Effects on the Post-translational Modification of H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 Levels in Cerebral Cortex, Hypothalamus and Pons of Rats after a Systemic Administration of Cannabidiol: A Preliminary Study

Abstract

Background: Cannabidiol (CBD), a non-psychotropic constituent of Cannabis sativa, has shown therapeutic promises by modulating several pathological conditions, including pain, epilepsy autism, among others. However, the molecular mechanism of action of CBD remains unknown and recent data suggest the engagement on CBD´s effects of nuclear elements, such as histone activity. Aim: This study assessed the changes on the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions of rats after the administration of CBD (20mg/Kg/i.p.). Objective: To evaluate the effects on the PTM of histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels in the cerebral cortex, hypothalamus and pons of CBD-treated rats. Method: Ten adult rats were randomly assigned into 2 groups: Control or CBD (20mg/Kg/i.p). Animals were sacrificed after treatments and brains were collected for dissections of the cerebral cortex, hypothalamus and pons. Samples were analyzed for PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels by Western blot procedure. Results: CBD increased the PTM levels on the histones H3K4Me3, H3K9ac, and H3K27Me3 in the cerebral cortex whereas no significant differences were found in H3K9Me2 and H3K36Me2. In addition, in the hypothalamus, CBD decreased the contents of H3K9ac while no significant effects were observed in H3K4Me3, H3K9Me2, H3K27Me3, and H3K36Me2. Lastly, in the pons, CBD-treated rats showed a significant decline on the PTM levels of H3K4Me3 whereas no statistical differences were found in H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2. Conclusion: The study showed that CBD induced differential effects in levels of PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions.

Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research

“…This was evidenced by a recent study that examined the levels of five different histone modifications (H3K4me3, H3K9ac, H3K9me2, H3K27me3, and H3K36me2) in the cerebral cortex, hypothalamus, and pons following the systemic administration of CBD (20 mg/kg, i.p.) to adult rats [ 60 ]. In the cerebral cortex, CBD enhanced H3K4me3, H3K9ac, and H3K27me3 levels, without producing any significant differences in H3K9me2 or H3K36me2 levels [ 60 ].…”

“…to adult rats [ 60 ]. In the cerebral cortex, CBD enhanced H3K4me3, H3K9ac, and H3K27me3 levels, without producing any significant differences in H3K9me2 or H3K36me2 levels [ 60 ]. In the hypothalamus, CBD lowered H3K9ac levels, without producing any significant effects on H3K4me3, H3K9me2, H3K27me3, and H3K36me2 levels [ 60 ].…”

“…In the cerebral cortex, CBD enhanced H3K4me3, H3K9ac, and H3K27me3 levels, without producing any significant differences in H3K9me2 or H3K36me2 levels [ 60 ]. In the hypothalamus, CBD lowered H3K9ac levels, without producing any significant effects on H3K4me3, H3K9me2, H3K27me3, and H3K36me2 levels [ 60 ]. Finally, in the pons, CBD reduced H3K4me3 levels, without any significant effects on the levels of H3K9ac, H3K9me2, H3K27me3, or H3K36me2 [ 60 ].…”

“…In the hypothalamus, CBD lowered H3K9ac levels, without producing any significant effects on H3K4me3, H3K9me2, H3K27me3, and H3K36me2 levels [ 60 ]. Finally, in the pons, CBD reduced H3K4me3 levels, without any significant effects on the levels of H3K9ac, H3K9me2, H3K27me3, or H3K36me2 [ 60 ]. The histone modifications affected by CBD have been linked to anxiety- and stress-related characteristics in separate preclinical studies.…”

“…By contrast, a week of restraint stress increased H3K9me3 but lowered H3K27me3 and H3K4me3 levels in the same region [ 61 ]. Thus, it is tempting to speculate that the observed stress-induced reductions in the hippocampal levels of H3K27me3 and H3K4me3 following a week of restraint stress [ 61 ] may be reversed by CBD’s enhancing effects on these same modifications, as reported in the cerebral cortex [ 60 ]. A close relationship is also known to exist between H3K27me and de novo DNA methylation [ 41 ], thus providing a possible link between CBD’s effects on histone modifications and the previously discussed effects of CBD on DNA methylation [ 54 ].…”