Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells

Faria, Juliana; Barbosa, Joana; Queirós, Odília; Moreira, Roxana; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

doi:10.1016/j.tox.2016.06.010

Cited by 36 publications

(33 citation statements)

References 43 publications

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“…In line with this, previous studies by our group have shown toxicological damage, using in vitro and in vivo approaches, following an acute exposure to tramadol and tapentadol [ 97 , 98 , 99 ]. In particular, hepato- and nephrotoxicity were found upon Wistar rat exposure to therapeutic doses [ 98 ].…”

Section: Introductionsupporting

confidence: 78%

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

et al. 2020

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Tramadol and tapentadol are fully synthetic and extensively used analgesic opioids, presenting enhanced therapeutic and safety profiles as compared with their peers. However, reports of adverse reactions, intoxications and fatalities have been increasing. Information regarding the molecular, biochemical, and histological alterations underlying their toxicological potential is missing, particularly for tapentadol, owing to its more recent market authorization. Considering the paramount importance of liver and kidney for the metabolism and excretion of both opioids, these organs are especially susceptible to toxicological damage. In the present study, we aimed to characterize the putative hepatic and renal deleterious effects of repeated exposure to therapeutic doses of tramadol and tapentadol, using an in vivo animal model. Male Wistar rats were randomly divided into six experimental groups, composed of six animals each, which received daily single intraperitoneal injections of 10, 25 or 50 mg/kg tramadol or tapentadol (a low, standard analgesic dose, an intermediate dose and the maximum recommended daily dose, respectively). An additional control group was injected with normal saline. Following 14 consecutive days of administration, serum, urine and liver and kidney tissue samples were processed for biochemical, metabolic and histological analysis. Repeated administration of therapeutic doses of both opioids led to: (i) increased lipid and protein oxidation in liver and kidney, as well as to decreased total liver antioxidant capacity; (ii) decreased serum albumin, urea, butyrylcholinesterase and complement C3 and C4 levels, denoting liver synthesis impairment; (iii) elevated serum activity of liver enzymes, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase, as well as lipid profile alterations, also reflecting hepatobiliary commitment; (iv) derangement of iron metabolism, as shown through increases in serum iron, ferritin, haptoglobin and heme oxygenase-1 levels. In turn, elevated serum cystatin C, decreased urine creatinine output and increased urine microalbumin levels were detected upon exposure to tapentadol only, while increased serum amylase and urine N-acetyl-β-D-glucosaminidase activities were observed for both opioids. Collectively, these results are compatible with kidney injury. Changes were also found in the expression levels of liver- and kidney-specific toxicity biomarker genes, upon exposure to tramadol and tapentadol, correlating well with alterations in lipid profile, iron metabolism and glomerular and tubular function. Histopathological analysis evidenced sinusoidal dilatation, microsteatosis, mononuclear cell infiltrates, glomerular and tubular disorganization, and increased Bowman’s spaces. Although some findings are more pronounced upon tapentadol exposure, our study shows that, when compared with acute exposure, prolonged administration of both opioids smooths the differences between their toxicological effects, and that these occur at lower doses within the therapeutic range.

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Section: Introductionsupporting

confidence: 78%

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

et al. 2020

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“…One study, concerning human exposure, reports the case of a 19‐year‐old male patient with a history of tramadol abuse for 6 months, who was found unconscious with multiple organ dysfunction syndrome. In this situation, toxicological analyses only detected toxic tramadol levels (blood concentration of 9.5 mg/L), and medical analyses described several alterations, comprising deep coma, acute respiratory distress syndrome, electrocardiogram with sinus tachycardia, as well as hepatic, cardiac and renal dysfunction (Wang et al., ), in accordance with nonclinical in vitro and in vivo acute exposure studies (Faria et al., , ; Barbosa et al., ). Hepatic dysfunction was characterized by increased alanine and aspartate aminotransferase activities and BUN levels (Wang et al., ).…”

Section: Toxicitymentioning

confidence: 72%

Comparative pharmacology and toxicology of tramadol and tapentadol

Faria

Barbosa

Moreira

et al. 2018

European Journal of Pain

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“…To study the effects of curcumin on oxidative stress, we used the human neuroblastoma SH-SY5Y cell line, which is widely used for studying oxidative stress in vitro [ 37 ]. SH-SY5Y cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM)/HAM F12 (1:1) (Gibco, Life Technologies, Grand Island, NY, USA) supplemented with 1% penicillin/streptomycin and 10% FCS (Gibco, Life Technologies, Grand Island, NY, USA).…”

Section: Methodsmentioning

confidence: 99%

Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo — in search of potential anti-epileptogenic strategies for temporal lobe epilepsy

Drion

Scheppingen

Arena

et al. 2018

J Neuroinflammation

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BackgroundPrevious studies in various rodent epilepsy models have suggested that mammalian target of rapamycin (mTOR) inhibition with rapamycin has anti-epileptogenic potential. Since treatment with rapamycin produces unwanted side effects, there is growing interest to study alternatives to rapamycin as anti-epileptogenic drugs. Therefore, we investigated curcumin, the main component of the natural spice turmeric. Curcumin is known to have anti-inflammatory and anti-oxidant effects and has been reported to inhibit the mTOR pathway. These properties make it a potential anti-epileptogenic compound and an alternative for rapamycin.MethodsTo study the anti-epileptogenic potential of curcumin compared to rapamycin, we first studied the effects of both compounds on mTOR activation, inflammation, and oxidative stress in vitro, using cell cultures of human fetal astrocytes and the neuronal cell line SH-SY5Y. Next, we investigated the effects of rapamycin and intracerebrally applied curcumin on status epilepticus (SE)—induced inflammation and oxidative stress in hippocampal tissue, during early stages of epileptogenesis in the post-electrical SE rat model for temporal lobe epilepsy (TLE).ResultsRapamycin, but not curcumin, suppressed mTOR activation in cultured astrocytes. Instead, curcumin suppressed the mitogen-activated protein kinase (MAPK) pathway. Quantitative real-time PCR analysis revealed that curcumin, but not rapamycin, reduced the levels of inflammatory markers IL-6 and COX-2 in cultured astrocytes that were challenged with IL-1β. In SH-SY5Y cells, curcumin reduced reactive oxygen species (ROS) levels, suggesting anti-oxidant effects. In the post-SE rat model, however, treatment with rapamycin or curcumin did not suppress the expression of inflammatory and oxidative stress markers 1 week after SE.ConclusionsThese results indicate anti-inflammatory and anti-oxidant properties of curcumin, but not rapamycin, in vitro. Intracerebrally applied curcumin modified the MAPK pathway in vivo at 1 week after SE but failed to produce anti-inflammatory or anti-oxidant effects. Future studies should be directed to increasing the bioavailability of curcumin (or related compounds) in the brain to assess its anti-epileptogenic potential in vivo.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1247-9) contains supplementary material, which is available to authorized users.

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Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells

Cited by 36 publications

References 43 publications

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

Comparative pharmacology and toxicology of tramadol and tapentadol

Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo — in search of potential anti-epileptogenic strategies for temporal lobe epilepsy

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