Glutamate Transporters/Na(+), K(+)-ATPase Involving in the Neuroprotective Effect as a Potential Regulatory Target of Glutamate Uptake.

The glutamate (Glu) transporters GLAST and GLT-1, as the two most important transporters in brain tissue, transport Glu from the extracellular space into the cell protecting against Glu toxicity. Furthermore, GLAST and GLT-1 are sodium-dependent Glu transporters (GluTs) that rely on sodium and potassium gradients generated principally by Na(+), K(+)-ATPase to generate ion gradients that drive Glu uptake. There is an interaction between Na(+), K(+)-ATPase and GluTs to modulate Glu uptake, and Na(+), K(+)-ATPase α, ß or γ subunit can be directly coupled to GluTs, co-localizing with GLAST or GLT-1 in vivo to form a macromolecular complex and operate as a functional unit to regulate glutamatergic neurotransmission. Therefore, GluTs/Na(+), K(+)-ATPase may be involved in the neuroprotective effect as a potential regulatory target of Glu uptake in neurodegenerative diseases induced by Glu-mediated neurotoxicity as the final common pathway.

Neuroprotective effect of resveratrol against glutamate-induced excitotoxicity.

As the major neurotransmitter in the mammalian central nervous system (CNS), excessive extracellular glutamate (Glu) can activate the Glu receptors and neuronal calcium (Ca2+) overload, then produce neurotoxicity, which is a common pathway for neuronal injury or death, and is associated with acute and chronic neurodegenerative diseases. Therefore, it has been a therapeutic strategy to investigate neuroprotective effects against Glu-induced neurotoxicity for treating both acute and chronic forms of neurodegeneration. Resveratrol (Res), as a naturally occurring polyphenol mainly found in grapes and red wine, has shown a neuroprotective effect in a variety of experimental models for neurodegenerative diseases in vitro and in vivo. This review will focus on the neuroprotective effect of Res against Glu-induced excitotoxicity in neurodegenerative diseases by blocking different Glu receptors and Ca2+ ion channels.

Crosstalk between dopamine receptors and the Na⁺/K⁺-ATPase (review).

Dopamine (DA) receptors, which belong to the G protein-coupled receptor family, are the target of ~50% of all modern medicinal drugs and constitute a large and diverse class of proteins whose primary function is to transduce extracellular stimuli into intracellular signals. Na+/K+-ATPase (NKA) is ubiquitous and crucial for the maintenance of intracellular ion homeostasis and excitability. Furthermore, it plays a critical role in diverse effects, including clinical cardiotonic and cardioprotective effects, ischemic preconditioning in the brain, natriuresis, lung edema clearance and other processes. NKA regulation is of physiological and pharmacological importance and has species- and tissue-specific variations. The activation of DA receptors regulates NKA expression/activity and trafficking in various tissues and cells, for example in the kidney, lung, intestine, brain, non-pigmented ciliary epithelium and the vascular bed. DA receptor-mediated regulation of NKA mediates a diverse range of cellular responses and includes endocytosis/exocytosis, phosphorylation/dephosphorylation of the α subunit of NKA and multiple signaling pathways, including phosphatidylinositol (PI)-phospholipase C/protein kinase (PK) C, cAMP/PKA, PI3K, adaptor protein 2, tyrosine phosphatase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase. Furthermore, in brain and HEK293T cells, D1 and D2 receptors exist in a complex with NKA. Among D1 and D2 receptors and NKA, regulations are reciprocal, which leads to crosstalk between DA receptors and NKA. In the present study, the current understanding of signaling mechanisms responsible for the crosstalk between DA receptors and NKA, as well as with specific consequent functions, is reviewed.

Na⁺-K⁺-ATPase, a potent neuroprotective modulator against Alzheimer disease.

Alzheimer disease (AD) is a neurodegenerative disorder clinically characterized by progressive cognitive and memory dysfunction, which is the most common form of dementia. Although the pathogenesis of neuronal injury in AD is not clear, recent evidences suggest that Na⁺-K⁺-ATPase plays an important role in AD, and may be a potent neuroprotective modulator against AD. This review aims to provide readers with an in-depth understanding of Na⁺-K⁺-ATPase in AD through these modulations of some factors that are as follows, which leads to the change of learning and memory in the process of AD. 1. The deficiency in Na⁺, K⁺-ATPase α1, α2 and α3 isoform genes induced learning and memory deficits, and α isoform was evidently changed in AD, revealing that Na⁺, K⁺-ATPase α isoform genes may play an important role in AD. 2. Some factors, such as ß-amyloid, cholinergic and oxidative stress, can modulate learning and memory in AD through the mondulation of Na⁺-K⁺-ATPase activity. 3. Some substances, such as Zn, s-Ethyl cysteine, s-propyl cysteine, citicoline, rivastigmine, Vit E, memantine, tea polyphenol, curcumin, caffeine, Alpinia galanga (L.) fractions, and Bacopa monnieri could play a role in improving memory performance and exert protective effects against AD by increasing expression or activity of Na⁺, K⁺-ATPase.

[Pharmacokinetics of pingyangmycin hydrochloride in rabbits determined by microdialysis coupled with RP-HPLC].

Microdialysis coupled with RP-HPLC was used to study the blood pharmacokinetics of pingyangmycin hydrochloride in rabbits. Supelco RP-amide C16 column was adopted for the analysis of pingyangmycin hydrochloride. The data was analyzed with 3P87 program. The calibration curve was linear in the concentration range from 1.04 to 66.56 microg x mL(-1) (r2 = 0.999 4). The in vivo recovery of microdialysis probe was (42.8 +/- 3.4)% (n = 4). The concentration-time curve of pingyangmycin hydrochloride was fitted to two-compartment model. T1/2 alpha and T1/2 beta were 14.9 and 60.3 min, respectively. The method is proved to be accurate, simple and suitable for the pharmacokinetics study of pingyangmycin hydrochloride in rabbits.

[Drug release mechanism of famotidine time-controlled release pellets].

AIM: To study the drug release mechanism of famotidine time-controlled release pellets and to explore the mechanism of "organic acid-induced type drug delivery system". METHODS: The effects of dissociated and undissociated forms of succinic acid on the drug release behavior of famotidine time-controlled release pellets were studied from the following aspects: ion-exchange reaction, hydration, etc. RESULTS: The dissociated succinic acid created new ionic circumstances by ion-exchange reaction with Eudragit RS100. Whereas undissociated succinic acid increased the flexibility of the film by distribution in the hydrophobic segment of Eudragit RS100. Effects of both forms of the succinic acid could improve the hydration of Eudragit RS film. As a result, the permeability of the film was improved evidently. CONCLUSION: The lag time of famotidine time-controlled release pellets is induced by the hydrophobicity of the film. After water dissolve the organic acid, the dissociated and undissociated forms of succinic acid interact with the film through different ways. These interactions can change the structure of the film. Therefore the permeability of the film will be improved markedly.

Application of microdialysis to study the in vivo release of pingyangmycin from in situ gels in rabbits.

Microdialysis was used together with HPLC to monitor the local concentration of pingyangmycin hydrochloride (PYM) after embolizing rabbit ear-veins with an injectable sustained release formulation, PYM-Zein/PYM-Zein-sucrose acetate isobutyrate (SAIB), in situ gel. The dialysis probe was perfused at 2 microL/min. The in vivo recovery was 46.6 3.1% (n = 4). The samples were injected directly into HPLC. PYM was detected using UV detector at 291 nm. Separation from other components in the dialysate was performed using a Discovery((R)) RP-Amide C(16) column within 12 min. The response for PYM in the dialysate was linear (r(2) > 0.996) over the range of 2.5-212 microg/mL. The limit of detection and limit of quantitation of PYM in the dialysate were 0.4 and 1.5 microg/mL, respectively. The results demonstrated that the in situ gel of PYM-Zein-SAIB could extend the release of PYM to 4 days. SAIB could significantly cut down the initial burst of PYM from the in situ gels (p < 0.05).

Expression of matrix metalloproteinase 2 and its tissue inhibitor in oral squamous cell carcinoma.

The aim of this study is to investigate the expression of matrix metalloproteinase 2 (MMP-2) and the tissue inhibitor of metalloproteinase 2 (TIMP-2) in oral squamous cell carcinoma (OSCC) and adjacent normal tissues, and explore the role of MMP-2 and TIMP-2 in carcinoma metastasis and invasion. Expression of MMP-2 and TIMP-2 was evaluated in 40 cases with semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical techniques. The values of MMP-2/beta-actin and TIMP-2/beta-actin in OSCC were significantly higher than those in adjacent normal tissues 2 cm and > or = 5 cm from carcinoma tissues (p<0.05). The results of immunohistochemical analysis show that the positive expression of MMP-2 and TIMP-2 protein in tumor tissues (60.0 and 52.5%) was higher than that in adjacent normal tissues 2 cm (30.0 and 22.5%) and 5 cm (22.5 and 25.0%) from cancer tissues, and the difference was significant p<0.05). The expression of MMP-2 and TIMP-2 was related to the differentiation degree of tumor cells, metastatic lymph node status and stage of carcinoma, but not related to the age and gender of patients, or location of the carcinoma. Therefore, MMP-2 and TIMP-2 may play important roles in the invasion and metastasis of OSCC.