Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages prevents schizophrenia-relevant phenotypes in adult offspring after maternal immune activation: a role of TrkB signaling

Maternal immune activation (MIA) plays a role in the etiology of schizophrenia. MIA by prenatal exposure of polyinosinic:polycytidylic acid [poly(I:C)] in rodents caused behavioral and neurobiological changes relevant to schizophrenia in adult offspring. We investigated whether the novel antidepressant (R)-ketamine could prevent the development of psychosis-like phenotypes in adult offspring after MIA. We examined the effects of (R)-ketamine (10 mg/kg/day, twice weekly for 4 weeks) during juvenile and adolescent stages (P28–P56) on the development of cognitive deficits, loss of parvalbumin (PV)-immunoreactivity in the medial prefrontal cortex (mPFC), and decreased dendritic spine density in the mPFC and hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, we examined the role of TrkB in the prophylactic effects of (R)-ketamine. Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages significantly blocked the development of cognitive deficits, reduced PV-immunoreactivity in the prelimbic (PrL) of mPFC, and decreased dendritic spine density in the PrL of mPFC, CA3 and dentate gyrus of the hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, pretreatment with ANA-12 (TrkB antagonist: twice weekly for 4 weeks) significantly blocked the beneficial effects of (R)-ketamine on cognitive deficits of adult offspring after prenatal poly(I:C) exposure. These data suggest that repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages could prevent the development of psychosis in adult offspring after MIA. Therefore, (R)-ketamine would be a potential prophylactic drug for young subjects with high-risk for psychosis.

Intermittent administration sodium valproate has a protective effect on bone health in ovariectomized rats

Objective: the present work was aimed to evaluate the effect of different administration modes of sodium valproate(VPA) on bone strength, bone mass and bone mineral density in ovariectomized(OVX) rats and further investigation of the possible mechanism. Methods: 60 female SD rats were randomly divided into 4 groups: Sham group (Sham, n=15), OVX group (OVX, n=15), OVX rats received intermittent VPA treatment group(IVPA, n=15) and OVX rats received daily VPA treatment group(EVPA, n=15). After 12 weeks of treatment, the rats were sacrificed, and serum and femur samples were harvested. DEXA, Micro-CT, histology, biomechanical testing, biochemical index and western blot analysis were used to observe the therapeutic effect and explore the possible mechanism. Results: Micro-CT and DEXA analysis of bones revealed better BMD and higher BV/TV, Tb.Th, Tb.N, Conn. D and lower Tb.Sp at femoral metaphysis with evaluated in IVPA when compared with OVX and EVPA group(P＜0.05). Histological, fluorescent analysis and biological strength revealed more trabecular bone and higher relative mineral apposition rate, maximal load, elastic modulus and energy at break with evaluated in IVPA when compared with OVX and EVPA group(P＜0.05). The levels of P1NP, estrogen, CTX, TRAP5b and RANKL of IVPA group showed a significant increase when compared with the OVX and EVPA group(P＜0.05). We confirm adverse effects on protein expressions including Notch1, Jagged1, HEY1, Wnt 1, β‐catenin and RUNX2 following daily VPA treatment in OVX female rats. Conclusions: Our current study demonstrated that intermittent administration sodium valproate has a protective effect on bone health in ovariectomized rats and these effects may be achieved by activating Notch/Wnt/β-catenin/ RUNX2 signal axis.

MO544EFFECT OF DIFFERENT FREQUENCY OF FG-4592 ON CHRONIC KIDNEY DISEASE

Background and Aims Hypoxia inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is a novel small molecule inhibitor in clinical treatment for renal anemia. Several studies have shown that sustained HIF activation may also have deleterious effects, such as tubulointerstitial fibrosis. Here, the potential effects of different treatment frequency of HIF-PHI (FG-4592) on CKD (chronic kidney disease) mice were investigated. Method Male C57BL/6J mice were constructed by subtotal nephrectomy of 5/6 to serve as a model for CKD. We then compared four different strategies based on the frequency of FG-4592(intragastric administration, 30mg/kg) over 9 weeks: once a week (qw), twice a week (biw), three times a week (tiw), and every day (qd). In vitro, HK-2 cells were divided into three groups according to the different administration methods of FG-4592(30μM): FG-4592 for 20h (FG0); FG-4592 for 8h, followed by washing with medium for 12h(FG1); twice FG-4592 for 8h, followed by washing twice with medium for2h(FG2). Results Hemoglobin in the biw group, tiw group or qd group was significantly higher than that in vehicle group. EPO, HIF-1α and HIF-2α of tiw group, biw group and qd group were significantly higher than those in vehicle group. Makers of fibrosis and inflammation in qd group were higher than that in vehicle group, while there was no statistical difference in the changes of the above indicators in tiw group and biw group. HIF-1α and HIF-2α were increased in intermittent administration, but the expression of VEGF, makers of fibrosis or inflammation were not affected. In HK2, HIF-1α and HIF-2α were activated by continuous administration of FG-4592. At the same time, the expression of VEGF, inflammatory and fibrosis indicators were increased significantly during continuous administration. In HepG2, EPO was increased in intermittent administration in HepG2 cells without VEGF increasing. Conclusion Taken together, our studies demonstrated that FG-4592 administration 2-3 times a week can effectively improve renal anemia without side effects on inflammatory and fibrosis.