Ketamine Influences CLOCK:BMAL1 Function Leading to Altered Circadian Gene Expression

Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies

Dopaminergic drugs and the risk of hip or femur fracture: a population-based case–control study

SUMMARY: The effect of dopaminergic medication on the risk of hip/femur fractures is not clear. Our results showed a nearly twofold increased risk of hip/femur fractures in current dopaminergic drug users. Concomitant use of antidepressants further increased this risk. Fracture risk assessment may be warranted in elderly users of dopaminergic drugs. INTRODUCTION: Dopaminergic drugs, often used in the treatment of Parkinson's disease, have several pharmacological effects that may increase or decrease the risk of falling and fractures. Thus, the effect of dopaminergic medication on the risk of hip/femur fractures is not clear. The objective of the study was to examine the effect of dopaminergic medication and concomitant use of psychotropics on the risk of hip/femur fractures taking into account the timing of dopaminergic drug use. METHODS: A population-based case-control study in the PHARMO database was conducted for the period 1991 to 2002. Cases were patients aged 18 years and older with a first hip or femur fracture and matched to four control patients by year of birth, sex and geographical region. RESULTS: The study population included 6,763 cases and 26,341 controls. Current use of dopaminergic drugs (1-30 days before the index date) was associated with an increased risk of hip/femur fractures compared to never use (OR(adj) 1.76, 95% CI = 1.39-2.22), but this excess risk rapidly dropped to baseline levels when treatment had been discontinued >1 year ago. Concomitant use of antidepressants among current dopaminergic drug users further increased the risk of hip/femur fractures (OR(adj) 3.51, 95% CI = 2.10-5.87) while there was no additional risk with concomitant use of other psychotropics. CONCLUSIONS: Although the observed association between dopaminergic drugs and fracture risk may not be entirely causal, due to absence of information on the (severity of the) underlying disease, fracture risk assessment may be warranted in elderly users of dopaminergic drugs

Risk of fracture in patients with Parkinson's disease

The aim of the study was to determine fracture risk in incident Parkinson's disease (PD) patients. This study showed that fracture risk assessment may be indicated among patients with PD, in particular when they have recently used selective serotonin re-uptake inhibitors or high-dose antipsychotics, or have a history of fracture, falling, low body mass index (BMI) or renal disease. Introduction: PD is a movement disorder associated with falling and detrimental effects on bone. Both are recognized risk factors for fracture. Therefore, the aim was to determine fracture risk in incident PD patients stratified by treatment, severity, duration of disease and related comorbidities. Methods: We conducted a retrospective cohort study using the UK General Practice Research Database (1987-2011). Each PD patient was matched by age, sex, calendar time and practice to a control patient without history of PD. Results: We identified 4,687 incident PD patients. Compared to controls, a statistically significant increased risk was observed for any fracture (adjusted hazard ratio [AHR], 1.89; 95 % confidence interval [CI], 1.67-2.14), osteoporotic fracture (AHR, 1.99; 95 % CI, 1.72-2.30) and hip fracture (AHR 3.08; 95 % CI, 2.43-3.89). Fracture risk further increased with history of fracture, falling, low BMI, renal disease, antidepressant use and use of high-dose antipsychotics. Conclusion: This study showed that incident PD patients have a statistically significant increased risk of fracture. Therefore, fracture risk assessment may be indicated among PD patients, who, besides the general risk factors for fracture, like increasing age and female gender, have recently used selective serotonin re-uptake inhibitors or high-dose antipsychotics or have a history of fracture, falling, low BMI or renal disease. © 2013 International Osteoporosis Foundation and National Osteoporosis Foundation

Osteosarcoma cell proliferation and survival requires mGluR5 receptor activity and is blocked by Riluzole

Osteosarcomas are malignant tumors of bone, most commonly seen in children and adolescents. Despite advances in modern medicine, the poor survival rate of metastatic osteosarcoma has not improved in two decades. In the present study we have investigated the effect of Riluzole on a human and mouse metastatic osteosarcoma cells. We show that LM7 cells secrete glutamate in the media and that mGluR5 receptors are required for the proliferation of LM7 cells. Riluzole, which is known to inhibit glutamate release, inhibits proliferation, induces apoptosis and prevents migration of LM7 cells. This is also seen with Fenobam, a specific blocker of mGluR5. We also show that Riluzole alters the phosphorylation status of AKT/P70 S6 kinase, ERK1/2 and JNK1/2. Thus Riluzole is an effective drug to inhibit proliferation and survival of osteosarcoma cells and has therapeutic potential for the treatment of osteosarcoma exhibiting autocrine glutamate signaling