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Oral Cannabidiol Prevents Allodynia and Neurological Dysfunctions in a Mouse Model of Mild Traumatic Brain Injury

Published

2 years ago

May 2, 2019

Republished by Plato

. 2019 Apr 16;10:352.

doi: 10.3389/fphar.2019.00352. eCollection 2019.

Affiliations

Free PMC article

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Carmela Belardo et al. Front Pharmacol. 2019.

Free PMC article

. 2019 Apr 16;10:352.

doi: 10.3389/fphar.2019.00352. eCollection 2019.

Affiliations

¹ Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.
² Enecta s.r.l., Bologna, Italy.
³ Department of Plastic Surgery, University of Campania Luigi Vanvitelli, Naples, Italy.
⁴ Drug Addiction Unit (SerT), Naples, Italy.

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Abstract

Neurological dysfunctions are the most impactful and persistent consequences of traumatic brain injury (TBI). Indeed, previous reports suggest that an association between TBI and chronic pain syndromes, as well anxio-depressive behaviors, tends to be more common in patients with mild forms of TBI. At present, no effective treatment options are available for these symptoms. In the present study, we used a weight drop mild TBI mouse model to investigate the effect of a commercially available 10% Cannabidiol (CBD) oil on both the sensorial and neuropsychiatric dysfunctions associated with mild TBI through behavioral and biomolecular approaches. TBI mice developed chronic pain associated with anxious and aggressive behavior, followed by a late depressive-like behavior and impaired social interaction. Such behaviors were related with specific changes in neurotransmitters release at cortical levels. CBD oral treatment restored the behavioral alterations and partially normalized the cortical biochemical changes. In conclusion, our data show some of the brain modifications probably responsible for the behavioral phenotype associated with TBI and suggest the CBD as a pharmacological tool to improve neurological dysfunctions caused by the trauma.

Keywords: behavior; cannabidiol; microdialysis; pain; traumatic brain injury.

Figures

**FIGURE 1**

Timeline of mTBI induction, treatments and behavioral and biochemical characterization.

**FIGURE 2**

Microdialysis probe location. **(A)** Shows a panoramic picture of the pre-frontal cortex, the star indicates the prelimbic area. **(B)** Shows a high magnification of the microdialysis probe location for amino acid collection within the pre/infra-limbic cortex.

**FIGURE 3**

Effect of CBD on behavioral evaluations in sham and mTBI mice. **(A)** Shows Tactile withdrawal thresholds (TWT) measured through Von Frey monofilaments, **(B)** shows the latency to fall in the rotarod test, **(C–F)** show the number of transitions, number of rearing, the time spent in the periphery or in the center, in the open field test, respectively. Data are represented as mean ± SEM of 10–11 mice per group. ^∗, ^# and ° indicate significant differences compared to sham/vehicle, sham/CBD 10 or TBI/vehicle, respectively. P < 0.05 was considered statistically significant. One-way ANOVA, followed by Bonferroni’s Multiple Comparison *post hoc* tests.

**FIGURE 4**

Effect of CBD on behavioral evaluations in sham and mTBI mice. **(A-D)** show the latency to the first attack and the number of attacks in the resident intruder test, respectively, at 14- and 60-days post mTBI. Data are represented as mean ± SEM of 10 mice per group. ^∗ and ° indicate significant differences compared to sham/vehicle or TBI/vehicle, respectively. P < 0.05 was considered statistically significant. One-way ANOVA, followed by Tukey *post hoc test*.

**FIGURE 5**

Effect of CBD on behavioral evaluations in sham and mTBI mice. **(A)** Shows the duration of immobility in the tail suspension test. **(B,C)** Show the duration of the time spent with an object or mouse in the three chambers sociability apparatus. Data are expressed in seconds and represented as mean ± SEM of 10–12 mice per group. ^∗ and ° indicate significant differences compared to sham/vehicle or TBI/vehicle, respectively. P < 0.05 was considered statistically significant. One-way ANOVA, followed by Bonferroni’s Multiple Comparison *post hoc* test.

**FIGURE 6**

Effect of CBD on the release of glutamate **(B,E)**, GABA **(C,F)** and D-Aspartate **(A,D)** in sham or mTBI mice at 14 and 60 days after trauma. The values of extracellular amino acids in the mPFC were expressed as pmol in 10 μl of perfusate. Each point represents the mean ± SEM of 3–4 animals per group. ^∗, ^# and ° indicate significant differences compared to sham/vehicle, sham/CBD 10 or TBI/vehicle, respectively. P < 0.05 was considered statistically significant. One- Way ANOVA, *post hoc* test Newman-Keuls Multiple Comparison.

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