Acute acetaminophen intoxication induces direct neurotoxicity in rats manifested as astrogliosis and decreased dopaminergic markers in brain areas associated with locomotor regulation

Vigo, María Belén; Pérez, Miguel A.; Fino, Fernanda De; Gómez, Gimena; Martínez, Sonia A.; Bisagno, Verónica; Carlo, María Beatriz Di; Scazziota, Alejandra; Manautou, José E.; Ghanem, Carolina Inés

doi:10.1016/j.bcp.2019.113662

Cited by 10 publications

(11 citation statements)

References 73 publications

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“…APAP‐induced ALF in mice leads to brain oedema and coma together with increased blood ammonia levels 19 . Additionally, activation of intracellular signalling mechanisms, including elevated levels of cytokines, activation of brain transcription factors (increased levels of NF‐kB, NRf2 etc), induction of oxidative stress, glial fibrillary acidic protein expression, as well as autophagy‐related events have been observed in the brains of these animals 19‐27 …”

Section: Current Animal Models Of Hementioning

confidence: 99%

“…However, in vivo, the hyperpermeability of the BBB is either not observed 143 or if it is, it is not until the later stages of HE 37,142‐144 and requires the presence of systemic proinflammatory signals, 37,145 suggesting that direct effects of AOM on the permeability of the BBB is negligible in vivo. APAP has been demonstrated to have a direct toxic effect on the brain in rats 22,25 and issues may be present in other toxin models as well and therefore experiments should be designed to consider these possible off target effects. Secondly, issues with reproducibility of these models, both between laboratories and between experiments within a single laboratory are often observed.…”

Section: Current Animal Models Of Hementioning

confidence: 99%

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2021 ISHEN guidelines on animal models of hepatic encephalopathy

DeMorrow

Cudalbu

Davies

et al. 2021

Liver International

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This working group of the International Society of Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) was commissioned to summarize and update current efforts in the development and characterization of animal models of hepatic encephalopathy (HE). As defined in humans, HE in animal models is based on the underlying degree and severity of liver pathology. Although hyperammonemia remains the key focus in the pathogenesis of HE, other factors associated with HE have been identified, together with recommended animal models, to help explore the pathogenesis and pathophysiological mechanisms of HE. While numerous methods to induce liver failure and disease exist, less have been characterized with neurological and neurobehavioural impairments. Moreover, there still remains a paucity of adequate animal models of Type C HE induced by alcohol, viruses and non‐alcoholic fatty liver disease; the most common etiologies of chronic liver disease.

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Section: Current Animal Models Of Hementioning

confidence: 99%

Section: Current Animal Models Of Hementioning

confidence: 99%

2021 ISHEN guidelines on animal models of hepatic encephalopathy

DeMorrow

Cudalbu

Davies

et al. 2021

Liver International

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“…Similarly, in a recently published study, paracetamol at a dose of 1 g/ kg has been shown to have toxic effects on neuron cells without ALF. Again in this study, rats were hypoactive due to the inhibitory effects of paracetamol on the dopaminergic pathway and dopamine [28]. In a different study, paracetamol caused neuronal damage in the rat brain dose dependently.…”

Section: Discussionmentioning

confidence: 47%

Comparison of effects of high and low dose paracetamol treatment and toxicity on brain and liver in rats

Oksuz

Yaşar

Erten

et al. 2020

North Clin Istanbul

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P aracetamol is one of the most widely used drugs in the world as analgesics and antipyretics. Although it has been classified as non-steroidal anti-inflammatory drugs (NSAIDs) for many years, it has been classified as "other" analgesic and antipyretic drugs in recent years due to lack of anti-inflammatory properties. Although it acts by inhibiting the cyclooxygenase (COX) enzyme and prostaglandin synthesis, such as NSAIDs, several studies have shown that the potential for inhibition of COX enzymes in peripheral tissues is quite low [1]. Therefore, ABSTRACT OBJECTIVE: Paracetamol is thought that it acts by inhibiting the central cyclooxygenase (COX) enzyme; its mechanism of action is still not fully explained. Although its most important side effect is hepatoxicity, it is thought to cause toxicity on the brain in recent years. The present study aims to investigate the treatment and toxic effects of low and high doses of paracetamol on the liver and brain. METHODS: Wistar-albino rats were used in this study. At doses of 20-500 mg/kg, paracetamol was administered intraperitoneally once a day for one and three days. The brain and liver were used for immunohistochemical evaluation using COX-3, prostaglandin E 2 (PGE 2) and caspase 3 antibodies and for total antioxidant (TAS), total oxidant (TOS) and oxidative stress index (OSI) measurements. Results were evaluated using the Kruskal Wallis test (SPSS ver.24). RESULTS: The liver COX-3 levels were significantly lower in both groups with higher doses (p<0.05). In the brain, there was no statistically significant difference in COX-3 levels between the groups. There was no statistically significant difference in PGE 2 levels in the liver and brain between the groups (p>0.05). The caspase 3 level in the liver was statistically significantly higher in the low dose group compared to the other groups (p<0.05). In both liver and brain, OSI values were significantly higher in the 3-day high-dose group compared to others (p<0.05). There was no statistically significant difference between the groups in ALT and AST values (p>0.05). CONCLUSION: The results of our study show that paracetamol inhibits the COX-3 enzyme in the liver but has no effect in the brain, and COX-3 does not have an effect on PGE 2. Paracetamol causes apoptosis in the liver only in low doses; higher doses may cause toxicity by increasing oxidative stress, especially in the brain.

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“…Transverse sections (5-µm thick) were mounted on slides for subsequent staining. Hematoxylin and eosin (H&E) and Nissl staining were performed to observe histopathological changes according to the manufacturer's protocol (Vigo et al, 2019). Images were acquired using a light microscope.…”

Section: Histological Analysismentioning

confidence: 99%

FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response

Wang

et al. 2021

Front. Pharmacol.

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Disruption of the blood-brain barrier (BBB) and the cerebral inflammatory response occurring after traumatic brain injury (TBI) facilitate further brain damage, which leads to long-term complications of TBI. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in brain development and neuronal homeostasis. The aim of the current study was to assess the protective effects of FGF20 on TBI via BBB maintenance. In the present study, recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema, Evans blue extravasation and neuroinflammation in a TBI mouse model. In an in vitro TNF-α-induced human brain microvascular endothelial cell (HBMEC) model of BBB disruption, rhFGF20 reduced paracellular permeability and increased trans-endothelial electrical resistance (TEER). Both in the TBI mouse model and in vitro, rhFGF20 increased the expression of proteins composing in BBB-associated tight junctions (TJs) and adherens junctions (AJs), and decreased the inflammatory response, which protected the BBB integrity. Notably, rhFGF20 preserved BBB function by activating the AKT/GSK3β pathway and inhibited the inflammatory response by regulating the JNK/NFκB pathway. Thus, FGF20 is a potential candidate treatment for TBI that protects the BBB by upregulating junction protein expression and inhibiting the inflammatory response.

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Acute acetaminophen intoxication induces direct neurotoxicity in rats manifested as astrogliosis and decreased dopaminergic markers in brain areas associated with locomotor regulation

Cited by 10 publications

References 73 publications

2021 ISHEN guidelines on animal models of hepatic encephalopathy

2021 ISHEN guidelines on animal models of hepatic encephalopathy

Comparison of effects of high and low dose paracetamol treatment and toxicity on brain and liver in rats

FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response

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