The impact of phyto- and endo-cannabinoids on central nervous system diseases：A review

Abstract

Background and aim: Cannabis sativa L. is a medicinal plant with a long history. Phyto-cannabinoids are a class of compounds from C. sativa L. with varieties of structures. Endocannabinoids exist in the human body. This article provides an overview of natural cannabinoids (phyto-cannabinoids and endocannabinoids) with an emphasis on their pharmacology activities.

Experimental procedure: The keywords "Cannabis sativa L″, "cannabinoids", and "central nervous system (CNS) diseases" were used for searching and collecting pieces of literature from PubMed, ScienceDirect, Web of Science, and Google Scholar. The data were extracted and analyzed to explore the effects of cannabinoids on CNS diseases.

Result and conclusion: In this paper, schematic diagrams are used to intuitively show the phyto-cannabinoids skeletons' mutual conversion and pharmacological activities, with special emphasis on their relevant pharmacological activities on central nervous system (CNS) diseases. It was found that the endocannabinoid system and microglia play a crucial role in the treatment of CNS diseases. In the past few years, pharmacological studies focused on Δ⁹-THC, CBD, and the endocannabinoids system. It is expected to encourage new studies on a more deep exploration of other types of cannabinoids and the mechanism of their pharmacological activities in the future.

Keywords: CNS diseases; Cannabinoids; Chemical structures; Endocannabinoid system.

Graphical abstract

Fig. 1

The reciprocal transformation of the skeletal structure of the major cannabinoids.

Fig. 2

Schematic of the endocannabinoid system. The main endocannabinoids AEA and 2-AG are synthesized after postsynaptic cell stimulation. 2-AG is degraded by monoacylglycerol lipase (MAGL) which is expressed in the presynaptic terminal. While fatty acid amide hydrolase (FAAH) is localized to postsynaptic cells, which predominantly degrades AEA. AEA and 2-AG are transported across the membrane and respectively act on cannabinoid receptors (CB1 and CB2) which are expressed on presynaptic terminals, to exhibit the corresponding therapeutic effects.

Fig. 3

Schematic representation of mechanisms of neuroinflammation in CNS diseases. Neuroinflammatory is caused by proinflammatory cytokines, pathogenic molecules (e.g. LPS), Aβ and other infections, injury, etc. Amyloid β-peptide (Aβ) is produced by aging or senescence, which can be transported from blood to the brain via the low density lipoprotein receptor-related protein 1 (LRP-1). Lipopolysaccharide (LPS) works through toll Like Receptor 4 (TLR4). The activation of microglia leads to proinflammatory cytokines (IL-1β, IL-4, TNF-α, NO, ROS) synthesis and cytotoxic effect, which causes neuroinflammatory related to CNS diseases.

Fig. 4

The effect of activated microglia in several CNS diseases. Microglia has two phenotypes: M1 was activated by LPS which produces IL-1β, TNF, IL-6, and iNOS. M2 was activated by IL-4 and expressed IL-10, IL-4, and TGFβ, which contributes to brain injury recovery. M1 and M2 were interconvertible under certain circumstances.