α4β2-Nicotine acetylcholine receptor: advances in relevant diseases and drugs / 药学学报

The α4β2-nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel that is distributed throughout the nervous system. It is involved in the regulation of various neurotransmitters including acetylcholine, dopamine, γ-aminobutyric acid, and norepinephrine. α4β2-nAChR plays an important role in learning, memory, cognition, attention, inflammation, and pain. A large number of studies have shown that α4β2-nAChR is an important therapeutic target for neurological diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, depression, nicotine dependence, pain, etc. It is an important target in the early diagnosis and curative effect detection of neurodegenerative diseases including Alzheimer's disease. This review summarizes the role, mechanisms and related drug research advances on α4β2-nAChR ligand drugs in neurological diseases, as well as providing a theoretical basis for identifying and developing more suitable α4β2-nAChR-related compounds.

Isorhamnetin activates Sirt1/PGC-1α signaling pathway to inhibit MPP+-induced SH-SY5Y cell injury / 药学学报

We studied the protective effect and mechanism of isorhamnetin (ISO) on 1-methyl-4-phenylpyridiniumion (MPP+)-induced SH-SY5Y cells injury. MPP+-induced SH-SY5Y cell injury model was established, and cell viability was measured by MTT and LDH methods. The activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in cells were determined to investigate the level of oxidative stress. DCFH-DA and MitoSOX fluorescence probes were used to detect the levels of intracellular reactive oxygen species (ROS) and mitochondria superoxide, respectively. JC-1 fluorescence probe was used to detect the changes of mitochondrial membrane potential. Western blot and immunofluorescence methods were used to determine the expressions of Sirt1 and PGC-1 proteins, as well as the expression levels of apoptosis-related proteins Bax and Bcl-2. MPP+ at the dose of 500 μmol·L-1 significantly reduced SH-SY5Y cells viability to 52.46% and increased LDH release to 417.63%. ISO at 5 and 15 μmol·L-1 significantly increased the expression of Sirt1 and PGC-1α, inhibited LDH release, reduced intracellular ROS and mitochondria superoxide, inhibited the decline of mitochondrial membrane potential and increased cell viability to 61.61% and 67.55%. In addition, ISO could downregulate the expression of Bax and upregulate the expression of Bcl-2 to reduce cell apoptosis. ISO-mediated inhibition of apoptosis could be reversed by Sirt1 specific inhibitor Sirtinol. Through activating Sirt1/PGC-1α signaling pathway, ISO could reduce oxidative stress injury and inhibit cell apoptosis to protect cells from MPP+ injury.

Comparison of antithrombotic effects between salvianolic acid A and aspirin / 药学学报

This study was designed to compare the antithrombotic effects of salvianolic acid A and aspirin. The anti-platelet aggregation and anticoagulant effects of salvianolic acid A and aspirin in vitro and in vivo were investigated in normal rats. The anti-cerebral ischemia and anti-platelet aggregation effects of salvianolic acid A and aspirin were also investigated in rats with thrombotic cerebral ischemia. All animal care and experimental procedures were reviewed and approved by the Animal Ethics Committee of Chinese Academy of Medical Sciences. The results of antiplatelet aggregation in vitro and in vivo showed that salvianolic acid A could mildly inhibit adenosine diphosphate (ADP), arachidonic acid (AA) and thrombin (THR)-induced antiplatelet aggregation in a dose-dependent manner, while aspirin played a strong inhibitory effect on AA-induced platelet aggregation in vivo. The effects of salvianolic acid A and aspirin on the coagulation system were similar. At the same time, the results of maximum platelet aggregation rate (MAR) in the rat cerebral ischemia model [MARADP= (41.67±4.55)%, MARAA= (53.22±2.83)%, MARTHR= (73.33±5.04)%] indicated that salvianolic acid A could mildly inhibit ADP and AA-induced antiplatelet aggregation [MARADP= (26.13±4.60)%, MARAA= (35.53±13.73)%, P<0.01], while aspirin played a strong inhibitory effect on AA-induced platelet aggregation [MARAA= (8.13±2.99)%]. Salvianolic acid A (10 mg·kg-1) significantly improved the neurological function, cerebral infarction volume [(10.77±7.80)%] and brain edema [(79.72±0.83)%] compared with the model group [(43.50±12.69)%, (82.25±0.89)%] (P<0.01), while the effect of aspirin (100 mg·kg-1) was not obvious. The above results suggest that compared with aspirin, salvianolic acid A provided a mild inhibitory effect on platelet aggregation and protected against cerebral ischemia induced by thrombus. Therefore, salvianolic acid A has a good application prospect in the prevention and treatment of thrombotic diseases.

Salvianolic acid A attenuates ischemia reperfusion induced rat brain damage by protecting the blood brain barrier through MMP-9 inhibition and anti-inflammation / 中国天然药物

Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.

Research progress on pharmacological effect and mechanism of baicalein in Parkinson diseases / 中国药理学与毒理学杂志

Parkinson disease(PD)is characterized by the loss of dopaminergic neurons in the substantia nigra and deposition of cytosolic inclusions in surviving neurons (Lewy bodies), resulting in motor deficits and non-motor symptoms.Although Levodopa remains the gold standard treatment for PD,side effects like dyskinesia followed by long-term use could notbe ignored.Consequently,there is a need for devel-opment new drugs. Baicalein is a flavonoid isolated from traditional Chinese herb, Scutellaria baicalensis Georgi.Our laboratory discovered that baicalein could effectively attenuate neurotoxicity of 6-hydroxy-dopamine(6-OHDA)and promote the differentiation of PC12 cells through high throughput drug screen-ing at the cellularlevel. In vivo studies have shown that baicalein exerts significant therapeutic effect, particularly in the attenuation of muscle tremor in 6-OHDA-lesioned rats.Based on the result from the so far acquired knowledge and previous findings from our laboratory, we could consider neuroprotec-tive mechanism of baicalein focus on the activities ofanti-oxidation and anti-inflammation. Baicalein could prevent oxidative stress and apoptosis through maintaining the mitochondrial function, inhibition of collapse of mitochondrial membrane potential, increase the activity of antioxidant enzymes and restraint of lipid peroxidation via several pathways such as Keap1/Nrf2/HO-1.Anti-inflammatory activity of baicalein exert by attenuating activation of astrocyte and microglia, as well as the production of cathepsin B and cytokines. Additionally, promoting the degradation of α-synuclein contributes to the neuroprotective effect of baicalein against Lewy bodies toxicity.Furthermore,baicalein also modulates the metabolic balance between glutamate(GLu)and gamma-aminobutyric acid(GABA).Overall,baica-lein could protect nervous systemby inhibiting oxidative damage and neuroinflammation caused by environmental and genetic factors.This article reviewed the developments of studies on pharmacody-namics and mechanism of baicalein in PD therapy and provideda reference for further exploration.

Salvianolic acid A attenuates ischemia reperfusion induced rat brain damage by protecting the blood brain barrier through MMP-9 inhibition and anti-inflammation / 中国天然药物

Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.

Pharmacokinetics of two kinds of nimodipine crystal tablets in rhesus monkey / 药学学报

Nimodipine is a selective calcium channel antagonist of cerebral vessels smooth muscle and also has polymorphs. It hasn't been reported that different crystal forms influence the metabolism process in huge animals like rhesus monkeys in vivo. This article may provide reference in the control of the quality of nimodipine and quality consistency evaluation. The powder X-ray diffraction (PXRD) method was used to identify different crystal forms and the dissolution test in vitro was used to detect the dissolution. The LC-MS method of assay nimodipine in rhesus monkey plasm was established to determine pharmacokinetics characters of different tablets from different crystal forms in rhesus monkey in vivo. As a result, the tablets inherit difference crystal forms and the dissolution of reference tablets is 1.3% higher than crystal tablets. However, the maximal blood concentration (Cmax) of crystal tablet was 37.3% higher than reference tablet and AUC of crystal tablet was 29.8% higher than reference tablet. After administrated 2.5 mg·kg-1 orally, calculated pharmacokinetics characters were observed as following:Cmax was 381.4 ±327.3 and 178.0 ±214.8 μg·L-1; AUC0-t was 853.1 ±500.7 and 646.5 ±430.3 μg·L-1·h respectively. The serum concentration result of different nimodipine tablets in rhesus monkeys in vivo suggests that polymorphs has a significantly distinction, which points out that controlling the crystal forms of nimodipine is essential to ensure the therapeutic efficacy. It is essential to execute quality consistency evaluation.

Salvianolic acid A alleviate the brain damage in rats after cerebral ischemia-reperfusion through Nrf2/HO-1 pathway / 药学学报

The aim of present study is to investigate the protective effects and mechanism of salvianolic acid A (SAA) on cerebral ischemia-reperfusion injury in rats. The model was established with middle cerebral artery occlusion and reperfusion (MCAO/R) with ischemia for 1.5 h and reperfusion for 24 h in adult male SD rats. After the behavior assessment, TTC assay was used to calculate the infarct volume of rat brain; the distribution of Nrf2 in nuclear and cytoplasm and expression of HO-1 were detected by Western blot. The PC12 cells injury model was established with oxygen-glucose deprivation for 6 h and reintroduction for 24 h. Cell viability was determined with MTT assay, and the expression of Nrf2 and HO-1 were detected through immunofluorescence staining. The mechanisms were investigated in PC12 cells with Nrf2 knocking down by siRNA. SAA (10 and 20 mg·kg-1) significantly reduced the neuronal damage in MCAO/R model, and SAA (0.5 and 5 μmol·L-1) increased cell viability in PC12 cells injury model. Meanwhile, the nuclear translocation of Nrf-2 and the expression of HO-1 were increased in PC12 cell and rats brain. SAA exhibited anti-cerebral ischemia-reperfusion effects. The mechanism may be related to activation of Nrf2/HO-1 signaling pathway, which promotes the synthesis and nuclear translocation of Nrf2 to enhance the expression of the antioxidant protein HO-1.