RIS Treatment Research Articles

Risperidone accelerates bone loss in mice models of schizophrenia by inhibiting osteoblast autophagy

BackgroundRisperidone (RIS) is the first-line drug in the clinical treatment of schizophrenia, and long-term use may lead to bone loss and even osteoporosis. This study investigated whether the mechanism of RIS-induced bone loss is related to autophagy. MethodsThe schizophrenia mice were established with the administration of MK-801. Then, RIS were injected, or autophagy inducer rapamycin (RAPA) co-injected for 8 weeks. Cognitive performance was determined by the novel object recognition and Open field tests. Bone loss of schizophrenia mice were assessed using microCT, H&E staining, ALP staining, ARS staining and WB, respectively. Autophagy of schizophrenia mice were detected by immunofluorescence, transmission electron microscopy (TEM) and WB, respectively. In addition, osteogenic differentiation of MC3T3-E1 and BMSCs cells were assessed using H&E staining, ALP staining, ARS staining and WB, respectively. ResultsIn the present study, we found that RIS treatment can promote bone loss in schizophrenia mice and inhibit osteogenic differentiation of MC3T3-E1 and BMSCs cells. Interesting, the number of autophagosome and autophagy-related protein expression were decreased after RIS treatment. However, the bone loss and inhibition of osteogenic differentiation induced by RIS in schizophrenia mice were reversed by autophagy inducer RAPA. ConclusionRIS significantly increased bone loss and inhibited osteogenic differentiation in schizophrenia mice; the underlying mechanism entails suppressing osteoblast autophagy.

Skeletal and mineral metabolic effects of risedronate in a rat model of high-turnover renal osteodystrophy.

High-turnover bone disease is a major consequence of SHPT and may explain the high risk for fracture in patients with advanced chronic kidney disease (CKD). Bisphosphonates suppress bone turnover and improve bone strength, but their effects have not been fully characterized in advanced CKD with severe SHPT. Bisphosphonates also increase 1,25-dihydroxyvitamin D levels in normal and uremic rats, but the underlying mechanism remains to be determined. We investigated the skeletal and mineral metabolic effects of RIS, a pyridinyl bisphosphonate, in rats with severe SHPT induced by 5/6 nephrectomy plus a high phosphate diet. Nephrectomized rats developed severe SHPT, along with hyperphosphatemia, low 1,25-dihydroxyvitamin D, and markedly increased FGF23. Moreover, these rats exhibited characteristic features of high-turnover renal osteodystrophy, including increased indices of trabecular bone turnover, decreased cortical bone thickness, inferior cortical biomechanical properties, and a prominent increase in peritrabecular fibrosis. RIS treatment increased bone volume and partially attenuated trabecular bone remodeling, cortical bone loss, and mechanical properties, whereas it produced a marked improvement in peritrabecular fibrosis along with a corresponding decrease in osteogenic gene markers. RIS treatment also suppressed the elevation of FGF23, which was associated with increased 1,25-dihydroxyvitamin D. In a rat model of severe SHPT, treatment with RIS partially attenuated histological manifestations of high-turnover bone disease. RIS treatment also suppressed the elevation of FGF23, which may explain the increased 1,25-dihydroxyvitamin D production during the treatment.

Importance of intervention timing in the effectiveness of antipsychotics

The use of early pharmacological intervention in treating young patients with schizophrenia is a debating issue for psychiatrists. However, on the basis of developmental theory, early antipsychotic intervention can be beneficial in terms of protecting neurons from further deterioration. This study investigated whether the initiation of second-generation antipsychotic (SGA) treatment at a younger age can effectively reverse schizophrenia-relevant behavioral and neurochemical features, namely acoustic prepulse inhibition (PPI) and accumbal dopamine (DA) efflux, respectively. Risperidone (RIS, 1mg/kg/day) or olanzapine (OLA, 2.5mg/kg/day) was administered for 6weeks in rats subjected to isolation rearing (IR) in adolescence or young adulthood. Behavioral testing was performed at 3 and 5 (for locomotor activity) and 2 and 4 (for PPI) weeks after the initiation of the pharmacological regimen. An additional PPI test was performed 6weeks after the initiation of the pharmacological regimen to assess the acute add-on effect of RIS or OLA. Dopamine (DA) efflux of the nucleus accumbens was evaluated through in vivo microdialysis at the end of the study, for measuring both the baseline levels after the chronic regimen and the responsiveness to acute add-on RIS or OLA treatment. Our results demonstrated that the effects of SGAs on PPI and accumbal DA efflux were dissociated. Specifically, RIS intervention was more beneficial for adolescent than young adult IR rats in restoring their PPI deficit, whereas OLA was age-independently effective in stimulating the accumbal DA efflux. Both PPI and accumbal DA could be employed to reflect IR-induced abnormalities, in which accumbal DA appeared to be more suitable in depicting the long-term effect of IR, whereas PPI might be a more accurate biological index for revealing the advantages of early RIS intervention.

Expression of mRNA of Neurotrophic Factors and their Receptors are Significantly Altered After Subchronic Ketamine Treatment

The neurotrophic factors play an important role in the maintenance of neurone viability and neuronal communication which are considered to be altered in schizophrenia. Subchronic application of ketamine (Ket) was found to be a useful model in schizophrenia research. To further validate this model the mRNA levels of neurotrophic factors NGF, NT-3, and BDNF and their receptors TrkA, TrkB, and TrkC, respectively, were measured in different brain areas in Ket-pretreated rats subchronically dosed with the atypical antipsychotic drug risperidone (Ris). With the exception of NGF in the frontal cortex, Ket pretreatment did change NGF, NT-3, and BDNF mRNA levels in the frontal cortex, the hippocampus, the striatum, the thalamus/hypothalamus region, and in the cerebellum. These changes correspond with changes at their tyrosine kinase receptors. Ris treatment normalised altered NT-3 levels in the hippocampus and balanced BDNF levels in the same structure. It was concluded that the Ket model might reflect distinct alterations in neurotrophic factor activity as found in schizophrenic patients and, moreover, that Ris treatment rebalances disturbed neurotrophic factor activity.

Comparative Effects of Risedronate and Calcitriol on Cancellous Bone in Rats with Glucocorticoid-Induced Osteopenia

To compared the effects of risedronate (Ris) and calcitriol (Cal) on cancellous bone in rats with glucocorticoid (GC)-induced osteopenia. Thirty female Sprague-Dawley rats, 4 mo of age, were randomly divided by the stratified weight method into three groups of 10 rats each according to the following treatment schedule: 8-wk GC administration with 4-wk vehicle (control), Ris, and Cal as therapeutic treatment initiated after 4-wk GC administration. The GC (methylprednisolone sodium succinate, 5.0 mg/kg, s.c.), Ris (10 microg/kg, s.c.), and Cal (0.1 microg/kg. p.o.) were administered 3 times a week. At the end of the 8-wk treatment period, two-dimensional (2D) bone histomorphometric analysis was performed for cancellous bone of the proximal tibial metaphysis, 3D micro-computed tomographic analysis was performed for the distal femoral metaphysis, and the mechanical strength of the distal femoral metaphysis was evaluated by a compression test. Ris and Cal treatment increased both 2D and 3D cancellous bone mass. However, Ris treatment exhibited more pronounced effects on 2D and 3D cancellous bone mass than Cal treatment, and the effects of both Ris and Cal treatment were greater on 3D cancellous bone mass than on 2D cancellous bone mass. The response of 2D and 3D cancellous bone mass to Ris treatment was characterized by its effect on trabecular number and thickness, which was associated with markedly suppressed bone resorption and bone formation in terms of suppressed bone turnover. On the other hand, the response of 2D cancellous bone mass to Cal treatment was attributed to the effect of Cal on 2D trabecular thickness, and the response of 3D cancellous bone mass to Cal treatment might be characterized by the effect of Cal on 3D trabecular number and thickness, with a more marked effect of trabecular thickness. These effects were primarily due to mildly suppressed bone resorption and maintained or even increased bone formation. Despite the differential effect of Ris and Cal treatment on the cancellous bone structure and bone metabolism, both treatment increased the maximum load and braking energy of the distal femoral metaphysis to a similar extent, suggesting different mechanisms for improving bone strength. This study showed the differential effects of Ris and Cal on cancellous bone in rats with GC-induced osteopenia.

Preventive Effects of Risedronate and Calcitriol on Cancellous Osteopenia in Rats Treated with High-Dose Glucocorticoid

We compared the effects of risedronate (Ris) and calcitriol (Cal) on cancellous osteopenia in rats treated with high-dose glucocorticoid (GC). Forty female Sprague-Dawley rats, 4 months of age, were randomized by the stratified weight method into four groups of 10 rats each according to the following treatment schedule: intact control, and GC administration with vehicle, Ris, or Cal. The GC (methylprednisolone sodium succinate, 5.0 mg/kg, s.c.), Ris (10 microg/kg, s.c.), and Cal (0.1 microg/kg, p.o.) were administered 3 times a week. At the end of the 4-week treatment period, bone histomorphometric analysis was performed for cancellous bone of the proximal tibial metaphysis. The GC administration decreased cancellous bone volume (BV/total tissue volume [TV]), trabecular number (Tb N), and trabecular thickness (Tb Th), as a result of increased bone resorption and decreased bone formation. Ris treatment markedly increased cancellous BV/TV and Tb N above the control level as a result of suppressed bone turnover. On the other hand, Cal treatment attenuated the GC-induced decrease in cancellous BV/TV and Tb Th as a result of suppressed bone resorption and maintained bone formation. This study showed the differential effects of Ris and Cal on cancellous osteopenia in rats treated with high-dose GC.

Effects of risedronate on femoral bone mineral density and bone strength in sciatic neurectomized young rats

Immobilization induces a rapid loss of bone density and bone strength in rats. The purpose of the present study was to examine the effects of risedronate (Ris) on the femoral bone density and bone strength of sciatic neurectomized young rats. Forty male Sprague-Dawley rats, 6 weeks of age, were randomized by the stratified weight method into the following four treatment groups of 10 rats each: sham-operation, bilateral sciatic neurectomy (NX), NX + low-dose Ris (0.25 mg/kg/day, orally), and NX + high-dose Ris (0.5 mg/kg/day, orally). After 8 weeks of feeding, the volumetric bone mineral density (vBMD) and stress strain index (SSI) of the femoral distal metaphysis and middiaphysis of the rats were measured by peripheral quantitative computed tomography. The mechanical properties of the femoral distal metaphysis and middiaphysis were measured by the compression and three-point bending tests, respectively. The femoral length was also measured. As compared with the findings in the sham-operated controls, NX resulted in a loss of femoral length, cancellous vBMD, SSI, maximum load, stiffness, and breaking energy of the femoral distal metaphysis; there was also loss of cortical thickness, SSI, maximum load, and stiffness of the femoral middiaphysis, with no significant effects on the cortical vBMD or breaking energy of the femoral middiaphysis. High-dose Ris increased the vBMD to values higher than those in the sham-operated controls, and prevented the loss of SSI, maximum load, and stiffness of the femoral distal metaphysis, while low-dose Ris prevented the loss of cancellous vBMD of the femoral distal metaphysis. Neither high- nor low-dose Ris affected any of the cortical bone parameters of the femoral middiaphysis, except for cortical thickness, or the femoral length. These findings suggest that Ris may prevent immobilization-induced loss of cancellous bone density and bone strength in a dose-dependent manner without interfering with bone growth, but has no apparent effects on the cortical bone in sciatic neurectomized young rats. The results of the present preclinical study should be taken into consideration prior to the commencement of Ris treatment for disabled children.

Long-Term Disuse Osteoporosis Seems Less Sensitive to Bisphosphonate Treatment Than Other Osteoporosis

We sought to determine whether risedronate can preserve cortical bone mass and mechanical properties during long-term disuse in dogs, assessed by histomorphometry and biomechanics on metacarpal diaphyses. Risedronate slowed cortical thinning and partially preserved mechanical properties, but it was unable to suppress bone loss to the degree seen in other osteoporoses. Disuse induces dramatic bone loss resulting from greatly elevated osteoclastic resorption. Targeting osteoclasts with antiresorptive agents, such as bisphosphonates, should be an effective countermeasure for preventing disuse osteoporosis. Single forelimbs from beagles (5-7 years old, n = 28) were immobilized (IM) for 12 months. Age-matched, non-IM dogs served as controls. One-half the animals received either risedronate (RIS, 1 mg/kg) or vehicle daily. Histomorphometry was performed on second metacarpal mid-diaphyses. Cortical mechanical properties were determined by testing third metacarpal diaphyses in four-point bending. IM caused marked reduction in cortical area (-42%) and cortical thinning (-40%) through endocortical resorption, extensive intracortical tunneling, and periosteal resorption; both bone resorption and formation were significantly elevated over control levels on all envelopes. IM also decreased maximum load and stiffness by approximately 80% compared with controls. RIS reduced both periosteal bone loss and marrow cavity expansion; however, cortical area remained significantly lower in RIS-treated IM animals than in untreated non-IM controls (-16%). RIS also increased resorption indices in all envelopes compared with nontreated IM, indicating that RIS suppressed osteoclast activity but not osteoclast recruitment. RIS did not affect bone formation. RIS treatment conserved some whole bone mechanical properties, but they were still significantly lower than in controls. There were no significant differences in tissue level material properties among the groups. RIS treatment reduces cortical bone loss at periosteal and endocortical surfaces caused by long-term immobilization, thus partially conserving tissue mechanical properties. This modest effect contrasts with more dramatic actions of the bisphosphonate in other osteoporoses. Our results suggest that risedronate impairs osteoclastic function but cannot completely overcome the intense stimulus for osteoclast recruitment during prolonged disuse.

A RIS treatment of the mean-square dipole moment of PMMA chains in consideration of the pendant ester group orientations

According to the six-state scheme proposed by Vacatello and Flory, the mean-square dipole moments 〈 M 2〉/ x ( x: number of monomeric units) of poly(methyl methacrylate) (PMMA) chains and their temperature dependence d ln 〈M 2〉/ dT were calculated by the matrix algebra method of rotational isomeric state theory. To take account of the orientation effect of polar ester groups, the statistical weight matrices, U′ and U″, were recast into an expanded form. A Bernoullian probability λ introduced to measure the preference between the two alternative orientations ( χ=0 and χ= π) of the side ester groups was found to give rise to a large effect on the mean-square dipole moment of polymers. When the skeletal bonds of a meso dyad are both in trans, an exceptionally strong dipole-dipole interaction may take place. If the two adjacent ester groups adopt the same orientation, the dipoles must be situated nearly parallel to each other in a close proximity. Such repulsive interactions may be alleviated by taking a staggered conformation, i.e. ( χ, χ′)=(0, π) or ( π,0). Such neighbor-dependent correlation inherent to the meso dyad is considered by assigning a parameter λ′ to the proper element of the U m ″ matrix. The values of 〈 M 2〉/ x observed at 30 °C were satisfactorily reproduced by adopting λ=0.270 and λ′=0.865. The thermal coefficients d ln 〈M 2〉/ dT were found to be reconciled with the available experimental data by allowing the orientation parameters λ and λ′ to be slightly temperature dependent. The stereochemical characteristics of the chain terminals were examined in order to extend the treatment to include the dipole moment of PMMA oligomers.

Skeletal effects of constant and terminated use of risedronate on cortical bone in ovariectomized rats.

To study the skeletal effects of continual and terminated use of risedronate treatment on cortical bone in ovariectomized (Ovx) rats, we used risedronate (Ris), 5 microg x kg(-1), by subcutaneous injections, twice per week. The middle part of the tibial shafts (Tx) were processed undecalcified for quantitive bone histomorphometry. Cortical bone and the marrow areas of the tibial shaft did not change in either sham-Ovx or Ovx rats during the 150-day experimental period. Continued administration of Ris for 150 days decreased the marrow area and increased the percentage of cortical area compared with the matching sham and Ovx group. A decrease in bone formation indices in both periosteal and endocortical surfaces of Tx in sham-operated rats between the age of 5 and 8 months was seen. Ovariectomy increased the percentage of labeled perimeter in the periosteal area, and markedly increased the percentage of eroded perimeter in the endocortical surface compared with sham control groups in 81 and 150 days. Bone formation indices of Ris treatment were increased in periosteal surfaces, and percentages of eroded perimeter were decreased more in endocortical surfaces in 150 days than in the matching sham and Ovx groups. These data matched our static data, which showed a significantly increased percentage of cortical bone area and decreased percentage of marrow area. These bone gains were not maintained in the 90-day Ris withdrawal group. For cancellous bone, the 60-day Ris-treated high bone mass was maintained in the withdrawal group and not maintained in Ris continmuously treated group. These results indicate the effects of constant and terminated use of Ris in cortical bone were different from those in trabecular bone in the proximal tibial metaphysis.

A new approach to polymer crystallization used in an analysis of data of syndiotactic polypropylene

AbstractUnder the conditions of “normal growth” on rough surfaces, crystallization rates follow from the balance between the attachment and detachment of the chain sequences building up the layer‐like crystallites. In the proposed model, detachment rates are related to the change in the mean‐field potentials experienced in the crystal and the melt; attachment rates are associated with the population number of straight sequences in the melt. Both rates show an exponential dependence on the sequence length. Combination of this picture with the basic kinetic criterion that the crystallite thickness found at a chosen crystallization temperature maximizes the growth rate yields equations that agree with the general observations. A detailed check of the model predictions is carried out in a discussion of data recently obtained for syndiotactic polypropylene. Attachment rates calculated using an RIS treatment are in fair agreement with those derived from the experimental data on the basis of the model.

Risperidone: a novel antipsychotic with many “atypical” properties?

The acute and chronic administration effects of risperidone (Ris), a mixed 5HT2/D2 receptor antagonist, versus haloperidol (Hal) on dopaminergic and serotoninergic activity were investigated in the rat prefrontal cortex (Pfc), and the whole striatum (Str) as well as separately, in dorsal striatum (StrD) and nucleus accumbens (Acb). During acute administration, Hal was found to be more potent than Ris in increasing DA turnover rate in StrD. In contrast, during chronic administration, Ris but not Hal, continued to increase DA turnover activity in StrD. Moreover, in contrast to Hal, chronic Ris treatment continued to increase DA and 5-HT turnover rate in Pfc. These differential effects reveal that Hal does not share common characteristics with Ris with respect to its neurochemical profile in the Str and Pfc.

Configurational statistics of poly(dimethylsiloxane). 2. A new rotational isomeric state approach

A new RIS treatment, compatible with the molecular mechanics and dynamics considerations of a preceding paper, is introduced. The model yields satisfactory agreement with experiments on the mean-square unperturbed end-to-end separations, the mean-square dipole moment and its temperature dependence, and the molar cyclization equilibrium constants for dimethylsiloxane oligomers. It cannot account for the positive temperature coefficient of the unperturbed chain dimensions

A molecular model for the strength of the dielectric β relaxation in methyl acrylate and vinyl acetate polymers

As a test of the supposition that flexible side-group motion is responsible for subglass relaxation in some polymers, a molecular model based on a RIS treatment for the overall relaxation, α glass-rubber relaxation+β process, has been developed for poly (methyl acrylate) and poly (vinyl acetate) homopolymers and their copolymers with ethylene. A good account of the experimental behavior was obtained throughout the subglass temperature range for the β processes in both PMA and PVAc homopolymers