Endocannabinoid system in neurodegenerative disorders

Abstract

Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well-defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs.

Keywords: Alzheimer's disease; CB1 receptors; Huntington's disease; Loss of neurons; Parkinson's disease; motor and memory behavior.

Figure 1. CB1R signaling pathway

Both endogenous and synthetic cannabinoids elicit their effects by binding to CB1Rs (Breivogel & Childers 2000, Derkinderen et al. 2003, Mackie 2006, Mechoulam & Parker 2013). CB1Rs are seven-transmembrane-domain, G protein-coupled receptors located in the cell membrane (Howlett 1995). CB1R signaling leads to inhibition of adenylate cyclase (AC) activity (Childers et al. 1994, Pinto et al. 1994, Howlett & Mukhopadhyay 2000), N-type voltage-gated calcium channels (Caulfield & Brown 1992, Mackie & Hille 1992, Nogueron et al. 2001, Pan et al. 1996), N-type and P/Q-type calcium channels and D-type potassium channels (Howlett & Mukhopadhyay 2000, Howlett et al. 2002) and activate A-type and inwardly rectifying potassium channels (GIRKs) (Mu et al. 1999). CB1Rs also participate in the regulation of neurotransmitter release (Freund et al. 2003, Howlett et al. 2002) and inhibit synaptic transmission (Freund et al. 2003, Howlett et al. 2002). The actions on Ca²⁺ channels and AC are thought to be mediated by the G protein α subunits, while the βγ subunits activate GIRK and PI3K. The βγ complex further activates the p38/JNK/ERK1/2 pathways, followed by phosphorylation of several downstream targets, such as cPLA2, ELK-1, c-fos, c-Jun and CREB, leading to the expression of target genes such as krox-24 and BDNF (Derkinderen et al. 2003, Graham et al. 2006). PI3K mediates the AKT-induced inhibition of CREB activation (Graham et al. 2006). Inhibition of AC and the subsequent decrease in cAMP reduces the activation of cAMP-dependent protein kinase (PKA), resulting in reduced phosphorylation of K⁺ channels (Basavarajappa & Arancio 2008, Mechoulam & Parker 2013, Ozaita et al. 2007). Inhibition of ERK1/2 activation followed by inhibition of CaMKIV and CREB phosphorylation has also been found under certain conditions in vivo, leading to inhibition of Arc expression (Basavarajappa 2015, Basavarajappa & Subbanna 2014). Stimulatory effects are shown by (→) arrows and inhibitory effects by (⊥) arrows.

Figure 2. CB2R signaling pathway

Both endogenous and synthetic cannabinoids bind to CB2Rs. CB2Rs are also seven-transmembrane-domain, G protein-coupled receptors located in the cell membrane (Bouaboula et al. 1996, Pertwee 1997, Buckley et al. 1998, Onaivi et al. 2006). Activation of CB2R is coupled to several different cellular pathways, including AC, cAMP, PKA, ERK1/2, p38 MAPK, and AKT and a pathway for de novo synthesis of ceramide (Bouaboula et al. 1996, Carracedo et al. 2006a, Carracedo et al. 2006b, Carrier et al. 2004, Choi et al. 2013, Gertsch et al. 2004, Herrera et al. 2005, Molina-Holgado et al. 2002a, Palazuelos et al. 2006, Samson et al. 2003). These signaling cascades may participate in the regulation of cell function and behavior. Stimulatory effects are shown by (→) arrows and inhibitory effects by (⊥) arrows.

Figure 3

The AEA and 2-AG chemical structures.

Figure 4. The schematic enzymatic pathway that regulates catabolism of AEA (A) and 2-AG (B)

A. Stimulation of AC and PKA potentiates the N-acyltransferase (Ca²⁺-dependent transacylase, CDTA). An arachidonic acid chain is transferred by CDTA from the sn-1 position of a phospholipid to the primary amine of phosphatidylethanolamine, in a Ca²⁺-dependent manner, forming N-arachidonoyl phosphatidylethanolamine (N-ArPE), an intermediate. This N-ArPE is then hydrolyzed by a phospholipase D (PLD)-like enzyme to yield anandamide (AEA) (Natarajan et al. 1981, Schmid et al. 1983, Di Marzo et al. 1994). It is not clear whether the N-acyltransferase (NAT) or the N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) controls the rate-limiting step of AEA synthesis (Di Marzo 1998, Sugiura et al. 2002, Hansen et al. 2000). NAPE-PLD knockout mice exhibit normal AEA biosynthesis, suggesting the involvement of other enzymes (Leung et al. 2006). Another pathway that regulates the conversion of NAPE into 2-lysol-NAPEs by the activity of secretory PLA₂ (sPLA2) has also been proposed. 2-Lysol-NAPEs by the action of selective lysophospholipase D (lyso-PLD) (Sun et al. 2004) is then converted into N-acyl-ethanolamides, including AEA. 2-Lysol-NAPEs, through the action of abhydrolase domain 4 (ABHD4) (Liu et al. 2008), are turned into glycero-p-AEA, which is then converted by glycerol phosphodiesterase (GDE1) (Simon & Cravatt 2008) into AEA. A recent study using mouse brain and RAW264.7 macrophages proposed the existence of an analogous pathway where NAPE converted into pAEA by the action of PLC. The pAEA is subsequently dephosphorylated by a protein tyrosine phosphatase (PTPN22) (Liu et al. 2006). As a putative neuromodulator, AEA that is released into the synaptic cleft is expected to be rapidly inactivated. In general, there are two known mechanisms for removing endocannabinoids from the synaptic cleft to ensure rapid signal inactivation: re-uptake or enzymatic degradation. AEA is inactivated by reuptake (Beltramo & Piomelli 2000, Bisogno et al. 2001) via an uncharacterized membrane transport molecule, the ‘AEA membrane transporter’ (AMT) (Hillard et al. 1997, Beltramo et al. 1997, Beltramo & Piomelli 2000, Hillard & Jarrahian 2000, Maccarrone et al. 1998, Giuffrida et al. 2001, Basavarajappa et al. 2003), and subsequently, undergoes intracellular enzymatic degradation. FAAH metabolizes AEA to arachidonic acid, and ethanolamine leading to rapid clearance of AEA from extracellular compartments (Deutsch et al. 2001, Glaser et al. 2003). B. Intracellular Ca²⁺ initiates 2-AG biosynthesis by activating the process of formation of diacylglycerol (DAG) (Prescott & Majerus 1983, Sugiura et al. 1995) in the membrane by stimulating the phosphatidyl-inositol-phospholipase C (PI-PLC) pathway. 2-AG is the product of DAG-lipase (DAGL) acting on DAG (Bisogno et al. 1999b, Carrier et al. 2004). The second route involves hydrolysis of phosphatidylinositol (PI) by phospholipase A1 (PLA₁) and hydrolysis of the resultant lyso-PI by a specific lyso-PLC (Sugiura et al. 1995). 2-AG is also synthesized through the conversion of 2-arachidonyl lysophosphatidic acid (LPA) by phosphatase (Nakane et al. 2002). 2-AG activates CB1Rs with greater efficacy than does AEA. Like AEA, 2-AG is inactivated by reuptake (Beltramo & Piomelli 2000, Bisogno et al. 2001) via the AMT (Hillard et al. 1997, Beltramo et al. 1997, Beltramo & Piomelli 2000, Hillard & Jarrahian 2000, Maccarrone et al. 1998, Giuffrida et al. 2001, Basavarajappa et al. 2003) and subsequently undergoes intracellular enzymatic degradation (Di Marzo et al. 1994, Day et al. 2001, Deutsch et al. 2001) by monoacylglycerol lipase (MAGL).