The Role of Cannabinoids in CNS Development: Focus on Proliferation and Cell Death

Abstract

The active principles of Cannabis sativa are potential treatments for several diseases, such as pain, seizures and anorexia. With the increase in the use of cannabis for medicinal purposes, a more careful assessment of the possible impacts on embryonic development becomes necessary. Surveys indicate that approximately 3.9% of pregnant women use cannabis in a recreational and/or medicinal manner. However, although the literature has already described the presence of endocannabinoid system components since the early stages of CNS development, many of their physiological effects during this stage have not yet been established. Moreover, it is still uncertain how the endocannabinoid system can be altered in terms of cell proliferation and cell fate, neural migration, neural differentiation, synaptogenesis and particularly cell death. In relation to cell death in the CNS, knowledge about the effects of cannabinoids is scarce. Thus, the present work aims to review the role of the endocannabinoid system in different aspects of CNS development and discuss possible side effects or even opportunities for treating some conditions in the development of this tissue.

Keywords: Apoptosis; Cannabinoids; Cell death; Development; Endocannabinoids; Proliferation.

Fig. 1

Signaling in the endocannabinoid synapse. Glutamate released by presynaptic cells stimulates ionotropic and metabotropic receptors in postsynaptic cells, leading to an increase in Ca²⁺ influx/concentration. Ca²⁺ and/or Gq stimulate PLC, which leads to the production of DAG, the substrate for DAGL to form 2-AG, while NAPE-PLD hydrolyses NAPE to form AEA. Endocannabinoids diffuse through the synaptic cleft, reaching the CB1 and CB2 receptors TRPV1 and GPR55, among others. The classical downstream pathway of the CB receptor occurs through Gi-protein: inhibition of AC activity, modulation of K⁺ and Ca²⁺ channels, and subsequent inhibition of NT release. The signaling is ended by endocannabinoid degradation. FAAH metabolizes AEA into AA and ethanolamine, while COX-2 can eventually generate prostamide from AEA. MAGL, ABHD12, and ABHD6 degrade 2-AG in AA and glycerol, while COX-2 is metabolized in PGE2-G. The thickness of arrows from metabolizing enzymes represents the importance in the control of AEA and 2-AG availability

Fig. 2

Primary metabolic pathways of AEA and 2-AG synthesis and degradation. a. AEA synthesis—An increase in Ca²⁺ stimulates NAPE-PLD to hydrolyze NAPE, producing AEA. PLC catalyzes the formation of phospho-NAE, and the phosphatases PTPN22 and INPP5D then convert phospho-NAE to AEA. NAPE is catalyzed by sPLA2 or ABHD4, generating lyso-NAPE. Then, ABHD4 catalyzes the formation of GP-NAE, which is converted to AEA by the phosphodiesterase GDE1. 2-AG synthesis—PLC mediates the hydrolysis of PIP₂, which produces DAG, which is converted to 2-AG by DAGLα/β. Phosphatidic acid (PA) is hydrolyzed by PA phosphohydrolase, producing DAG, which is converted by DAGLα/β into 2-AG. b. AEA degradation—AEA is degraded primarily by FAAH into AA and ethanolamine, while COX-2 degrades into prostamide. 2-AG degradation—2-AG is degraded primarily by MAGL into AA and glycerol. ABHD6 and ABHD12 also degrade 2-AG into AA and glycerol, although they are less common. COX-2 degrades 2-AG into PGE2-G

Fig. 3

Apoptosis induced by cannabinoids. AEA and 2-AG activate CB1R and COX-2, inducing apoptosis in a manner dependent on the cholesterol-rich lipid rafts in cultured decidual cells. 2-AG causes an increase in ROS, leading to reticulum stress and apoptosis through PERK-ATF4-CHOP in the placenta via CB2R. 2-AG, Δ9-THC and synthetic cannabinoids increased ROS, causing reticulum stress-induced apoptosis in the cytotrophoblastic cell lineage

Fig. 4

Apoptosis induced by cannabinoids in the CNS. CP-55,940 activates CB1R and causes apoptosis via caspase-3 in forebrain cultures. Δ9-THC, through CB1R, leads to cytochrome c release and caspase-3 activation, inducing apoptosis in cultured cortical neuron cells. Δ9-THC increases AA through PLA2, activating COX-2 and culminating in an increase in ROS, causing hippocampal neural death. P2X7 activation increases the activity of NAPE-PLD and DAGL, leading to an increase in 2-AG and AEA. 2-AG, AEA and WIN activate CB1R and CB2R signaling through P2X7R and cytoplasmic Ca²⁺, causing an increase in superoxide and cytochrome c release and leading to apoptosis in the retina during development