Modulating NMDA receptors to treat MK-801-induced schizophrenic cognition deficit: effects of clozapine combining with PQQ treatment and possible mechanisms of action.

BACKGROUND: Clozapine has remarkable efficacy on both negative and cognitive symptoms of schizophrenia due to its slight activation of NMDA receptor. In fact, much evidence to the contrary. NMDAR is a complex containing specific binding sites, which are regulated to improve negative symptoms and cognitive deficits associated with individuals affected by schizophrenia. PQQ is a powerful neuroprotectant that specifically binds with NMDA receptors in the brain to produce beneficial physiological and cognitive outcomes. The aim of this study was to enhance NMDAR function and improve cognitive ability in schizophrenia by PQQ combined with clozapine. METHODS: Rats were divided into four groups (n = 5) including control (saline), model (MK-801, 0.5 mg·kg- 1·d- 1), atypical antipsychotic (MK-801 (0.5 mg·kg- 1·d- 1) + Clozapine (1.0 mg·kg- 1·d- 1), and co-agonist NMDA receptor (MK-801 (0.5 mg·kg- 1·d- 1) + Clozapine (0.5 mg·kg- 1·d- 1) + PQQ (1.0 µg·kg- 1·d- 1) group. Each group of rats was injected subcutaneously every day for 6 weeks. Behavior test, including stereotyped behavior, locomotor hyperactivity, learning and memory, was performed. The Western blot assay was performed to analyze the expression of GSK-3ß, Akt, NMDAR1, and MGLUR in rat hippocampus. RESULTS: Results indicated that clozapine and PQQ combination therapy can improve MK801-induced schizophrenia behavior including stereotyped behavior, locomotor hyperactivity and cognitive impairment. Furthermore, we found that modulating NMDA receptors could ameliorate the memory impairments in Mk-801 induced schizophrenia rats by reducing the expression of NMDAR1 and MGLUR3, decreasing hippocampal tau hyperphosphorylation and inhibiting apoptosis through Akt /GSK-3ß signaling pathway. CONCLUSIONS: These findings suggest that combination therapy for enhancing NMDA receptors may be able to rescue cognition deficit in schizophrenia. More studies are needed to better elucidate these mechanisms.

[Improvement of remote sensing ecological index in arid regions: Taking Ulan Buh Desert as an example]. / 干旱地区遥感生态指数的改进­­ä»¥ä¹Œå °å¸ƒå’Œæ²™æ¼ 为例.

The arid area is mainly composed of desert, with fragile eco-environment and being extremely vulnerable to the influence of natural and human perturbations. Based on the remote sen-sing ecological index (RSEI), the arid remote sensing ecological index (ARSEI) was formed to improve the remote sensing ecological index for arid area, which was coupled with the information of greenness, humidity, salinity, heat and land degradation to quantitatively evaluate the eco-environment quality. We used ARSEI and RSEI to dynamically monitor and evaluate the eco-environment quality of Ulan Buh Desert from 2000 to 2019, and analyzed their differences and their applicability in arid area. We further examined the characteristics and reasons of the temporal and spatial variations of the eco-environment quality of Ulan Buh Desert. The results showed that the ARSEI index had better applicability to the eco-environment quality in arid area than the RSEI, and it enhanced the role of land use changes in the ecological environment quality assessment. From 2000 to 2019, the overall eco-environmental quality of Ulan Buh Desert was worse. The parts under better, good, and medium grades were mainly distributed in the northern region, the parts with worse grades were mainly concentrated in the gobi and sandy land, and the poor ones were mainly located in area with low coverage vegetation. From 2000 to 2019, the overall quality of the eco-environment in the Ulan Buh Desert were becoming better. Meanwhile, the eco-environment quality of towns and farms in the northern part of the desert changed complexly, with deterioration and improvement alternately distributed. The main reason for the changes in the eco-environment of Ulan Buh Desert was the positive effects of ecological agriculture and sand industry.

Dehydroepiandrosterone activates cyclic adenosine 3',5'-monophosphate/protein kinase A signalling and suppresses sterol regulatory element-binding protein-1 expression in cultured primary chicken hepatocytes.

Dehydroepiandrosterone (DHEA), a steroid hormone that is secreted by the adrenal cortex in mammals, has an array of biological actions, including inhibition of fat synthesis, decreasing the number of adipocytes, and a reduction in mammalian metabolic efficiency. Recent studies showed that DHEA may decrease fat deposition in poultry, but the mechanism of action is unclear. In the present study, we demonstrate that DHEA stimulates intracellular cyclic adenosine 3',5'-monophosphate (cAMP) accumulation in chicken hepatocytes during a 30 min incubation period. Increases in intracellular cAMP are evoked by as low as 0.1 microm-DHEA. The cAMP induced by DHEA, while suppressing cAMP-specific phosphodiesterase activity, also activates cAMP-dependent protein kinase A (PKA) in chicken hepatocytes. In addition, the activation of PKA leads to down-regulation of sterol regulatory element-binding protein-1 (SREBP-1). These findings demonstrate that direct action by DHEA leads to activation of the cAMP/PKA signalling system in the modulation of lipid metabolism by repressing SREBP-1, thereby providing a novel explanation for some of the underlying effects proposed for DHEA in the prevention of fat deposition in poultry.

Effects of anesthetics on vesicular monoamine transporter type 2 binding to ¹8F-FP-(+)-DTBZ: a biodistribution study in rat brain.

OBJECTIVES: The in vivo binding analysis of vesicular monoamine transporter type 2 (VMAT2) to radioligand has provided a means of investigating related disorders. Anesthesia is often inevitable when the investigations are performed in animals. In the present study, we tested effects of four commonly-used anesthetics: isoflurane, pentobarbital, chloral hydrate and ketamine, on in vivo VMAT2 binding to (18)F-FP-(+)-DTBZ, a specific VMAT2 radioligand, in rat brain. METHODS: The transient equilibrium time window for in vivo binding of (18)F-FP-(+)-DTBZ after a bolus injection was firstly determined. The brain biodistribution studies under anesthetized and awake rats were then performed at the equilibrium time. Standard uptake values (SUVs) of the interest brain regions: the striatum (ST), hippocampus (HP), cortex (CX) and cerebellum (CB) were obtained; and ratios of tissue to cerebellum were calculated. RESULTS: Isoflurane and pentobarbital did not alter distribution of (18)F-FP-(+)-DTBZ in the brain relative to the awake group; neither SUVs nor ratios of ST/CB and HP/CB were altered significantly. Chloral hydrate significantly increased SUVs of all the brain regions, but did not significantly alter ratios of ST/CB and HP/CB. Ketamine significantly increased SUVs of the striatum, hippocampus and cortex, and insignificantly increased the SUV of the cerebellum; consequently, ketamine significantly increased ratios of ST/CB and HP/CB. CONCLUSIONS: It is concluded that in vivo VMAT2 binding to (18)F-FP-(+)-DTBZ are not altered by isoflurane and pentobarbital, but altered by chloral hydrate and ketamine. Isoflurane and pentobarbital may be promising anesthetic compounds for investigating in vivo VMAT2 binding. Further studies are warranted to investigate the interactions of anesthetics with VMAT2 binding potential with in vivo PET studies.

Preparation of 99mTc-PQQ and preliminary biological evaluation for the NMDA receptor.

Pyrroloquinoline quinone (PQQ), an essential nutrient, antioxidant, redox modulator and nerve growth factor found in a class of enzymes called quinoproteins, was labeled with 99mTc by using stannous fluoride (SnF2) method. Radiolabeling qualification, quality control and characterization of 99mTc-PQQ and its biodistribution studies in mice were performed and discussed. Effects of pH values, temperature, time and reducing agents concentration on the radiolabeling yield were investigated. The quality control procedure of 99mTc-PQQ was determined by thin layer chromatography (TLC), radio high-performance liquid chromatography (RHPLC) and paper electrophoresis methods. The average radiolabeling yield was 94 ± 1% under optimum conditions of 0.99 mg of PQQ, 30 µg of SnF2, 0.5 mg of ethylenediaminetetraacetic acid disodium salt (EDTA-2Na) and 18.5 MBq of Na99mTcO4 at pH 6 and 25 °C with a response volume of 1 ± 0.1 mL. 99mTc-PQQ was stable and anionic. Lipid-water partition coefficient of 99mTc-PQQ was -1.49 ± 0.16. The pharmacokinetics parameters of 99mTc-PQQ were t1/2α = 18.16 min, t1/2ß = 100.45 min, K12 = 0.013 min-1, K21 = 0.017 min-1, Ke = 0.016 min-1, AUC (area under the curve) = 1040.78 ID% g-1 min and CL (plasma clearance) = 0.096 mL min-1. The dual-exponential equation was Y = 10.88e-0.038t  + 5.21e-0.0069t . The biodistribution of 99mTc-PQQ was studied in ICR (Institute for Cancer Research 7701 Burhelme Are., Fox Chase, Philadelphia, PA 1911 USA) mice. In vitro autoradiographic studies clearly showed that the 99mTc-PQQ radioactivity accumulated predominantly in the hippocampus and cortex, which had a high density of N-methyl-d-aspartate Receptor (NMDAR). The enrichment can be blocked by NMDAR redox modulatory site antagonists-ebselen (EB) and 99mTc-PQQ is therefore a promising candidate for the molecular imaging of NMDAR. To date, however, there have been no studies characterizing 99mTc-PQQ.