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A Single δ 9-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis

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A Single δ 9-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis

Gaëtan Philippot et al. Front Pharmacol.

Abstract

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.

Keywords: Trkb; acetaminophen (paracetamol); brain growth spurt; critical window development; developmental toxicology and neurotoxicology; neurotrophic; oxidative stress; δ9-tetrahydrocannabinol.

Figures

Figure 1
Figure 1
Neurotrophic gene markers. Transcript levels of neurotrophic genes Bdnf and Trkb 24 h after PND 10 exposure to vehicle, 10 mg THC/kg or 50 mg THC/kg in the (A) frontal cortex, (B) parietal cortex, and (C) hippocampus. Statistical difference from post hoc test is indicated as * if p < 0.05. Height of bars represents the mean fold change ± SEM of 8 mice.
Figure 2
Figure 2
Endocannabinoid gene markers. Transcript levels of endocannabinoid genes Cb1r and Faah 24 h after PND 10 exposure to vehicle, 10 mg THC/kg or 50 mg THC/kg in the (A) frontal cortex, (B) parietal cortex, and (C) hippocampus. Statistical difference from post hoc test is indicated as * if p < 0.05 Height of bars represents the mean fold change ± SEM of 8 mice.
Figure 3
Figure 3
Synaptic density genes. Transcript levels of synaptic density gene markers Syp and Psd95 24 h after PND 10 exposure to vehicle, 10 mg THC/kg or 50 mg THC/kg in the (A) frontal cortex, (B) parietal cortex, and (C) hippocampus. Height of bars represents the mean fold change ± SEM of 8 mice.
Figure 4
Figure 4
Oxidative stress genes. Transcript levels of oxidative stress genes Nrf2 and Keap1, together with a Nrf2/Keap1 expression ratio, 24 h after PND 10 exposure to vehicle, 10 mg THC/kg or 50 mg THC/kg in the (A) frontal cortex, (B) parietal cortex, and (C) hippocampus. Statistical difference from post hoc test is indicated as * if p < 0.05. Height of bars represents the mean fold change ± SEM of 8 mice.

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