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Decreased bone mineral density in ovariectomized mice is ameliorated after subsequent repeated intermittent administration of (R)-ketamine, but not (S)-ketamine.

ABSTRACT: Aim: Depression is a common symptom in people with osteoporosis. (R)-ketamine produced greater potency and longer-lasting antidepressant-like actions than (S)-ketamine in rodents. Here, we examined the effects of two ketamine enantiomers on the reduced bone mineral density (BMD) in the ovariectomized (OVX) mice which is an animal model of postmenopausal osteoporosis.

Methods: Female ddY mice were OVX or sham-operated. Subsequently, saline (10 mL/kg/d, twice weekly), (R)-ketamine (10 mg/kg/d, twice weekly), or (S)-ketamine (10 mg/kg/d, twice weekly) was administered intraperitoneally into OVX or sham mice for the 6 weeks. The femur from all mice was collected 3 days after the final injection, and BMD in the femur was measured.

Results: The reduction of cortical BMD and total BMD in the OVX mice was significantly ameliorated after subsequent repeated intermittent administration of (R)-ketamine, but not (S)-ketamine.

Conclusion: The study shows that (R)-ketamine can ameliorate the reduced cortical BMD and total BMD in OVX mice. Therefore, (R)-ketamine would be a novel therapeutic drug for women with osteoporosis.

SUBMITTER: Fujita Y

PROVIDER: S-EPMC7722686 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Decreased bone mineral density in ovariectomized mice is ameliorated after subsequent repeated intermittent administration of (R)-ketamine, but not (S)-ketamine.

Fujita Yuko Y Hashimoto Kenji K

Neuropsychopharmacology reports 20200819 4

<h4>Aim</h4>Depression is a common symptom in people with osteoporosis. (R)-ketamine produced greater potency and longer-lasting antidepressant-like actions than (S)-ketamine in rodents. Here, we examined the effects of two ketamine enantiomers on the reduced bone mineral density (BMD) in the ovariectomized (OVX) mice which is an animal model of postmenopausal osteoporosis.<h4>Methods</h4>Female ddY mice were OVX or sham-operated. Subsequently, saline (10 mL/kg/d, twice weekly), (R)-ketamine (10 ...[more]

PMID: 32812706

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Project description:Genetic risk of low bone mineral density in women remains unclear. This study found that a large percentage of Caucasian women have a high genetic risk of osteoporosis, and genetic risk scores are significantly associated with BMD variation in a bone healthy sample of Caucasian women. INTRODUCTION:We aimed to examine the distribution of risk alleles in an independent sample and to determine if such genetic components are associated with bone mineral density (BMD) variation in the sample. METHODS:Existing genotype data of 1205 women in the cross-sectional Genomic Wide Scans for Female Osteoporosis Gene Study (GWSFO) were analyzed. Multi-loci genetic risk scores (GRSs) based on 62 BMD-associated single nucleotide polymorphisms (SNPs) were calculated. Regression analysis was employed to assess the association between GRSs and BMD. To examine the effect of SNPs clustered within key pathways associated with the development of osteoporosis, subtype weighted GRS specific to WNT signaling (6 SNPs), RANK-RANKL-OPG (3 SNPs), and mesenchymal stem differentiation (3 SNPs) were generated for analysis. RESULTS:The unweighted GRS ranged from 48 to 80. One third of the women carried 66% risk alleles. After adjusting for age, height, and body weight, each unit increase of weighted GRS was associated with a decrease in BMD of 0.097 at femur (p?<?0.0001) and 0.110 (p?<?0.0001) at lumbar spine. The weighted GRS accounted for only 3.17-4.52% of BMD variance. The WNT signaling pathway GRS (6 SNPs) and the RANK-RANKL-OPG signaling pathway GRS (3 SNPs) both were significantly associated with decreased BMD at femur neck (p?=?0.0004 and p?=?0.0063, respectively) and lumbar spine (p?<?0.0001 and p?=?0.0001, respectively), while the mesenchymal stem cell differentiation pathway (3 SNPs) GRSs were associated only with the lumbar spine BMD (p?=?0.045). CONCLUSIONS:A substantially large percentage of healthy Caucasian women have a high genetic risk of osteoporosis. Weighted GRS was significantly associated with decreased BMD. The contribution of subtype GRS to the BMD variation differs by specific biological pathway and skeletal regions.

Project description:ObjectivesCathepsin K is expressed by osteoclasts and synovial fibroblasts and degrades key components of bone and cartilage. Inhibition of cathepsin K protease activity may be beneficial for the prevention of bone erosion and cartilage degradation in rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) rat model is well established for studying the pathology and treatment of RA. We investigated the effect of ONO-KK1-300-01, a cathepsin K inhibitor (CKI), on arthritis and bone mineral density (BMD) in rats with CIA.MethodsSeven-month-old female Sprague Dawley rats were divided into 5 groups: rats without CIA (CNT); CIA rats that underwent ovariectomy (OVX) and were treated with CKI; CIA rats that underwent OVX and were treated with vehicle (Veh); CIA rats that underwent sham surgery and were treated with CKI; and CIA rats that underwent sham surgery and were treated with Veh. CKI was orally administered at a dose of 15 mg/kg, thus initiating collagen sensitization, until death at 4 weeks. We evaluated hind paw thickness and the arthritis score every week until death. Radiographs of the resected left foot were obtained with a soft X-ray apparatus. Destruction of bone and cartilage was classified and scored as previously described by Engelhardt et al. BMD was measured by bone densitometry at the halfway point between the distal metaphysis and the diaphysis of the resected right femur. We also performed histomorphometry of the proximal left tibia, histological evaluation of arthritis, and a bone strength test.ResultsCKI administration significantly reduced hind paw thickness and the arthritis score, and prevented a decrease in BMD. The radiographic score was significantly lower in the CKI group than in the Veh group. In the histomorphometric analysis, bone-resorption parameters were significantly lower in the CKI groups than in the Veh groups. CKI significantly inhibited synovial proliferation in the CIA rats. In the bone strength test, the ultimate stress was significantly higher in the CKI groups than in the Veh groups.ConclusionOur findings indicate that cathepsin K inhibitors may inhibit systemic and local bone loss, ameliorate arthritis, and attenuate the decrease of bone strength in an animal model of arthritis.

Project description:BackgroundDue to unmet clinical needs for efficient drugs with a rapid onset of antidepressant effects, we aimed to evaluate the efficacy of single-dose ketamine in different subgroups of patients with major depression and establish whether repeated ketamine administration could be a viable strategy to maintain treatment gains.MethodsElectronic databases (Medline via PubMed, Embase, Cochrane Library, Trip Database) were systematically searched until February 22, 2019, for published peer-reviewed randomized controlled trials (RCTs) concerning a single and repeated administration of ketamine in patients with major depression. All relevant RCTs were selected and critically appraised, and a meta-analysis of eligible studies was performed.ResultsA total of 20 studies were included in the meta-analysis. The largest effect of ketamine vs. controls in reducing depressive symptoms was observed at 24 h (SMD = - 0.89; 95% CI - 1.24; - 0.53; p < 0.00001); however, a significant difference was shown for up to 7 days after a single dose. Significant differences compared with controls were observed for up to 7 days in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, while there were no significant differences at 7 days when ketamine was used as monotherapy. In patients with major depression, initial antidepressant effects of ketamine were maintained during repeated dosing. At 2-3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD = - 0.70; 95% CI - 1.15; - 0.25 or SMD = - 0.81; 95% CI - 1.41; - 0.20 (depending on the dosing regimen used); p ≤ 0.009 vs placebo.ConclusionsOur meta-analysis revealed rapid and robust antidepressant effects of single-dose ketamine in patients with treatment-resistant depression (TRD). By pooling data from RCTs, we showed for the first time that repeated ketamine administration is effective in sustaining initial antidepressant effects observed after single dosing.

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Decreased bone mineral density in ovariectomized mice is ameliorated after subsequent repeated intermittent administration of (R)-ketamine, but not (S)-ketamine.

Publications

Decreased bone mineral density in ovariectomized mice is ameliorated after subsequent repeated intermittent administration of (R)-ketamine, but not (S)-ketamine.

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