Higher proportion of inactive Gsk3β in platelets of elderly patients with bipolar disorder: an effect of treatment?

Ladeira, Rodolfo Braga; Joaquim, Helena Passarelli Giroud; Talib, Leda Leme; Nunes, Paula Villela; Forlenza, Orestes Vicente

doi:10.1590/1516-4446-2012-0921

Cited by 8 publications

(14 citation statements)

References 15 publications

(20 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, consistent with the present findings, elderly patients with BD who were under lithium treatment (plus other drugs) showed increased platelets phospho-GSK3b in platelets compared to healthy controls (Ladeira et al, 2013). Moreover, BD patients taking lithium with other agents showed an increase on phospho-GSK3b relative to healthy subjects in PBMCs (Li et al, 2007).…”

Section: Discussionsupporting

confidence: 91%

“…However, Ladeira et al (2013) reported increased GSK3b phosphorylation in elderly BD patients in comparison to healthy subjects.…”

Section: Discussionmentioning

confidence: 91%

“…Platelets were lysed in RIPA cell buffer modified by the addition of the protease inhibitors PIC (Sigma P8340) and PMSF (Sigma P7626). The levels of GSK3b protein levels were determined by a specific Enzyme Immunometric Assay (EIA), which assessed total and Serine-9 phosphorylated GSK3b (phospho-GSK3b) (Titer-Zyme EIA & Assay Designs Inc., MI, USA) (Ladeira et al, 2013). The protocol followed the instructions of the manufacturer.…”

Section: Blood Sampling and Laboratorial Analysismentioning

confidence: 99%

See 1 more Smart Citation

Lithium increases platelet serine-9 phosphorylated GSK-3β levels in drug-free bipolar disorder during depressive episodes

Sousa

Zanetti

Talib

et al. 2015

Journal of Psychiatric Research

View full text Add to dashboard

“…In addition, lithium may specifically modify pathological processes implicated in AD 75. The mechanism of action could be attributed to the fact that lithium inhibits both the expression76 and activity77 of the enzyme glycogen synthase kinase-3β,71 as well as the inhibition of the overproduction of Aβ and the hyperphosphorylation of tau protein,78 all directly involved in the neurodegenerative process in AD.…”

Section: Neurobiological Correlates Of Geriatric Depression and Bd Gementioning

confidence: 99%

Mood disorders in the elderly: prevalence, functional impact, and management challenges

Valiengo

Stella

Forlenza

2016

NDT

Self Cite

View full text Add to dashboard

Despite the lower prevalence of severe mood disorders in the elderly as compared to younger adults, late-life depression and bipolar disorder (BD) are more strongly associated with negative outcomes related to the presence of medical comorbidities, cognitive deficits, and increased suicide risk and overall mortality. The mechanisms that contribute to these associations are probably multifactorial, involving pathological factors related directly and indirectly to the disease itself, ranging from biological to psychosocial factors. Most of the accumulated knowledge on the nature of these associations derives from naturalistic and observational studies, and controlled data are still scarce. Nonetheless, there has clearly been a recent growth of the scientific interest on late-life BD and geriatric depression. In the present study, we review the most relevant studies on prevalence, clinical presentation, and cognitive/functional impact of mood disorders in elderly. Several clinical–epidemiological studies were dedicated to the study of the prevalence of mood disorders in old age in distinct settings; however, fewer studies investigated the underlying neurobiological findings and treatment specificities in late-life depression and BD. In the present study, we further discuss the implications of these findings on the management of mood disorders in older adults.

show abstract

“…Only in a subgroup of patients with combined lithium and olanzapine treatment was the P‐Ser‐9‐GSK‐3β/total GSK‐3β ratio significantly increased. Ladeira et al . reported significantly higher platelet P‐Ser‐9‐GSK‐3β levels and P‐Ser‐9‐GSK‐3β/total GSK‐3β ratio in patients with bipolar disorder as compared to control subjects.…”

mentioning

confidence: 99%

Whether lithium inhibits glycogen synthase kinase (GSK)-3β activity in vivo in humans is still an open question

Agam

Azab

2016

Bipolar Disord

View full text Add to dashboard

Recently, a paper by Jacoby et al. 1 titled 'Glycogen synthase kinase-3β in patients with bipolar I disorder-results from a prospective study' was published in Bipolar Disorders. Glycogen synthase kinase (GSK)-3β is a kinase ubiquitously abundant in mammalian tissues, in general, and in the brain, in particular. 2,3 GSK-3β regulates the activity of multiple proteins involved in regulation of gene expression, apoptosis, survival pathways, inflammation, autophagy and neuronal plasticity. 2,4-7 Klein and Melton 8 and Stambolic et al. 9 have demonstrated that lithium inhibits GSK-3β in vitro at therapeutically relevant concentrations.Subsequently, in vivo studies in animals also found that lithium inhibits GSK-3β activity. 10-13 Following these findings it has been hypothesized that chronic lithium treatment inhibits GSK-3β activity in vivo in humans and that this inhibition mediates the beneficial therapeutic effects of the drug.A major mechanism controlling GSK-3β activity is phosphorylation on its serine (Ser) 9 residue resulting in inhibition of the catalytic activity. 5,14 Thus, phosphorylated-Ser-9-GSK-3β (P-Ser-9-GSK-3β) protein levels are regarded as an indirect measure of the inhibited fraction of GSK-3β. Other indirect measures of GSK-3β activity use β-catenin or phosphorylated tau protein levels. 9,14 GSK-3β phosphorylates a myriad of proteins, in most cases resulting in inactivation of the downstream target. To be phosphorylated by GSK-3β many of its substrates require a 'priming' pre-phosphorylation step, an additional regulatory mechanism of GSK-3β activity. 5Lithium-induced inhibition of GSK-3β is obviously an important pharmacological aspect of this mood stabilizer. However, whether lithium inhibits GSK-3β activity in vivo in humans is a crucial question to which an unequivocal answer has not yet been obtained. Multiple human studies used P-Ser9-GSK-3β protein levels as a measure of GSK-3β activity. This approach might introduce bias since changes in P-Ser9-GSK-3β levels per se may merely reflect changes in total GSK-3β, while the percentage of the phosphorylated form out of the total amount of the enzyme is unaltered. The assessment of the P-Ser9-GSK-3β/total GSK-3β protein level ratio overcomes this specific limitation. Yet, it has to be kept in mind that even the P-Ser9-GSK-3β/total GSK-3β ratio is not a direct measure of the in vivo activity of the enzyme. In a recent seminal review by Beurel et al.,15 the authors indicate that the serine-phosphorylation inhibitory mechanism does not cause absolute inhibition of GSK-3β activity and that increased serine-9 phosphorylation of GSK-3β does not inhibit GSK-3β in the β-catenin destruction complex. These points suggest that relying solely on the determination of the P-Ser-9 GSK-3β/total GSK-3β ratio or β-catenin levels as indirect measures of the extent of the in vivo inhibition of GSK-3β activity by lithium might be misleading. Yet, multiple studies that examined

show abstract

Higher proportion of inactive Gsk3β in platelets of elderly patients with bipolar disorder: an effect of treatment?

Cited by 8 publications

References 15 publications

Lithium increases platelet serine-9 phosphorylated GSK-3β levels in drug-free bipolar disorder during depressive episodes

Mood disorders in the elderly: prevalence, functional impact, and management challenges

Whether lithium inhibits glycogen synthase kinase (GSK)-3β activity in vivo in humans is still an open question

Contact Info

Product

Resources

About