Publications by authors named "Jian-Dong Long"

7 Publications

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Alteration of twinfilin1 expression underlies opioid withdrawal-induced remodeling of actin cytoskeleton at synapses and formation of aversive memory.

Mol Psychiatry 2021 May 7. Epub 2021 May 7.

Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Exposure to drugs of abuse induces alterations of dendritic spine morphology and density that has been proposed to be a cellular basis of long-lasting addictive memory and heavily depend on remodeling of its underlying actin cytoskeleton by the actin cytoskeleton regulators. However, the actin cytoskeleton regulators involved and the specific mechanisms whereby drugs of abuse alter their expression or function are largely unknown. Twinfilin (Twf1) is a highly conserved actin-depolymerizing factor that regulates actin dynamics in organisms from yeast to mammals. Despite abundant expression of Twf1 in mammalian brain, little is known about its importance for brain functions such as experience-dependent synaptic and behavioral plasticity. Here we show that conditioned morphine withdrawal (CMW)-induced synaptic structure and behavior plasticity depends on downregulation of Twf1 in the amygdala of rats. Genetically manipulating Twf1 expression in the amygdala bidirectionally regulates CMW-induced changes in actin polymerization, spine density and behavior. We further demonstrate that downregulation of Twf1 is due to upregulation of miR101a expression via a previously unrecognized mechanism involving CMW-induced increases in miR101a nuclear processing via phosphorylation of MeCP at Ser421. Our findings establish the importance of Twf1 in regulating opioid-induced synaptic and behavioral plasticity and demonstrate its value as a potential therapeutic target for the treatment of opioid addiction.
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http://dx.doi.org/10.1038/s41380-021-01111-3DOI Listing
May 2021

Discovery of 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones as Highly Potent and Selective SIRT1 Inhibitors.

ACS Med Chem Lett 2021 Mar 1;12(3):397-403. Epub 2021 Mar 1.

State Key Laboratory of Drug Research, Department of Pharmacology III, and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China.

SIRT1, a member of the sirtuin family, catalyzes the deacetylation of proteins with the transformation of NAD into nicotinamide and 2'--acetyl-ADP-ribose. Selective SIRT1/2 inhibitors have potential application in the chemotherapy of colorectal carcinoma, prostate cancer, and myelogenous leukemia. Here we identified novel SIRT1 inhibitors with the scaffold of 5-benzylidene-2-phenyl-1,3-dioxane-4,6-dione. The most potent inhibitor displayed an IC of 460 nM and a selectivity for SIRT1 over SIRT2, SIRT3, and SIRT5 of 113.5-, 254.3-, and 10.83-fold, respectively. It did not affect the activity of SIRT6. To elucidate the inhibitory mechanism, we determined the inhibition type of the inhibitor by enzyme kinetic analysis, showing that the inhibitor was competitive to the acetyl peptide and noncompetitive to NAD. Further, the interaction of the inhibitor in SIRT1 was studied by using molecular docking, which was validated by the structure-activity relationship analysis of the inhibitors and the site-directed mutagenesis of SIRT1. Consistent with the assays, the inhibitors increased the acetylation level of p53 in a concentration-dependent manner in cells.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957943PMC
March 2021

Pharmacological Characterization of Dezocine, a Potent Analgesic Acting as a ╬║ Partial Agonist and ╬╝ Partial Agonist.

Sci Rep 2018 09 20;8(1):14087. Epub 2018 Sep 20.

Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Science, Shanghai, 201203, China.

Dezocine is becoming dominated in China market for relieving moderate to severe pain. It is believed that Dezocine's clinical efficacy and little chance to provoke adverse events during the therapeutic process are mainly attributed to its partial agonist activity at the ╬╝ opioid receptor. In the present work, we comprehensively studied the pharmacological characterization of Dezocine and identified that the analgesic effect of Dezocine was a result of action at both the ╬║ and ╬╝ opioid receptors. We firstly found that Dezocine displayed preferential binding to ╬╝ opioid receptor over ╬║ and ╬┤ opioid receptors. Dezocine, on its own, weakly stimulated G protein activation in cells expressing ╬║ and ╬╝ receptors, but in the presence of full ╬║ agonist U50,488ÔÇëH and ╬╝ agonist DAMGO, Dezocine inhibited U50,488H- and DAMGO-mediated G protein activation, indicating that Dezocine was a ╬║ partial agonist and ╬╝ partial agonist. Then the in intro results were verified by in vivo studies in mice. We observed that Dezocine-produced antinociception was significantly inhibited by ╬║ antagonist nor-BNI and ╬╝ antagonist ╬▓-FNA pretreatment, indicating that Dezocine-mediated antinociception was via both the ╬║ and ╬╝ opioid receptors. When co-administrating of Dezocine with U50,488ÔÇëH or morphine, Dezocine was capable of inhibiting U50,488H- or morphine-induced antinociception. Finally, ╬║ receptor activation-associated side effect sedation was investigated. We found that Dezocine displayed limited sedative effect with a ceiling effecting at a moderate dose. Thus, our work led to a better understanding of the analgesic mechanism of action of Dezocine in vivo.
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http://dx.doi.org/10.1038/s41598-018-32568-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148296PMC
September 2018

SYVN1, an ERAD E3 Ubiquitin Ligase, Is Involved in GABA╬▒1 Degradation Associated with Methamphetamine-Induced Conditioned Place Preference.

Front Mol Neurosci 2017 5;10:313. Epub 2017 Oct 5.

Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, China.

Abuse of methamphetamine (METH), a powerful addictive amphetamine-type stimulants (ATS), is becoming a global public health problem. The gamma-aminobutyric acid (GABA)ergic system plays a critical role in METH use disorders. By using rat METH conditioned place preference (CPP) model, we previously demonstrated that METH-associated rewarding memory formation was associated with the reduction of GABA╬▒1 expression in the dorsal straitum (Dstr), however, the underlying mechanism was unclear. In the present study, we found that METH-induced CPP formation was accompanied by a significant increase in the expression of Synovial apoptosis inhibitor 1 (SYVN1), an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase, in the Dstr. The siRNA knockdown of SYVN1 significantly increased GABA╬▒1 protein levels in both primary cultured neurons and rodent Dstr. Inhibition of proteasomal activity by MG132 and Lactacystin significantly increased GABA╬▒1 protein levels. We further found that SYVN1 knockdown increased GABA╬▒1 in the intra-ER, but not in the extra-ER. Accordingly, endoplasmic reticulum stress (ERS)-associated Glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) increased. Thus, this study revealed that SYVN1, as the ERAD E3 ubiquitin ligase, was associated with Dstr GABA╬▒1 degradation induced by METH conditioned pairing.
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http://dx.doi.org/10.3389/fnmol.2017.00313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633679PMC
October 2017

The neuroprotective effect of memantine on methamphetamine-induced cognitive deficits.

Behav Brain Res 2017 04 29;323:133-140. Epub 2017 Jan 29.

Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai 201203, China.

Repeated exposure to methamphetamine (METH) can cause severe neurotoxicity to the cortical neurons. In the present study, we investigated the effect of METH on cognitive function deficits, and determined the neuroprotective effects of memantine (MEM) on memory impairment induced by METH. The protein levels of Bcl-2 and cleaved caspase-3 in prefrontal cortex (PFC) were further examined to exploring the underlying mechanism. We found that repeated METH administration impaired long term (24h) memory retention without affecting short term (5min) memory retention. Co-administration of MEM with METH before training session significantly improved METH-induced cognitive function. METH significantly decreased expression level of Bcl-2 and increased expression level of cleaved caspase-3 in the PFC. The changes can be prevented by MEM pretreatment. Thus, these results demonstrated that MEM pretreatment reversed METH-induced changes of protein levels of apoptotic-related gene, and produced protective effects against METH-induced cognitive deficits, suggesting the effectiveness of MEM may be due to its anti-apoptotic activity.
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http://dx.doi.org/10.1016/j.bbr.2017.01.042DOI Listing
April 2017

The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent ╬║-Opioid Agonistic Activities.

ACS Chem Neurosci 2017 04 19;8(4):766-776. Epub 2017 Jan 19.

Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.

To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, ╬║-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6╬▒,14╬▒-endo-ethenylthebaine and the 7╬▒-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (K = 0.4 ┬▒ 0.1 nM) and the highest selectivity (╬╝/╬║ = 339, ╬┤/╬║ = 2034) toward KOR. The in vivo tests revealed that compound 4 is able to induce stronger (ED = 2.1 mg/kg) and much longer antinociceptive effect than that of the typical KOR agonist U50488H (ED = 4.4 mg/kg). Therefore, compound 4 can be used as a perfect lead compound for future design of potent analgesics acting through KOR.
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http://dx.doi.org/10.1021/acschemneuro.6b00321DOI Listing
April 2017

Formation of aversive memories associated with conditioned drug withdrawal requires BDNF expression in the amygdala in acute morphine-dependent rats.

Acta Pharmacol Sin 2015 Dec 16;36(12):1437-43. Epub 2015 Nov 16.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Aim: Brain-derived neurotrophic factor (BDNF) plays an important role in learning and memory in multiple brain areas. In the present study, we investigated the roles of BDNF in aversive memories associated with conditioned drug withdrawal in acute morphine-dependent rats.

Methods: Conditioned place aversion (CPA) was induced in male SD rats exposed to a single dose of morphine (10 mg/kg, sc) followed by naloxone (0.3 mg/kg, sc). In some rats, BDNF receptor antagonist K252a (8.5 ng per side) or BDNF scavenger TrkB-FC (0.65 ╬╝g per side) was bilaterally microinjected into amygdala before naloxone injection. BDNF mRNA and protein expression levels in amygdala were detected after the behavior testing.

Results: CPA behavior was induced in rats by the naloxone-precipitated morphine withdrawal, which was accompanied by significantly increased levels of BDNF mRNA and protein in the amygdala. Bilateral microinjection of TrkB-FC or K252a into the amygdala completely blocked CPA behavior in the rats.

Conclusion: Formation of aversive memories associated with conditioned drug withdrawal in acute morphine-dependent rats requires BDNF expression in the amygdala.
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http://dx.doi.org/10.1038/aps.2015.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816238PMC
December 2015
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