Rationale Acute antipsychotic treatment disrupts conditioned avoidance responding, and repeated treatment induces a sensitization- or tolerance-like effect. However, the neurochemical mechanisms underlying both acute and repeated antipsychotic effects remain to be determined. Objective The present study examined the neuroreceptor mechanisms of haloperidol, clozapine, and olanzapine effect in a rat two-way conditioned avoidance model. Methods Well-trained Sprague–Dawley rats were administered with haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with either saline, quinpirole (a selective dopamine D2/3 agonist, 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI; a selective 5-HT2A/2C agonist, 2.5 mg/kg, sc), and their conditioned avoidance responses were tested over 3 days. After 2 days of drug-free retraining, the repeated treatment effect was assessed in a challenge test. Results Pretreatment of quinpirole, but not DOI, attenuated the acute haloperidol-induced disruption of avoidance responding and to a lesser extent, olanzapine-induced disruption. In contrast, pretreatment of DOI, but not quinpirole, attenuated the acute effect of clozapine. On the repeated effect, pretreatment of DOI, but not quinpirole, attenuated the potentiated disruption of haloperidol, whereas pretreatment of quinpirole attenuated the potentiated disruption of olanzapine but enhanced the tolerance-like effect of clozapine. Conclusions These findings suggest that acute haloperidol and olanzapine disrupt avoidance responding primarily by blocking dopamine D2 receptors, whereas acute clozapine exerts its disruptive effect primarily by blocking the 5-HT2A receptors. The repeated haloperidol effect may be mediated by 5-HT2A/2C blockade-initiated neural processes, whereas the repeated clozapine and olanzapine effect may be mediated by D2/3 blockade-initiated neural processes.

PurposeThe aim of this study was to evaluate the therapeutic efficacy and safety of mesenchymal stem cells (MSCs) for the treatment of patients with knee osteoarthritis (OA).MaterialsWe performed a meta-analysis of relevant published clinical studies. An electronic search was conducted for randomized controlled trials (RCTs) of MSC-based therapy in knee OA. The visual analogue scale (VAS), International Knee Documentation Committee (IKDC) form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne algofunctional indices (Lequesne), Lysholm knee scale (Lysholm), Tegner activity scale (Tegner) and adverse events (AEs) were evaluated.ResultsEleven eligible trials with 582 knee OA patients were included in the present meta-analysis. We demonstrated that MSC treatment could significantly decrease VAS and increase IKDC scoresafter a 24-month follow-up compared with controls (P<0.05). MSC therapy also showed significant decreases in WOMAC and Lequesne scores after the 12-month follow-up (P<0.01). Analysis of Lysholm (24-month) and Tegner (12- and 24-month) scores also demonstrated favorable results for MSC treatment (P<0.05).ConclusionOverall, MSC transplantation treatment was shown to be safe and has great potential as an efficacious clinical therapy for patients with knee OA.

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We investigated whether the activation of astroglial group II and III metabotropic glutamate receptors (mGluRs) could exert neuroprotective effects and whether the neuroprotection was related to glutamate uptake. Our results showed that the activation of astroglial group II or III mGluRs exerted neuroprotection against 1-methyl-4-phenylpyridinium (MPP + ) astroglial conditioned medium-induced neurotoxicity in midbrain neuron cultures. Furthermore, MPP + decreased glutamate uptake of primary astrocytes and C6 glioma cells, which was recovered by activating group II or III mGluRs. Specific group II or III mGluRs antagonists completely abolished the neuroprotective effects and the enhancement of glutamate uptake of their respective agonists. Our results showed that the primary cultured rat astrocytes and C6 glioma cells expressed receptor proteins for group II mGluR2/3, group III mGluR4, mGluR6 and mGluR7. C6 glioma cells expressed mRNA for group II mGluR3, group III mGluR4, mGluR6, mGluR7 and mGluR8. In conclusion, we confirmed that the activation of astroglial mGluRs exerted neuroprotection, and demonstrated that the mechanism underlying this protective role was at least partially related to the enhancement of glutamate uptake.

As activated microglia (MG) is an early sign that often precedes and triggers neuronal death, inhibition of microglial activation and reduction of subsequent neurotoxicity may offer therapeutic benefit. The present study demonstrates that rat primary cultured MG expressed Kir6.1 and SUR2 subunits of KATP channel, which was identical to that expressed in BV-2 microglial cell line. The classic KATP channel opener pinacidil and selective mitochondrial KATP (mito-KATP) channel opener diazoxide prevented rotenone-induc microglial activation and production of pro-inflammatory factors (tumour necrosis factor[TNF]-α and prostaglandin E2[PGE2]). And the effects of pinacidil and diazoxide were reversed by mito-KATP blocker 5-hydroxydecanoate (5-HD), indicating that mito-KATP channels participate in the regulation of microglial activation. Moreover, the underlying mechanisms involved the stabilization of mitocho drial membrane potential and inhibition of p38/c-Jun-N-terminal kinase (JNK) activation in microglia. Furthermore, the in vivo study confirmed that diazoxide exhibited neuroprotective effects against rotenone along with the inhibition of microglial activation and neuroinflammation. Thus, microglial mito-KATP channel might be a novel prospective target for the treatment of neuroinflammation-related degenerative disorders such as Parkinson's disease.

Both short (<7 hours) and long sleep durations (>9 hours) can increase the risk of overall cardiovascular disease mortality, particularly in Asian populations and elderly individuals. Future epidemiological studies would ideally include objective sleep measurements, rather than self-report measures, and all potential confounders, such as genetic variants.

The present study was designed to assess the role of 5-HT2A/2C receptors in the acute and repeated effect of clozapine and olanzapine in a rat conditioned avoidance response model (CAR), a validated model of antipsychotic activity. Male Sprague-Dawley rats that were previously treated with either phencyclidine (0.5-2.0 mg/kg, sc), amphetamine (1.25-5.0 mg/kg, sc), or saline and tested in a prepulse inhibition of acoustic startle study were used. They were first trained to acquire avoidance response to a white noise (CS1) and a pure tone (CS2) that differed in their ability to predict the occurrence of footshock. Those who acquired avoidance response were administered with clozapine (10.0 mg/kg, sc) or olanzapine (1.0 mg/kg, sc) together with either saline or 1-2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT2A/2C agonist, 1.0 or 2.5 mg/kg, sc), and their conditioned avoidance responses were tested for four consecutive days. After two drug-free retraining days, the long-term repeated effect was assessed in a challenge test during which all rats were injected with a low dose of clozapine (5 mg/kg, sc) or olanzapine (0.5 mg/kg). Results show that pretreatment of DOI dose-dependently reversed the acute disruptive effect of clozapine on both CS1 and CS2 avoidance responses, whereas it had little effect in reversing the acute effect of olanzapine. On the challenge test, pretreatment of DOI did not alter the clozapine-induced tolerance or the olanzapine-induced sensitization effect. These results confirmed our previous findings and suggest that clozapine, but not olanzapine acts on through 5-HT2A/2C receptors to achieve its acute avoidance disruptive effect and likely its therapeutic effects. The long-term clozapine tolerance and olanzapine sensitization effects appear to be mediated by non-5-HT2A/2C receptors.