Assessing the treatment of cannabidiolic acid methyl ester: a stable synthetic analogue of cannabidiolic acid on c‑Fos and NeuN expression in the hypothalamus of rats

Eric Murillo‑Rodríguez, Diana Millán‑Aldaco, Gloria Arankowsky‑Sandoval, Tetsuya Yamamoto,
Roger G. Pertwee, Linda Parker and Raphael Mechoulam

 

 

Abstract

Background : Cannabidiol (CBD), the non-psychotropic compound from Cannabis sativa, shows positive results on controlling several health disturbances; however, comparable data regarding additional chemical from C. sativa, such as cannabidiolic acid (CBDA), is scarce due to its instability. To address this limitation, a stable CBDA analogue, CBDA methyl ester (HU-580), was synthetized and showed CBDA-like effects. Recently, we described that HU-580 increased wakefulness and wake-related neurochemicals.

Objective : To extend the comprehension of HU-580´s properties on waking, the c-Fos and NeuN expression in a wake-linked brain area, the hypothalamus was evaluated.

Methods : c-Fos and NeuN expression in hypothalamic sections were analyzed after the injections of HU-580 (0.1 or 100 μg/kg, i.p.).

Results : Systemic administrations of HU-580 increased c-Fos and neuronal nuclei (NeuN) expression in hypothalamic nuclei, including the dorsomedial hypothalamic nucleus dorsal part, dorsomedial hypothalamic nucleus compact part, and dorsomedial hypothalamic nucleus ventral part.

Conclusion : HU-580 increased c-Fos and NeuN immunoreactivity in hypothalamus nuclei suggesting that this drug might modulate the sleep–wake cycle by engaging the hypothalamus.

Keywords : Cannabis, Hypothalamus, Rat, Sleep, Wakefulness

Background

Several pieces of evidence have suggested that the nonpsychotropic molecule derived from Cannabis sativa, cannabidiol (CBD), exerts positive therapeutic pharmacological properties for the management of several health disturbances, including epilepsy, pain, anxiety, among many others (Fraguas-Sánchez and Torres-Suárez, 2018; Friedman and Wongvravit, 2018; Millar, et al. 2019; Premoli, et al. 2019; Pretzsch, et al. 2019). However, only limited experimental data is available concerning the effects of another molecule from C. sativa, cannabidiolic acid (CBDA). The lack of evidence of this cannabinoid lies in its chemical instability (Citti, et al. 2018; Mechoulam and Hanus, 2002). Hence, to tackle this problem, our group has synthetized a stable CBDA analogue named CBDA methyl ester of HU-580, which produces certain CBDA-like effects more potently than CBDA.

These pharmacological properties of HU-580 include the management of anxiety and depression in experimental models (Hen-Shoval, et al. 2018; Pertwee, et al. 2018). In addition, HU-580 modulates the sleep–wake cycle by increasing wakefulness as well as wake-related neurochemicals such as dopamine, serotonin, adenosine, and acetylcholine (Murillo-Rodríguez et al. 2020). Despite these fascinating results, the mechanism of action activated by HU-580 for modulation of the sleep–wake cycle is unknown. Therefore, to provide further evidence of the neurobiological effects of HU-580 on sleep control, we evaluated whether administrations of this chemical might induce changes on the expression of neural markers, such as c-Fos and neuronal nuclei (NeuN), in the hypothalamus, a brain region that has been linked to the regulation of wakefulness (Aston-Jones et al. 2001; Chen, et al. 2018; Saper et al. 2005; Sapin et al. 2010).

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JCR-2021