scholarly journals Interleukin-1β Protects Neurons against Oxidant-Induced Injury via the Promotion of Astrocyte Glutathione Production

Antioxidants ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 100 ◽  
Author(s):  
Twinkle Chowdhury ◽  
Matthew Allen ◽  
Trista Thorn ◽  
Yan He ◽  
Sandra Hewett
Keyword(s):  
Neurological Diseases ◽  
Oxidant Stress ◽  
Cortical Cell ◽  
Mixed Cultures ◽  
Interleukin 1Β ◽  
Neuronal Cultures ◽  
Dependent Manner ◽  
Protective Effects ◽  
Oxidant Injury

Interleukin-1β (IL-1β), a key cytokine that drives neuroinflammation in the Central Nervous System (CNS), is enhanced in many neurological diseases/disorders. Although IL-1β contributes to and/or sustains pathophysiological processes in the CNS, we recently demonstrated that IL-1β can protect cortical astrocytes from oxidant injury in a glutathione (GSH)-dependent manner. To test whether IL-1β could similarly protect neurons against oxidant stress, near pure neuronal cultures or mixed cortical cell cultures containing neurons and astrocytes were exposed to the organic peroxide, tert-butyl hydroperoxide (t-BOOH), following treatment with IL-1β or its vehicle. Neurons and astrocytes in mixed cultures, but not pure neurons, were significantly protected from the toxicity of t-BOOH following treatment with IL-1β in association with enhanced GSH production/release. IL-1β failed to increase the GSH levels or to provide protection against t-BOOH toxicity in chimeric mixed cultures consisting of IL-1R1+/+ neurons plated on top of IL-1R1−/− astrocytes. The attenuation of GSH release via block of multidrug resistance-associated protein 1 (MRP1) transport also abrogated the protective effect of IL-1β. These protective effects were not strictly an in vitro phenomenon as we found an increased striatal vulnerability to 3-nitropropionic acid-mediated oxidative stress in IL-1R1 null mice. Overall, our data indicate that IL-1β protects neurons against oxidant injury and that this likely occurs in a non-cell-autonomous manner that relies on an increase in astrocyte GSH production and release.

scholarly journals GPR68 Is a Neuroprotective Proton Receptor in Brain Ischemia

Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3690-3700
Author(s):  
Tao Wang ◽  
Guokun Zhou ◽  
Mindi He ◽  
Yuanyuan Xu ◽  
W.G. Rusyniak ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Neuronal Injury ◽  
Artery Occlusion ◽  
Dependent Manner ◽  
Protective Effects ◽  
Pkc Protein Kinase C ◽  
Neuroprotective Function ◽  
Cerebral Artery Occlusion

Background and Purpose: Brain acidosis is prevalent in stroke and other neurological diseases. Acidosis can have paradoxical injurious and protective effects. The purpose of this study is to determine whether a proton receptor exists in neurons to counteract acidosis-induced injury. Methods: We analyzed the expression of proton-sensitive GPCRs (G protein-coupled receptors) in the brain, examined acidosis-induced signaling in vitro, and studied neuronal injury using in vitro and in vivo mouse models. Results: GPR68, a proton-sensitive GPCR, was present in both mouse and human brain, and elicited neuroprotection in acidotic and ischemic conditions. GPR68 exhibited wide expression in brain neurons and mediated acidosis-induced PKC (protein kinase C) activation. PKC inhibition exacerbated pH 6-induced neuronal injury in a GPR68-dependent manner. Consistent with its neuroprotective function, GPR68 overexpression alleviated middle cerebral artery occlusion–induced brain injury. Conclusions: These data expand our knowledge on neuronal acid signaling to include a neuroprotective metabotropic dimension and offer GPR68 as a novel therapeutic target to alleviate neuronal injuries in ischemia and multiple other neurological diseases.

scholarly journals The impact of indole-3-lactic acid on immature intestinal innate immunity and development: a transcriptomic analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wuyang Huang ◽  
Ky Young Cho ◽  
Di Meng ◽  
W. Allan Walker
Keyword(s):  
Lactic Acid ◽  
Mechanistic Model ◽  
Transcriptomic Analysis ◽  
Dependent Manner ◽  
Protective Effects ◽  
Very Preterm Infants ◽  
Anti Inflammatory ◽  
The Impact

AbstractAn excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants. Indole-3-lactic acid (ILA) of breastmilk tryptophan was identified as the anti-inflammatory metabolite involved in probiotic conditioned media from Bifidobacteria longum subsp infantis. This study aimed to explore the molecular endocytic pathways involved in the protective ILA effect against inflammation. H4 cells, Caco-2 cells, C57BL/6 pup and adult mice were used to compare the anti-inflammatory mechanisms between immature and mature enterocytes in vitro and in vivo. The results show that ILA has pleiotropic protective effects on immature enterocytes including anti-inflammatory, anti-viral, and developmental regulatory potentials in a region-dependent and an age-dependent manner. Quantitative transcriptomic analysis revealed a new mechanistic model in which STAT1 pathways play an important role in IL-1β-induced inflammation and ILA has a regulatory effect on STAT1 pathways. These studies were validated by real-time RT-qPCR and STAT1 inhibitor experiments. Different protective reactions of ILA between immature and mature enterocytes indicated that ILA’s effects are developmentally regulated. These findings may be helpful in preventing NEC for premature infants.

Properties of neuroprotective cell-permeant Ca2+ chelators: effects on [Ca2+]i and glutamate neurotoxicity in vitro

1994 ◽  
Vol 72 (4) ◽  
pp. 1973-1992 ◽  
Author(s):  
M. Tymianski ◽  
M. P. Charlton ◽  
P. L. Carlen ◽  
C. H. Tator
Keyword(s):  
Time Course ◽  
Dependent Manner ◽  
Protective Effects ◽  
Tetraacetic Acid ◽  
Acetoxymethyl Ester ◽  
Neuroprotective Effects ◽  
Concentration Dependent Manner ◽  
Fura 2 ◽  
Glutamate Neurotoxicity

1. Cell-permeant Ca2+ chelators such as 1,2-bis-(2-amino-phenoxy)ethane- N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) protect neurons against excitotoxic and ischemic neuronal injury in vitro and in vivo. Here we provide the first steps toward characterizing the mechanisms by which these agents produce their neuroprotective effects. 2. Cultured mouse spinal neurons were simultaneously loaded with the Ca2+ indicator fura-2 and with one of three permeant chelators derived from the fast Ca2+ buffer BAPTA, or with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid acetoxymethyl ester (EGTA-AM). Adding these chelators did not interfere with the fluorescence spectrum of fura-2 and had no effect on baseline [Ca2+]i. 3. The neurons were challenged with 250 microM L-glutamate for 50 min, producing a marked transient [Ca2+]i increase followed by a decay of [Ca2+]i to a lower “plateau.” About 80% of control neurons succumbed to this excitotoxic insult. Neurons that survived adjusted their plateau [Ca2+]i to lower levels than those that succumbed. 4. Neurons that were pretreated with permeant Ca2+ chelators became more resistant to these neurotoxic challenges. 5. We examined whether this reduction in glutamate neurotoxicity could be related to the given buffer's known Ca2+ affinity (Kd), its Ca2+ binding kinetics, and its ability to attenuate glutamate-induced [Ca2+]i increases. 6. Pretreatment of neurons with BAPTA analogues having Kds ranging from 100 to 3,600 microM 1) attenuated the amplitude and 2) lengthened the time constant describing the rise and decay of the glutamate-evoked [Ca2+]i transient. The magnitude of these effects paralleled the affinity of the chelator for Ca2+. 7. BAPTA-AM and its analogues dramatically attenuated the early neurotoxicity of glutamate, reducing cell deaths by up to 80%. However, in contrast with the graded effects of chelators having different Ca2+ affinities on Ca2+ transients, all BAPTA analogues were equally protective. These protective effects did not relate to the chelators' Ca2+ affinity within a Kd range of 100 nM (for BAPTA) to 3,600 nM (for 5,5'-dibromo BAPTA). 8. BAPTA-AM protected neurons in a concentration-dependent manner with 50% protection obtained with 10 microM, a concentration having no effect on the [Ca2+]i transient amplitude. 9. EGTA, a slow Ca2+ buffer with a similar Ca2+ affinity to BAPTA produced the same effects as BAPTA on [Ca2+]i transient kinetics. However, it was far less protective than BAPTA. 10. The time course of early glutamate neurotoxicity was altered by the BAPTA analogues, but not EGTA. BAPTA analogues caused a small increase in cell deaths in the first minutes of each experiment, followed by relative sparing from further neurodegeneration. 11. The ability of low Ca2+ affinity chelators such as 5,5'-dibromo BAPTA to protect neurons without markedly attenuating measured [Ca2+]i increases conflicts with the hypothesis that global elevations in [Ca2+]i are responsible for triggering neurotoxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Protective Effects on Mitochondria and Anti-Aging Activity of Polysaccharides from Cultivated Fruiting Bodies of Cordyceps militaris

2010 ◽  
Vol 38 (06) ◽  
pp. 1093-1106 ◽  
Author(s):  
Xing-Tai Li ◽  
Hong-Cheng Li ◽  
Chun-Bin Li ◽  
De-Qiang Dou ◽  
Ming-Bo Gao
Keyword(s):  
Hydroxyl Radicals ◽  
Cordyceps Militaris ◽  
Mitochondrial Swelling ◽  
Dependent Manner ◽  
Protective Effects ◽  
Fruiting Bodies ◽  
Concentration Dependent Manner ◽  
Mitochondrial Injury

Cordyceps militaris (L.) Link is an entomopathogenic fungus parasitic to Lepidoptera larvae, and is widely used as a folk tonic or invigorant for longevity in China. Although C. militaris has been used in traditional Chinese medicine for millennia, there is still a lack convincing evidence for its anti-aging activities. This study was performed to investigate the effects of polysaccharides from cultivated fruiting bodies of C. militaris (CMP) on mitochondrial injury, antioxidation and anti-aging activity. Fruiting bodies of C. militaris were cultivated artificially under optimized conditions. The spectrophotometric method was used to measure thiobarbituric acid reactive substances (TBARS), mitochondrial swelling, and activities of scavenging superoxide anions in vitro. D-galactose (100 mg/kg/day) was injected subcutaneously into back of the neck of mice for 7 weeks to induce an aging model. The effects of CMP on the activities of catalase (CAT), surperoxide dismutase (SOD), glutathione peroxidase (GPx) and anti-hydroxyl radicals were assayed in vivo using commercial monitoring kits. The results showed that CMP could inhibit mitochondrial injury and swelling induced by Fe2+ -L-Cysteine in a concentration- dependent manner and it also had a significant superoxide anion scavenging effect. Moreover, the activities of CAT, SOD, GPx and anti-hydroxyl radicals in mice liver were increased significantly by CMP. These results indicate that CMP protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting mitochondrial swelling, and increasing the activities of antioxidases. Therefore, CMP may have pharmaceutical values for mitochondrial protection and anti-aging. CMP was the major bioactive component in C. militaris.

scholarly journals Protective Effects of Scolopendra Water Extract on Trimethyltin-Induced Hippocampal Neurodegeneration and Seizures in Mice

2019 ◽  
Vol 9 (12) ◽  
pp. 369
Author(s):  
Yun-Soo Seo ◽  
Mary Jasmin Ang ◽  
Byeong Cheol Moon ◽  
Hyo Seon Kim ◽  
Goya Choi ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Primary Cultures ◽  
Water Extract ◽  
Model Systems ◽  
Inflammatory Factor ◽  
Dependent Manner ◽  
Protective Effects ◽  
Cell Degeneration

Trimethyltin (TMT) is an organotin compound with potent neurotoxic action characterized by neuronal degeneration in the hippocampus. This study evaluated the protective effects of a Scolopendra water extract (SWE) against TMT intoxication in hippocampal neurons, using both in vitro and in vivo model systems. Specifically, we examined the actions of SWE on TMT- (5 mM) induced cytotoxicity in primary cultures of mouse hippocampal neurons (7 days in vitro) and the effects of SWE on hippocampal degeneration in adult TMT- (2.6 mg/kg, intraperitoneal) treated C57BL/6 mice. We found that SWE pretreatment (0–100 μg/mL) significantly reduced TMT-induced cytotoxicity in cultured hippocampal neurons in a dose-dependent manner, as determined by lactate dehydrogenase and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. Additionally, this study showed that perioral administration of SWE (5 mg/kg), from −6 to 0 days before TMT injection, significantly attenuated hippocampal cell degeneration and seizures in adult mice. Furthermore, quantitative analysis of Iba-1 (Allograft inflammatory factor 1)- and GFAP (Glial fibrillary acidic protein)-immunostained cells revealed a significant reduction in the levels of Iba-1- and GFAP-positive cell bodies in the dentate gyrus (DG) of mice treated with SWE prior to TMT injection. These data indicated that SWE pretreatment significantly protected the hippocampus against the massive activation of microglia and astrocytes elicited by TMT. In addition, our data showed that the SWE-induced reduction of immune cell activation was linked to a significant reduction in cell death and a significant improvement in TMT-induced seizure behavior. Thus, we conclude that SWE ameliorated the detrimental effects of TMT toxicity on hippocampal neurons, both in vivo and in vitro. Altogether, our findings hint at a promising pharmacotherapeutic use of SWE in hippocampal degeneration and dysfunction.

scholarly journals In Vivo and In Vitro Evaluation of the Protective Effects of Hesperidin in Lipopolysaccharide-Induced Inflammation and Cytotoxicity of Cell

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 478 ◽  
Author(s):  
Rasha Al-Rikabi ◽  
Hanady Al-Shmgani ◽  
Yaser Hassan Dewir ◽  
Salah El-Hendawy
Keyword(s):  
Breast Cancer ◽  
Chromatin Condensation ◽  
Control Group ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Protective Effects ◽  
Mcf7 Cells ◽  
Tnf Α

(1) Background: Plant flavonoids are efficient in preventing and treating various diseases. This study aimed to evaluate the ability of hesperidin, a flavonoid found in citrus fruits, in inhibiting lipopolysaccharide (LPS) induced inflammation, which induced lethal toxicity in vivo, and to evaluate its importance as an antitumor agent in breast cancer. The in vivo experiments revealed the protective effects of hesperidin against the negative LPS effects on the liver and spleen of male mice. (2) Methods: In the liver, the antioxidant activity was measured by estimating the concentration of glutathione (GSH) and catalase (CAT), whereas in spleen, the concentration of cytokines including IL-33 and TNF-α was measured. The in vitro experiments including MTT assay, clonogenity test, and sulforhodamine 101 stain with DAPI (4′, 6-diamidino-2-phenylindole) were used to assess the morphological apoptosis in breast cancer cells. (3) Results: The results of this study revealed a significant increase in the IL-33 and TNF-α cytokine levels in LPS challenged mice along with a considerable elevation in glutathione (GSH); moreover, the catalase (CAT) level was higher compared to that of the control group. Cytotoxicity of the MCF-7 cell line revealed significant differences among the groups treated with different concentrations when compared to the control groups, in a concentration-dependent manner. Hesperidin significantly inhibited the colony formation of MCF7 cells when compared to that of control. Clear changes were observed in the cell shape, including cell shrinkage and chromatin condensation, which were associated with a later apoptotic stage. (4) Conclusion: The results indicate that hesperidin might be a potential candidate in preventing diseases.

scholarly journals In Vitro and In Vivo Protective Effects of Lentil (Lens culinaris) Extract against Oxidative Stress-Induced Hepatotoxicity

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 59
Author(s):  
Yeon-Seop Jung ◽  
So-Hee Lee ◽  
So Young Chun ◽  
Dae Hwan Kim ◽  
Byung Ik Jang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Serum Levels ◽  
Liver Cells ◽  
Dependent Manner ◽  
Protective Effects ◽  
H2o2 Treatment ◽  
Antioxidant Genes ◽  
Hepatic Diseases

Excessive oxidative stress plays a role in hepatotoxicity and the pathogenesis of hepatic diseases. In our previous study, the phenolic extract of beluga lentil (BLE) showed the most potent in vitro antioxidant activity among extracts of four common varieties of lentils; thus, we hypothesized that BLE might protect liver cells against oxidative stress-induced cytotoxicity. BLE was evaluated for its protective effects against oxidative stress-induced hepatotoxicity in AML12 mouse hepatocytes and BALB/c mice. H2O2 treatment caused a marked decrease in cell viability; however, pretreatment with BLE (25–100 μg/mL) for 24 h significantly preserved the viability of H2O2-treated cells up to about 50% at 100 μg/mL. As expected, BLE dramatically reduced intracellular reactive oxygen species (ROS) levels in a dose-dependent manner in H2O2-treated cells. Further mechanistic studies demonstrated that BLE reduced cellular ROS levels, partly by increasing expression of antioxidant genes. Furthermore, pretreatment with BLE (400 mg/kg) for 2 weeks significantly reduced serum levels of alanine transaminase and triglyceride by about 49% and 40%, respectively, and increased the expression and activity of glutathione peroxidase in CCl4-treated BALB/c mice. These results suggest that BLE protects liver cells against oxidative stress, partly by inducing cellular antioxidant system; thus, it represents a potential source of nutraceuticals with hepatoprotective effects.

scholarly journals Protective Effects of a Human 18-Kilodalton Cationic Antimicrobial Protein (CAP18)-Derived Peptide against Murine Endotoxemia

1998 ◽  
Vol 66 (5) ◽  
pp. 1861-1868 ◽  
Author(s):  
Teruo Kirikae ◽  
Michimasa Hirata ◽  
Hiromi Yamasu ◽  
Fumiko Kirikae ◽  
Hiroshi Tamura ◽  
...  
Keyword(s):  
Endotoxic Shock ◽  
Endotoxin Shock ◽  
Antimicrobial Protein ◽  
Dependent Manner ◽  
Protective Effects ◽  
Amino Acid Peptide ◽  
Dose Dependent ◽  
Necrosis Factor ◽  
Lps Binding

ABSTRACT CAP18 (an 18-kDa cationic antimicrobial protein) is a granulocyte-derived protein that can bind lipopolysaccharide (LPS) and inhibit various activities of LPS in vitro. The present study examined the protective effect of a synthetic 27-amino-acid peptide (CAP18109–135) from the LPS-binding domain of CAP18 against antibiotic-induced endotoxin shock, using highly LPS-sensitived-(+)-galactosamine (d-GalN)-sensitized C3H/HeN mice. The antibiotic-induced endotoxin (CAZ-endotoxin) was prepared from the culture filtrate of Pseudomonas aeruginosa PAO1 exposed to ceftazidime (CAZ). Injection of CAP18109–135protected the mice injected with LPS or CAZ-endotoxin from death and lowered their tumor necrosis factor (TNF) levels in serum in a dose-dependent manner. Treatment with CAZ caused death of thed-GalN-sensitized P. aeruginosa PAO-infected mice within 48 h, while injection with CAP18109–135rescued the mice from death. In the mice rescued from death by injection with CAP18109–135, endotoxin levels in plasma and TNF production by liver tissues were decreased but the numbers of viable infecting bacteria in their blood were not decreased significantly and remained at the levels in CAZ-treated mice. These results indicate that CAP18109–135 is capable of preventing antibiotic-induced endotoxic shock in mice with septicemia and that the effect is due to its LPS-neutralizing activity rather than to its antibacterial activity.

The N-Terminal Domain of Thrombomodulin Sequesters HMGB1: A Novel Anti-Inflammatory Mechanism.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3435-3435
Author(s):  
Kazuhiro Abeyama ◽  
Yasushi Yoshimoto ◽  
Ikuro Maruyama
Keyword(s):  
Protein C ◽  
Statistical Significance ◽  
Dependent Manner ◽  
Protective Effects ◽  
Binding Studies ◽  
Terminal Domain ◽  
Anti Inflammatory ◽  
Dose Dependent

Abstract Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC), the latter an enzyme with potent anti-coagulant and anti-inflammatory properties. We have found that the N-terminal, lectin-like domain (D1) of thrombomodulin has unique anti-inflammatory properties. Thrombomodulin, via D1, binds high mobility group-B1 DNA binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing leukocyte activation in vitro, and ultraviolet radiation-induced cutaneous inflammation and lipopolysaccharide-induced lethality in vivo. Our data also demonstrate anti-inflammatory properties of a peptide spanning the D1 domain of TM and suggest its therapeutic potential. These findings highlight a novel mechanism through which an endothelial cofactor, TM, suppresses inflammation; i.e., sequestration of mediators thereby preventing their interaction with cell surface receptors on effector cells in the vasculature. Results: TM binds HMGB1 and prevents expression of pro-inflammatory activity. Our co-culture studies of leukocytes and HUVEC, and results in the cutaneous irritation model suggested that early release of a mediator, such as HMGB1, might contribute importantly to cellular activation in inflammation at later time points. In this context, TM might have the ability to decrease HMGB1-mediated inflammatory events. Binding studies using surface plasmon resonance (SPR), performed to directly assess the interaction of TM and immobilized HMGB1, demonstrated dose-dependent binding in the nanomolar range (Kd ~232 nM). Furthermore, addition of rhs-TM decreased, in a dose-dependent manner, the binding of HMGB1 to RAGE through the its N-terminal domain, but not anti-coagulant domain. TM and the N-terminal-derived TM peptide have anti-inflammatory effects in settings where HMGB1 is a likely key mediator. In HMGB1-mediated skin inflammation model, systemic administration of rhs-TM, its lectin-like domain and sRAGE resulted in a significant blunting of the inflammatory response. In contrast, the effect of anti-coagulant domain, although showing a trend toward decreased ear swelling, did not achieve statistical significance (anticoagulant domain has anti-inflammatory effects in vivo that probably reflect its ability to support thrombin-mediated activation of protein C; the latter does not occur in vitro after inactivation of the protein C zymogen by heat treatment). In view of recent data suggesting a link between HMGB1 released from injured tissue and endotoxin-induced lethality in mice, we also tested whether rhs-TM and its lectin-like domain might also have protective effects in this model. We employed a dose of intraperitoneal (IP) LPS (10 mg/kg) resulting in 100% lethality by 96 hrs. Systemic (IP) treatment of animals with anti-HMGB1 IgY had a protective effect with respect to lethality at 4 days, whereas the same regimen of nonimmune IgY was without effect. Similarly, IP administration of rhs-TM and its N-teminal lectin domain, but not anti-coagulant domain had complete protective effects compared with anti-HMGB1 IgY. Conclusion: Our findings have elucidated an unexpected anti-inflammatory property of TM residing in the D1 domain, namely binding of HMGB1.

scholarly journals Protective Effects of D-Penicillamine on Catecholamine-Induced Myocardial Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Michal Říha ◽  
Pavlína Hašková ◽  
Jan Martin ◽  
Tomáš Filipský ◽  
Kateřina Váňová ◽  
...  
Keyword(s):  
Iron Reduction ◽  
Myocardial Injury ◽  
Troponin T ◽  
High Dose ◽  
Plasma Vitamin ◽  
Specific Marker ◽  
Dependent Manner ◽  
Protective Effects ◽  
Copper Release

Iron and copper release participates in the myocardial injury under ischemic conditions and hence protection might be achieved by iron chelators. Data on copper chelation are, however, sparse. The effect of the clinically used copper chelator D-penicillamine in the catecholamine model of acute myocardial injury was tested in cardiomyoblast cell line H9c2 and in Wistar Han rats. D-Penicillamine had a protective effect against catecholamine-induced injury bothin vitroandin vivo. It protected H9c2 cells against the catecholamine-induced viability loss in a dose-dependent manner. In animals, both intravenous D-penicillamine doses of 11 (low) and 44 mg/kg (high) decreased the mortality caused by s.c. isoprenaline (100 mg/kg) from 36% to 14% and 22%, respectively. However, whereas the low D-penicillamine dose decreased the release of cardiac troponin T (specific marker of myocardial injury), the high dose resulted in an increase. Interestingly, the high dose led to a marked elevation in plasma vitamin C. This might be related to potentiation of oxidative stress, as suggested by additionalin vitroexperiments with D-penicillamine (iron reduction and the Fenton reaction). In conclusion, D-penicillamine has protective potential against catecholamine-induced cardiotoxicity; however the optimal dose selection seems to be crucial for further application.

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