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Dive into the research topics where Shih Heng Chen is active.

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Featured researches published by Shih Heng Chen.


The International Journal of Neuropsychopharmacology | 2015

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

Sheng Yu Lee; Shiou Lan Chen; Yun Hsuan Chang; Chun Hsien Chu; Shih Heng Chen; Po See Chen; San-Yuan Huang; Nian-Sheng Tzeng; Liang Jen Wang; I. Hui Lee; Tzu Yun Wang; Kao Chin Chen; Yen Kuang Yang; Jau Shyong Hong; Ru-Band Lu

Background: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Methods: Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Results: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. Conclusions: We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT.


British Journal of Pharmacology | 2012

Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage.

Shih Heng Chen; H. M. Wu; B. Ossola; N. Schendzielorz; Belinda Wilson; Chun Hsien Chu; Shiou Lan Chen; Qingshan Wang; Dan Zhang; Li Qian; X. Li; Jau Shyong Hong; Ru-Band Lu

BACKGROUND AND PURPOSE Prevention or disease‐modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimers disease, Parkinsons disease and Huntingtons disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinsons disease models.


Journal of Neuroimmune Pharmacology | 2012

Low-Dose Memantine Attenuated Morphine Addictive Behavior Through its Anti-Inflammation and Neurotrophic Effects in Rats

Shiou Lan Chen; Pao Luh Tao; Chun Hsien Chu; Shih Heng Chen; Hsiang En Wu; Leon F. Tseng; Jau Shyong Hong; Ru-Band Lu

Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer’s disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2–1xa0mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6xa0days of morphine treatment, cytokine (IL-1β, IL-6) levels had significantly increased in serum; IL-1β and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects.


Glia | 2015

Microglial regulation of immunological and neuroprotective functions of astroglia

Shih Heng Chen; Esteban Oyarzabal; Yueh Feng Sung; Chun Hsien Chu; Qingshan Wang; Shiou Lan Chen; Ru-Band Lu; Jau Shyong Hong

Microglia and astroglia play critical roles in the development, function, and survival of neurons in the CNS. However, under inflammatory conditions the role of astrogliosis in the inflammatory process and its effects on neurons remains unclear. Here, we used several types of cell cultures treated with the bacterial inflammogen LPS to address these questions. We found that the presence of astroglia reduced inflammation‐driven neurotoxicity, suggesting that astrogliosis is principally neuroprotective. Neutralization of supernatant glial cell line‐derived neurotrophic factor (GDNF) released from astroglia significantly reduced this neuroprotective effect during inflammation. To determine the immunological role of astroglia, we optimized a highly‐enriched astroglial culture protocol and demonstrated that LPS failed to induce the synthesis and release of TNF‐α and iNOS/NO. Instead we found significant enhancement of TNF‐α and iNOS expression in highly‐enriched astroglial cultures required the presence of 0.5–1% microglia, respectively. Thus suggesting that microglial‐astroglial interactions are required for LPS to induce the expression of pro‐inflammatory factors and GDNF from astroglia. Specifically, we found that microglia‐derived TNF‐α plays a pivotal role as a paracrine signal to regulate the neuroprotective functions of astrogliosis. Taken together, these findings suggest that astroglia may not possess the ability to directly recognize the innate immune stimuli LPS, but rather depend on crosstalk with microglia to elicit release of neurotrophic factors as a counterbalance to support neuronal survival from the collateral damage generated by activated microglia during neuroinflammation. GLIA 2015;63:118–131


The International Journal of Neuropsychopharmacology | 2016

The differential levels of inflammatory cytokines and bdnf among bipolar spectrum disorders

Tzu Yun Wang; Sheng Yu Lee; Shiou Lan Chen; Yi Lun Chung; Chia Ling Li; Yun Hsuan Chang; Liang Jen Wang; Po See Chen; Shih Heng Chen; Chun Hsien Chu; San-Yuan Huang; Nian-Sheng Tzeng; Tsai Hsin Hsieh; Yen Chu Chiu; I. Hui Lee; Kao Chin Chen; Yen Kuang Yang; Jau Shyong Hong; Ru-Band Lu

Objective: Emerging evidence suggests that inflammation and neurodegeneration underlies bipolar disorder. To investigate biological markers of cytokines and brain-derived neurotrophic factor between bipolar I, bipolar II, and other specified bipolar disorder with short duration hypomania may support the association with inflammatory dysregulation and bipolar disorder and, more specifically, provide evidence for other specified bipolar disorder with short duration hypomania patients were similar to bipolar II disorder patients from a biological marker perspective. Methods: We enrolled patients with bipolar I disorder (n=234), bipolar II disorder (n=260), other specified bipolar disorder with short duration hypomania (n=243), and healthy controls (n=140). Their clinical symptoms were rated using the Hamilton Depression Rating Scale and Young Mania Rating Scale. Inflammatory cytokine (tumor necrosis factor-α, C-reactive protein, transforming growth factor-β1, and interleukin-8) and brain-derived neurotrophic factor levels were measured in each group. Multivariate analysis of covariance and linear regression controlled for possible confounders were used to compare cytokine and brain-derived neurotrophic factor levels among the groups. Results: Multivariate analysis of covariance adjusted for age and sex and a main effect of diagnosis was significant (P<.001). Three of the 5 measured biomarkers (tumor necrosis factor-α, transforming growth factor-β1, and interleukin-8) were significantly (P=.006, .01, and <.001) higher in all bipolar disorder patients than in controls. Moreover, covarying for multiple associated confounders showed that bipolar I disorder patients had significantly higher IL-8 levels than did bipolar II disorder and other specified bipolar disorder with short duration hypomania patients in multivariate analysis of covariance (P=.03) and linear regression (P=.02) analyses. Biomarkers differences between bipolar II disorder and other specified bipolar disorder with short duration hypomania patients were nonsignificant. Conclusion: The immunological disturbance along the bipolar spectrum was most severe in bipolar I disorder patients. Other specified bipolar disorder with short duration hypomania patients and bipolar II disorder patients did not differ in these biological markers.


Brain | 2015

Post-treatment with an ultra-low dose of NADPH oxidase inhibitor diphenyleneiodonium attenuates disease progression in multiple Parkinson's disease models.

Qingshan Wang; Li Qian; Shih Heng Chen; Chun Hsien Chu; Belinda Wilson; Esteban Oyarzabal; Syed F. Ali; Bonnie L. Robinson; Deepa Rao; Jau Shyong Hong

Nicotinamide adenine dinucleotide phosphate oxidase, a key superoxide-producing enzyme, plays a critical role in microglia-mediated chronic neuroinflammation and subsequent progressive dopaminergic neurodegeneration in Parkinsons disease. Although nicotinamide adenine dinucleotide phosphate oxidase-targeting anti-inflammatory therapy for Parkinsons disease has been proposed, its application in translational research remains limited. The aim of this study was to obtain preclinical evidence supporting this therapeutic strategy by testing the efficacy of an ultra-low dose of the nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium in both endotoxin (lipopolysaccharide)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using post-treatment regimens. Our data revealed that post-treatment with diphenyleneiodonium significantly attenuated progressive dopaminergic degeneration and improved rotarod activity. Remarkably, post-treatment with diphenyleneiodonium 10 months after lipopolysaccharide injection when mice had 30% loss of nigral dopaminergic neurons, showed high efficacy in protecting the remaining neuronal population and restoring motor function. Diphenyleneiodonium-elicited neuroprotection was associated with the inhibition of microglial activation, a reduction in the expression of proinflammatory factors and an attenuation of α-synuclein aggregation. A pathophysiological evaluation of diphenyleneiodonium-treated mice, including assessment of body weight, organs health, and neuronal counts, revealed no overt signs of toxicity. In summary, infusion of ultra-low dose diphenyleneiodonium potently reduced microglia-mediated chronic neuroinflammation by selectively inhibiting nicotinamide adenine dinucleotide phosphate oxidase and halted the progression of neurodegeneration in mouse models of Parkinsons disease. The robust neuroprotective effects and lack of apparent toxic side effects suggest that diphenyleneiodonium at ultra-low dose may be a promising candidate for future clinical trials in Parkinsons disease patients.


Neuropharmacology | 2011

Verapamil protects dopaminergic neuron damage through a novel anti-inflammatory mechanism by inhibition of microglial activation

Yuxin Liu; Yi Ching Lo; Li Qian; Fulton T. Crews; Belinda Wilson; Hui Ling Chen; Hung Ming Wu; Shih Heng Chen; Ke Wei; Ru-Band Lu; Syed F. Ali; Jau Shyong Hong

Verapamil has been shown to be neuroprotective in several acute neurotoxicity models due to blockade of calcium entry into neurons. However, the potential use of verapamil to treat chronic neurodegenerative diseases has not been reported. Using rat primary mesencephalic neuron/glia cultures, we report that verapamil significantly inhibited LPS-induced dopaminergic neurotoxicity in both pre- and post-treatment experiments. Reconstituted culture studies revealed that the presence of microglia was essential in verapamil-elicited neuroprotection. Mechanistic studies showed that decreased production of inflammatory mediators from LPS-stimulated microglia underlay neuroprotective property of verapamil. Further studies demonstrated that microglial NADPH oxidase (PHOX), the key superoxide-producing enzyme, but not calcium channel in neurons, is the site of action for the neuroprotective effect of verapamil. This conclusion was supported by the following two observations: 1) Verapamil failed to show protective effect on LPS-induced dopaminergic neurotoxicity in PHOX-deficient (deficient in the catalytic subunit of gp91(phox)) neuron/glia cultures; 2) Ligand binding studies showed that the binding of [(3)H]Verapamil onto gp91(phox) transfected COS7 cell membranes was higher than the non-transfected control. The calcium channel-independent neuroprotective property of verapamil was further supported by the finding that R(+)-verapamil, a less active form in blocking calcium channel, showed the same potency in neuroprotection, inhibition of pro-inflammatory factors production and binding capacity to gp91(phox) membranes as R(-)-verapamil, the active isomer of calcium channel blocker. In conclusion, our results demonstrate a new indication of verapamil-mediated neuroprotection through a calcium channel-independent pathway and provide a valuable avenue for the development of therapy for inflammation-related neurodegenerative diseases.


Journal of Affective Disorders | 2012

The DRD2/ANKK1 gene is associated with response to add-on dextromethorphan treatment in bipolar disorder

Sheng Yu Lee; Shiou Lan Chen; Yun Hsuan Chang; Shih Heng Chen; Chun Hsieh Chu; San-Yuan Huang; Nian-Sheng Tzeng; Chen Lin Wang; I. Hui Lee; Tzung Lieh Yeh; Yen Kuang Yang; Ru-Band Lu

Dextromethorphan (DM) is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that may be neuroprotective for monoamine neurons. We hypothesized that adding DM to valproate (VPA) treatment would attenuate bipolar disorder (BP) symptoms. We evaluated in BP patients the association between the DRD2/ANKK1 TaqIA polymorphism with treatment response to VPA+add-on DM and to VPA+placebo. This double-blind, stratified, randomized study ran from January 2007 through December 2010. BP patients undergoing regular VPA treatments were randomly assigned to groups given either add-on DM (60 mg/day) (n=167) or placebo (n=83) for 12 weeks. The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) were used to evaluate clinical response. The genotypes of the DRD2/ANKK1 TaqIA polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. To adjust within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was used to analyze the effects of the DRD2/ANKK1 TaqIA polymorphism on clinical performance. Both groups showed significantly decreased YMRS and HDRS scores after 12 weeks of treatment; the differences between groups were non-significant. Decreases in YMRS scores were greater in patients with the A1A1 (P=0.004) genotypes than with the A2A2 genotype. We conclude that the DRD2/ANKK1 TaqIA polymorphism influenced responses to DM by decreasing manic symptoms in BP patients.


Glia | 2014

Subpicomolar diphenyleneiodonium inhibits microglial NADPH oxidase with high specificity and shows great potential as a therapeutic agent for neurodegenerative diseases

Qingshan Wang; Chun Hsien Chu; Esteban Oyarzabal; Lulu Jiang; Shih Heng Chen; Belinda Wilson; Li Qian; Jau Shyong Hong

Activation of microglial NADPH oxidase (NOX2) plays a critical role in mediating neuroinflammation, which is closely linked with the pathogenesis of a variety of neurodegenerative diseases, including Parkinsons disease (PD). The inhibition of NOX2‐generated superoxide has become an effective strategy for developing disease‐modifying therapies for PD. However, the lack of specific and potent NOX2 inhibitors has hampered the progress of this approach. Diphenyleneiodonium (DPI) is a widely used, long‐acting NOX2 inhibitor. However, due to its non‐specificity for NOX2 and high cytotoxicity at standard doses (µM), DPI has been precluded from human studies. In this study, using ultra‐low doses of DPI, we aimed to: (1) investigate whether these problems could be circumvented and (2) determine whether ultra‐low doses of DPI were able to preserve its utility as a potent NOX2 inhibitor. We found that DPI at subpicomolar concentrations (10−14 and 10−13 M) displays no toxicity in primary midbrain neuron‐glia cultures. More importantly, we observed that subpicomolar DPI inhibited phorbol myristate acetate (PMA)‐induced activation of NOX2. The same concentrations of DPI did not inhibit the activities of a series of flavoprotein‐containing enzymes. Furthermore, potent neuroprotective efficacy was demonstrated in a post‐treatment study. When subpicomolar DPI was added to neuron‐glia cultures pretreated with lipopolysaccharide, 1‐methyl‐4‐phenylpyridinium or rotenone, it potently protected the dopaminergic neurons. In summary, DPIs unique combination of high specificity toward NOX2, low cytotoxicity and potent neuroprotective efficacy in post‐treatment regimens suggests that subpicomolar DPI may be an ideal candidate for further animal studies and potential clinical trials. GLIA 2014;62:2034–2043


Addiction Biology | 2012

Interaction between ALDH2*1*1 and DRD2/ANKK1 TaqI A1A1 genes may be associated with antisocial personality disorder not co-morbid with alcoholism

Ru-Band Lu; Jia Fu Lee; San-Yuan Huang; Sheng Yu Lee; Yun Hsuan Chang; Po-Hsiu Kuo; Shiou Lan Chen; Shih Heng Chen; Chun Hsien Chu; Wei Wen Lin; Pei-Lin Wu; Huei-Chen Ko

Previous studies on acetaldehyde dehydrogenase 2 (ALDH2) focused on drinking behavior or alcoholism because the ALDH2*2 allele protects against the risk of developing alcoholism. The mechanism provides that the ALDH2 genes protective effect is also involved in dopamine metabolism. The interaction of the ALDH2 gene with neurotransmitters, such as dopamine, is suggested to be related to alcoholism. Because alcoholism is often co‐morbid with antisocial personality disorder (ASPD), previous association studies on antisocial alcoholism cannot differentiate whether those genes relate to ASPD with alcoholism or ASPD only. This study examined the influence of the interaction effect of the ALDH2*1*1, *1*2 or *2*2 polymorphisms with the dopamine 2 receptor (DRD2) Taq I polymorphism on ASPD. Our 541 Han Chinese male participants were classified into three groups: antisocial alcoholism (ASPD co‐morbid with alcohol dependence, antisocial ALC; nu2003=u2003133), ASPD without alcoholism (ASPD not co‐morbid with alcohol dependence, antisocial non‐ALC; nu2003=u2003164) and community controls (healthy volunteers from the community; nu2003=u2003244). Compared with healthy controls, individuals with the DRD2 A1/A1 and the ALDH2*1/*1 genotypes were at a 5.39 times greater risk for antisocial non‐ALC than were those with other genotypes. Our results suggest that the DRD2/ANKK1 and ALDH2 genes interacted in the antisocial non‐ALC group; a connection neglected in previous studies caused by not separating antisocial ALC from ASPD. Our study made this distinction and showed that these two genes may be associated ASPD without co‐morbid alcoholism.

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Ru-Band Lu

National Cheng Kung University

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Shiou Lan Chen

Kaohsiung Medical University

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Chun Hsien Chu

National Institutes of Health

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Sheng Yu Lee

National Cheng Kung University

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Yun Hsuan Chang

National Cheng Kung University

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Yen Kuang Yang

National Cheng Kung University

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Jau Shyong Hong

National Institutes of Health

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I. Hui Lee

National Cheng Kung University

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San-Yuan Huang

National Defense Medical Center

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Nian-Sheng Tzeng

National Defense Medical Center

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