A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol)

Philippot, Gaëtan; Hallgren, Stefan; Gordh, Torsten; Fredriksson, Anders; Fredriksson, Robert; Viberg, Henrik

doi:10.1093/toxsci/kfy199

Cited by 19 publications

(33 citation statements)

References 51 publications

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“…This is in line with our hypothesis proposed elsewhere (Viberg et al, 2014; Philippot et al, 2017) where we suggested that PND 10 exposure to AAP (through its metabolite AM404) activate CB 1 R during brain development, which in turn, affects the BDNF–TRKB pathway. Additionally, the negative effect of PND 10 AAP exposure on adult spontaneous behavior and habituation rates was enhanced by simultaneous exposure to CB 1 R agonist WIN 55 212-2 (Philippot et al, 2018), further indicating the critical role of the endocannabinoid system during brain development.…”

Section: Discussionmentioning

confidence: 96%

“…The transcriptional effect on Trkb following PND 10 exposure to THC is also interesting for the developmental neurotoxic evaluation of AAP; in a previous study, PND 10 exposure to AAP also decreased transcription of Trkb in mice (Philippot et al, 2018). Since both THC and AAP interact with the endocannabinoid system (Bertolini et al, 2006), together with the fact that PND 10 exposure to both these substances affect 1) adult spontaneous behavior and habituation rates and 2) decreased transcript levels of Trkb 24 h after exposure, there is a possibility that both these substances share important events in their respective AOP.…”

Section: Discussionmentioning

confidence: 99%

“…This is interesting because AAP, like THC, also interacts with the endocannabinoid system (Bertolini et al, 2006). Moreover, the neurotoxic effects following PND 10 AAP exposure were enhanced following co-exposure to CB 1 R agonist WIN 55 212-2 (WIN) (Philippot et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Primarily, this study aimed to investigate the possible key events in the adverse outcome pathway (AOP) in relation to our previous study (Philippot et al, 2016) where we showed that a single-dose of THC administered to 10-day-old mice induced long-term changes in their behavior. Secondly, the aim of this study was to compare these potential biochemical effects to those already observed following PND 10 AAP exposure (Philippot et al, 2018). Accordingly, a thorough analysis of the transcriptional changes following PND 10 exposure to THC was made in mice.…”

Section: Introductionmentioning

confidence: 99%

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A Single δ9-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis

et al. 2019

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δ9-tetrahydrocannabinol (THC) is one of the most used drugs during pregnancy and lactation and efficiently crosses the placental and blood–brain barriers. Despite the recent legalization initiatives worldwide, the adverse outcome pathway (AOP) of THC following exposure during brain development is incompletely understood. We have previously reported that a single injection of THC on postnatal day (PND) 10 altered adult spontaneous behavior and habituation rates in adult mice. Similar behavioral alterations have been reported following PND 10 exposure to the commonly used over-the-counter analgesic acetaminophen (AAP; also known as paracetamol); as both THC and AAP interact with the endocannabinoid system, we hypothesize that this system might be involved in the AOP of both these pharmaceuticals/drugs. Here, we report that a single THC dose on PND 10 decreased transcript levels of tropomyosin receptor kinase b (Trkb) 24 h after exposure in both the frontal and parietal cortex, and in the hippocampus in mice. An increase in the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) ratio were also found in both the parietal cortex and hippocampus following neonatal exposure to THC. In addition, THC exposure increased transcript levels of cannabinoid receptor type 1 (Cb1r) in the parietal cortex and increased the apoptosis regulator BAX in the frontal cortex. This study is important for mainly 3 reasons: 1) we are starting to get information on the developmental neurotoxic AOP of PND 10 exposure to THC, where we suggest that transcriptional changes of the neurotrophic receptor Trkb are central, 2) our PND 10 exposure model provides information relevant to human exposure and 3) since PND 10 exposure to AAP also decreased Trkb transcript levels, we suggest THC and AAP may share key events in their respective AOP through endocannabinoid-mediated alterations of the brain-derived neurotrophic factor (BDNF)-TRKB signaling pathway.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Single δ9-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis

et al. 2019

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“…Suggested mechanisms relate to modulation of central nervous system inflammation or to paracetamol metabolites, like cannabinoids. Related to this, paracetamol and (9)-tetrahydrocannabinol, but not ibuprofen, resulted in developmental neurotoxicity in a mice model (77,78).…”

Section: Paracetamol Use In Neonates: In Search Of a Better Benefit-rmentioning

confidence: 88%

A Critical Review on the Relevance of Paracetamol for Procedural Pain Management in Neonates

Allegaert

2020

Front. Pediatr.

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Effective and safe pain relief in neonates matters. This is not only because of ethical constraints or human empathy, but even more because pain treatment is an important and crucial part of contemporary medical, paramedical, and nursing care to improve the outcome in neonatal intensive care graduates. Paracetamol (acetaminophen) is likely one of the pharmacological tools to attain this, with data on prescription practices suggesting that paracetamol is somehow the "rising star" in neonatal pain management. Besides very rare topical clinical scenarios like peripartal asphyxia and subsequent whole body hypothermia or the use of cardiorespiratory support devices, data on paracetamol pharmacokinetics and metabolism were reported throughout neonatal age or weight ranges, and we have summarized these data. In this review, we subsequently aimed to provide the reader with the currently available observations on the use of paracetamol as analgesic for different pain syndromes (major surgery, minor surgery or trauma, and procedural pain), with focus on the limitations of paracetamol when prescribed for neonatal procedural pain management. We hereby intentionally will not discuss other indications (patent ductus arteriosus and fever) for paracetamol administration in neonates. Based on the available evidence, paracetamol has opioid-sparing effects for major pain syndromes, is effective to treat minor to moderate pain syndromes, but fails for effective procedural pain management in neonates. This efficacy failure for procedural pain management should stimulate us to continue to search for more effective interventions, including non-pharmacological interventions and preventive strategies. Furthermore, there are also upcoming association type of epidemiological studies on the relation between exposure to analgesics-including paracetamol-and the negative short-or long-term outcome characteristics (neuro-behavioral, atopy, and fertility). Consequently and in addition to the search for effective alternatives to prevent or treat pain, studies on long-term outcome following paracetamol exposure are needed to inform all stakeholders on the full effect-side effect balance of the different strategies to treat pain.

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Evaluation of the dentate gyrus in adult mice exposed to acetaminophen (paracetamol) on postnatal day 10

Philippot

Hellsten

Viberg

et al. 2021

Intl J of Devlp Neuroscience

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Acetaminophen (AAP; or paracetamol) is a widely used nonprescription drug with antipyretic and analgesic properties. Alarmingly, there is an increasing body of evidence showing that developmental exposure to AAP is associated with adverse behavioural outcomes later in life. We have previously shown that relevant doses of AAP in 10‐day‐old mice affected memory, learning and locomotor activity in the adult animals. Interestingly, the neurons of the dentate gyrus (DG) have a relatively late time of origin as they are generated during the first two weeks of postnatal life in rodents. Since the generation of these cells, which are important for memory processing, coincides with our AAP exposure, we aim to investigate if the cytoarchitecture of the DG is affected by postnatal day 10 AAP treatment. In addition, we investigate if markers for differentiation and migration in the hippocampus were affected by the same treatment. We did not observe any visual effects in adult DG cytoarchitecture, nor any changes of markers for differentiation/migration in the hippocampus in 24 hr after exposure. Even though a large effect size was estimated on adult DG thickness following AAP exposure, the estimated 95% CIs around the differences of the means reveal no significant effect. Hence, larger sample sizes are warranted to clarify if neonatal AAP exposure affects adult DG thickness in mice.

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A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol)

Cited by 19 publications

References 51 publications

A Single δ9-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis

A Single δ9-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis

A Critical Review on the Relevance of Paracetamol for Procedural Pain Management in Neonates

Evaluation of the dentate gyrus in adult mice exposed to acetaminophen (paracetamol) on postnatal day 10

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