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Publications (7)21.83 Total impact

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    ABSTRACT: Methamphetamine (METH) is a psychostimulant drug. Abuse of METH produces long-term behavioral changes including behavioral, sensitization, tolerance, and dependence. It induces neurotoxic effects in several areas of the brain via enhancing dopamine (DA) level abnormally, which may cause a secondary release of glutamate (GLU). However, repeated administration of METH still increases release of GLU even when dopamine tissue content is significantly depleted. It implies that some other mechanisms likely to involve in METH-induced GLU release. The goal of this study was to observe METH affected glutamatergic synaptic transmission in rat primary cultured hippocampal neurons and explore the mechanism of METH modulated GLU release. Using whole cell patch-clamp recordings, we found that METH (0.1–50.0 μM) increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs). However, METH decreased the frequency of sEPSCs and mEPSCs at high concentration of 100 μM. The Postsynaptic NMDA receptor currents and P/Q-type calcium channel were not affected by use of METH (10,100 μM). METH did not present visible effect on N-type Ca2+ channel current at the concentration lower than 50.0 μM, but it was inhibited by use of METH at a 100 μM. The effect of METH on glutamatergic synaptic transmission was not revered by pretreated with DA receptor antagonist SCH23390. These results suggest that METH directly modulated presynaptic GLU release at a different concentration, while dopaminergic system was not involve in METH modulate the release of GLU in rat primary cultured hippocampal neurons.
    Brain Research. 01/2014;
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    ABSTRACT: Amitriptyline (AMI), a tricyclic antidepressant, has been widely used to prevent migraine attacks and alleviate other various chronic pain, but the underlying mechanism remains unclear. Accumulated evidence suggests that the efficacy of AMI is related to the blockade of voltage-gated sodium channels. The aim of the present study was to investigate the effect of AMI on Nav1.8 currents in nociceptive trigeminal neurons and trigeminovascular nociception induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus (SSS) in rats, as in the animal model of vascular headaches such as migraines. Using a whole-cell voltage recording technique, we showed that Nav1.8 currents were blocked by AMI in a concentration-dependent manner, with an IC50 value of 6.82 μM in acute isolated trigeminal ganglion neurons of the rats. AMI caused a hyperpolarizing shift in the voltage-dependent activation and steady-state inactivation and significantly blocked in a use-dependent manner and slowed the recovery from the inactivation of Nav1.8 currents. In addition, the systemic administration of AMI and A-803467 (a selective Nav1.8 channel blocker) potently alleviated the nociceptive behaviors (head flicks and grooming) induced by the electrical stimulation of the dura mater surrounding the SSS. Taken together, our data suggest that Nav1.8 currents in nociceptive trigeminal neurons are blocked by AMI through modulating the activation and inactivation kinetics, which may contribute to anti-nociceptive effect of AMI in animal models of migraines.
    Neuromolecular medicine 11/2013; · 5.00 Impact Factor
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    ABSTRACT: N-methyl-D-aspartate receptors (NMDARs) mediate the predominantly excitatory neurotransmission in the central nervous system. Excessive release of glutamate and overactivation of NMDARs during brain ischemia and hypoxia process are causally linked to excitotoxicity and neuronal damage. GluN3 subunits, the third number of NMDAR family with two isoforms of GluN3A and GluN3B, have been confirmed to display an inhibitory effect on NMDAR activity. However, the effect of GluN3 subunits in brain ischemia and hypoxia is not clearly understood. In the present study, the influence of ischemia and hypoxia on GluN3 subunit expression was observed by using the two-vessel occlusion (2VO) rat brain ischemia model and cell oxygen and glucose deprivation (OGD) hypoxia model. It was found that GluN3A protein expression in rat hippocampus and the prefrontal cortex was increased quickly after brain ischemia and remained a high level for at least 24 hours. However, expression of GluN3B subunit was not changed remarkably in both of the animal and cell models. After OGD exposure, rat hippocampal neurons with GluN3A subunit overexpression displayed more viability than the wild-type neurons. NG108-15 cells overexpressing GluN3A presented pronounced resistance to glutamate insult. Blocking the increase of intracellular calcium concentration may underlie the neuroprotective mechanism of up-regulated GluN3A subunit. Suppressing.
    ASN Neuro 07/2013; · 3.64 Impact Factor
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    ABSTRACT: Many studies have provided convincing evidence for hERG as an important diagnostic and prognostic factor in human cancers, as well as a useful target for antineoplastic therapy. Our previous study also revealed that knockdown of herg gene expression by shRNA interference inhibited the growth of neuroblastoma cells in vitro and in vivo. In the experiment, a novel 4-amino piperidine analog, ZC88, was examined for its effect on hERG potassium channels and its antitumor potency was observed in vitro and in vivo. The results showed that ZC88 could block hERG1 and hERG1b channels expressed in Xenopus oocytes in a concentration-dependent manner. ZC88 displayed significant antiproliferative activity in several tumor cell lines and the tumor cells with higher expression of hERG presented higher sensitivity to ZC88. The mitotic progression of tumor cells was markedly suppressed in the presence of ZC88 through arresting cells in G 0/G 1 phase. ZC88 significantly inhibited the tumor growth in nude mice at a dosage with slight influence on the cardiac QT interval. The antitumor effect of ZC88 was correlated at least partly with its blockage of hERG channels, which implicated a positive role of hERG potassium channel in tumor cell proliferation.
    Cancer biology & therapy 05/2013; 14(5):450-7. · 3.29 Impact Factor
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    ABSTRACT: Amitriptyline (AMI) is tricyclic antidepressant that has been widely used to manage various chronic pains such as migraines. Its efficacy is attributed to its blockade of voltage-gated sodium channels (VGSCs). However, the effects of AMI on the tetrodotoxin-resistant (TTX-r) sodium channel Nav1.9 currents have been unclear to present. Using a whole-cell patch clamp technique, this study showed that AMI efficiently inhibited Nav1.9 currents in a concentration-dependent manner and had an IC50 of 15.16 μM in acute isolated trigeminal ganglion (TG) neurons of the rats. 10 μM AMI significantly shifted the steady-state inactivation of Nav1.9 channels in the hyperpolarizing direction without affecting voltage-dependent activation. Surprisingly, neither 10 nor 50 μM AMI caused a use-dependent blockade of Nav1.9 currents elicited by 60 pulses at 1 Hz. These data suggest that AMI is a state-selective blocker of Nav1.9 channels in rat nociceptive trigeminal neurons, which likely contributes to the efficacy of AMI in treating various pains, including migraines.
    Molecular Pain 01/2013; 9(1):31. · 3.77 Impact Factor
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    ABSTRACT: Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs). In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC) cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea. R2HBJJ markedly suppressed the growth of NSCLC cells, such as H1299, H460 and H157. In H1299 cells, both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin. Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition. Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection, respectively. Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb. Therefore, the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells. R2HBJJ, as a novel mAChRs antagonist, can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth, which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC.
    PLoS ONE 01/2012; 7(12):e53170. · 3.53 Impact Factor
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    ABSTRACT: N-type Ca2+ channels located on presynaptic nerve terminals regulate neurotransmitter release, including that from the spinal terminations of primary afferent nociceptors. Pharmacological and ion-channel gene knockdown approaches in animals have revealed N-type Ca2+ channels to be particularly attractive molecular targets for the discovery and development of new analgesic drugs. In recent years, some non-peptide small molecular N-type Ca2+ channel blockers have been reported. However, low selectivity and some side effects limit their further development. To overcome these disadvantages, some new compounds were designed and synthesized in our institute by optimizing the 4-amino-piperidine template. C101, one of these compounds, was demonstrated to block N-type Ca2+ channels with higher selectivity. It was found that C101 produced concentration-dependent inhibition on N-type Ca2+ channels expressed in Xenopus oocytes with an IC50 is 2.2+/-0.6 microM. The current-voltage relationship was not altered after 2-min exposure to C101. However, the steady-state inactivation relationship curve was shifted to more negative potentials for channels. Therefore, it seemed that C101 blocks the inactivated channel. C101 did not present any remarkable effects on voltage-gated potassium, sodium channels in cultured rat hippocampal neurons, and L-, P/Q-, R-type calcium channels and HERG channels expressed in Xenopus oocytes. The results suggested that C101 was a high selective blocker targeting N-type Ca2+ channels, and may have a potential to be developed as a novel analgesic agent.
    European Journal of Pharmacology 07/2008; 587(1-3):42-7. · 2.59 Impact Factor