-responsive element consensus. Finally, we postulate that two additional IMPA-like transcripts originate from the human genome, one from a position close to IMPA itself on chromosome 8 and the other from chromosome 18p. Our data may contribute to the identification of genetic factors involved in the pathogenesis and determination of treatment response in manic-Depressive Illness.
Ashok Jangra - One of the best experts on this subject based on the ideXlab platform.
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lipopolysaccharide induced behavioral alterations are alleviated by sodium phenylbutyrate via attenuation of oxidative stress and neuroinflammatory cascade
Inflammation, 2016Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Mangala LahkarAbstract:Oxido-nitrosative stress, neuroinflammation, and reduced level of neurotrophins are implicated in the pathophysiology of anxiety and Depressive Illness. A few recent studies have revealed the role of endoplasmic reticulum (ER) stress in the pathophysiology of stress and depression. The aim of the present study is to investigate the neuroprotective potential of sodium phenylbutyrate (SPB), an ER stress inhibitor against lipopolysaccharide (LPS)-induced anxiety and Depressive-like behavior in Swiss albino mice. Anxiety and Depressive-like behavior was induced by LPS (0.83 mg/kg; i.p.) administration. Various behavioral tests were conducted to evaluate the anxiety and Depressive-like behavior in mice. Real-time PCR was employed for the detection and expression of ER stress markers (78-kDa glucose-regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Pretreatment with SPB significantly ameliorated the LPS-induced anxiety and Depressive-like behavior as revealed by behavioral paradigm results. LPS-induced oxidative stress was ameliorated by SPB pretreatment in hippocampus (HC) and prefrontal cortex (PFC) region. Neuroinflammation was significantly reduced by SPB pretreatment in LPS-treated mice as evident from reduction in proinflammatory cytokines (IL-1β and TNF-α). Importantly, LPS administration significantly up-regulated the GRP78 mRNA expression level in the HC which suggests the involvement of unfolded protein response (UPR) in LPS-evoked behavioral anomalies. These results highlight the neuroprotective potential of SPB in LPS-induced anxiety and Depressive Illness model which may be partially due to inhibition of oxidative stress-neuroinflammatory cascade.
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lipopolysaccharide induced behavioral alterations are alleviated by sodium phenylbutyrate via attenuation of oxidative stress and neuroinflammatory cascade
Inflammation, 2016Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Mangala LahkarAbstract:Oxido-nitrosative stress, neuroinflammation, and reduced level of neurotrophins are implicated in the pathophysiology of anxiety and Depressive Illness. A few recent studies have revealed the role of endoplasmic reticulum (ER) stress in the pathophysiology of stress and depression. The aim of the present study is to investigate the neuroprotective potential of sodium phenylbutyrate (SPB), an ER stress inhibitor against lipopolysaccharide (LPS)-induced anxiety and Depressive-like behavior in Swiss albino mice. Anxiety and Depressive-like behavior was induced by LPS (0.83 mg/kg; i.p.) administration. Various behavioral tests were conducted to evaluate the anxiety and Depressive-like behavior in mice. Real-time PCR was employed for the detection and expression of ER stress markers (78-kDa glucose-regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Pretreatment with SPB significantly ameliorated the LPS-induced anxiety and Depressive-like behavior as revealed by behavioral paradigm results. LPS-induced oxidative stress was ameliorated by SPB pretreatment in hippocampus (HC) and prefrontal cortex (PFC) region. Neuroinflammation was significantly reduced by SPB pretreatment in LPS-treated mice as evident from reduction in proinflammatory cytokines (IL-1β and TNF-α). Importantly, LPS administration significantly up-regulated the GRP78 mRNA expression level in the HC which suggests the involvement of unfolded protein response (UPR) in LPS-evoked behavioral anomalies. These results highlight the neuroprotective potential of SPB in LPS-induced anxiety and Depressive Illness model which may be partially due to inhibition of oxidative stress-neuroinflammatory cascade.