Pattern of heat shock factor and heat shock protein expression in lymphocytes of bipolar patients: increased HSP70-glucocorticoid receptor heterocomplex.

Bipolar disorder (BD), a stress-related disease, is characterized by altered glucocorticoid receptor (GR) signalling. Stress response includes activation of heat shock factor (HSF) and subsequent heat shock protein (HSP) synthesis which regulate GR folding and function. The objective of this study was to investigate the possible role of HSFs, HSPs and their interaction with GR in BD. We applied immunoprecipitation, SDS-PAGE/Western blot analysis and electrophoretic mobility shift assay (EMSA) in lymphocytes (whole cell or nuclear extracts) from BD patients and healthy subjects and determined the HSPs (HSP90 and HSP70), the heterocomplexes HSP90-GR and HSP70-GR, the HSFs (HSF1 and HSF4) as well as the HSF-DNA binding. The HSP70-GR heterocomplex was elevated (p < 0.05) in BD patients vs healthy subjects, and nuclear HSP70 was reduced (p ≤ 0.01) in bipolar manic patients. Protein levels of HSF1, HSF4, HSP90, HSP90-GR heterocomplex, and HSF-DNA binding remained unaltered in BD patients vs healthy subjects. The corresponding effect sizes (ES) indicated a large ES for HSP70-GR, HSP70, HSF-DNA binding and HSF4, and a medium ES for HSP90, HSF1 and HSP90-GR between healthy subjects and bipolar patients. Significant correlations among HSFs, HSPs, GR and HSP70-GR heterocomplex were observed in healthy subjects, which were abrogated in bipolar patients. The higher interaction between GR and HSP70 and the disturbances in the relations among heat shock response parameters and GR as observed in our BD patients may provide novel insights into the contribution of these factors in BD aetiopathogenesis.

Glandular cystitis and lithium intoxication in a patient with bipolar disorder.

A 42-year-old woman, with a 12-year history of bipolar disorder was referred to our department due to tremor, sedation, dysarthria, polyuria and polydipsia. She had been on lithium monotherapy during the last 3 years. On admission, her cognitive status was intact, and neither depression nor euphoria was reported. Lithium plasma levels were 1.6 mEq/L, whereas creatinine and urea levels were 2.8 IU/L and 110 IU/L, respectively. The patient did not take other medications or misused lithium. Lithium was immediately discontinued. Ultrasound scans of the urinary tract were suggestive of bilateral hydronephrosis secondary to bladder contraction and cystoscopy-guided bladder biopsy revealed glandular cystitis a benign tumour into the bladder's wall, which impeded the bladder's contraction leading to hydronephrosis and subsequent toxic lithium plasma levels. The patient was switched to valproate and was referred for surgical excision of the lesion. One year later, she was in good physical and mental health under treatment with valproate (1000 mg/day). This is the first case report of glandular cystitis leading to lithium intoxication by impairing renal function. Acute renal failure leading to lithium intoxication would be possible. However, a thorough imaging, endoscopical and histological study revealed glandular cystitis as the cause of renal impairment. Although physicians are alert about lithium's toxicity and a monitoring of renal function is routinely prescribed, little focus has been made on the integrity of the urinary tract. We suggest that urinary tract imaging should be part of the routine work-up in patients presenting with symptoms and signs of lithium intoxication, since concomitant urinary tract lesions might occasionally be the cause of renal impairment leading to reduced lithium excretion.

Phosphorylation status of glucocorticoid receptor, heat shock protein 70, cytochrome c and Bax in lymphocytes of euthymic, depressed and manic bipolar patients.

Bipolar disorder (BD), a severe mental illness, has been correlated with alterations in glucocorticoid receptor (GR) signaling. Since it is phosphorylated GR that contributes to receptor function and determines its transcriptional activity, the Ser211 being a biomarker for activated GR in vivo, it is pertinent that we seek to determine the putative role of the total phosphorylation status of GR and site-specific phosphorylation at serine 211 (S211) in BD and their possible association with parameters of apoptosis. In lymphocytes from 48 BD patients under multiple psychotropic therapy and 20 healthy subjects, we measured whole cell GR, total GR phosphorylation, and phosphorylation of GR at serine 211 in nucleus, using immunoprecipitation, phosphospecific antibody and Western-blot analysis. Cytosolic cytochrome c and Bax and whole cell HSP70 were determined by immunoblot analysis. One-way ANOVA statistical analysis was carried out. Total phosphorylated GR was lower (P<0.001) while the GR S211 was higher (P<0.001) in all BD patients as compared to healthy subjects. HSP70 was reduced in euthymic (P<0.05), depressed (P<0.001) and manic (P<0.001) as compared to healthy subjects. Cytochrome c was higher in all-patient groups as compared to healthy subjects, however without reaching statistical significance (P>0.05). Bax levels were lower in the cytosolic fraction of all three BD groups. We provide the first evidence of altered GR phosphorylation joined with signs of apoptosis in lymphocytes of BD patients and suggest that the phosphorylation status of GR may play a role in the pathophysiology of bipolar disorder.