## Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders : From Pathogenesis to a Promising Therapeutic Target

Tommaso Cassano, Silvio Calcagnini, Lorenzo Pace, Federico De Marco, Adele Romano and Silvana Gaetani

Frontiers in Neuroscience, 2017, 11, article 30

DOI : 10.3389/fnins.2017.00030

Abstract :

As a consequence of an increasingly aging population, the number of people affected by neurodegenerative disorders,such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease, is rapidly increasing. Although the etiology of these diseases has not been completely defined, common molecular mechanisms including neuroinflammation, excitotoxicity and mitochondrial dysfunction have been confirmed and can be targeted therapeutically. Moreover, recent studies have shown that endogenous cannabinoid signaling plays a number of modulatory roles throughout the central nervous system (CNS), including the neuroinflammation and neurogenesis. In particular, the up-regulation of type-2 cannabinoid (CB2) receptors has been found in a number of neurodegenerative disorders. Thus, the modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neuronal degeneration. For these reasons this review will focus on the CB2 receptor as a promising pharmacological target in a number of neurodegenerative diseases.

Keywords : Alzheimer’s disease, Parkinson’s disease, neuroprotection, neuroinflammation, microglia, astrocytes

INTRODUCTION
The field of cannabinoid (CB) research has flourished over the past decade and has brought to light diverse functions of the CB system in normal and pathological conditions (D’Addario et al., 2014; Bonnet and Marchalant, 2015). In fact, several studies have demonstrated that endocannabinoid (eCB) system plays significant roles in many biological processes, including neurogenesis, synaptic plasticity, emotional regulation and stress responsiveness (Lu and Mackie, 2015).

The eCB system consists of eCBs, cannabinoid receptors and enzymes involved in the synthesis and degradation of endogenous ligands (Lu and Mackie, 2015).

The eCBs are endogenous lipids that engage CB receptors, affecting behavior in a fashion that at least partially recapitulates the effects produced by the psychoactive components of cannabis, most notably (2)-trans-19-tetrahydrocannabinol (THC) (Mechoulam and Gaoni, 1965; Mechoulam, 1970). The two best-characterizede CBs are N-arachidonoylethanolamide (anandamide, AEA) (Devaneetal., 1992) and 2-arachidonoylglycerol (2-AG) (Mechoulam et al.,1995; Sugiura et al., 1995). Both eCBs are synthetized at the post-synaptic terminal from membrane lipid precursors in response to high intracellular calcium concentration (Howlett et al., 2002). Thus, eCBs act as retrograde messengers to depress transmitter release from presynaptic terminals (Freund et al., 2003; Fagan and Campbell, 2014).

AEA and 2-AG possess specific pharmacological properties, are engaged in different forms of synaptic plasticity and modulate different behavioral functions (Mechoulam and Parker, 2013).

The CB type1 (CB1) and type2 (CB2) receptors are coupled to G protein, and their signal transduction is mediated by the inhibition of adenylyl cyclases and voltage-gated calcium channels (e.g., N-type, P/Q-type and L-type calcium currents), and by the activation of mitogen-activated protein kinases (MAPK) and inwardly rectifying potassium channels (Howlett et al., 2002; Lu and Mackie, 2015). AEA is a high affinity, CB1- selective partial agonist, whereas 2-AG is amoderate affinity, CB1/CB2 full agonist (Sugiura et al., 2000). AEA activates also peroxisome proliferator-activated receptors-alpha and transient receptor potential vannilloid-1 channels (Maccarrone et al., 2010). In humans, CB1 is localized preferentially in the terminals of central and peripheral neurons and glial cells, where it regulates neurotransmitter release and psychoactivity (Egertová et al., 2003; Sánchez and García-Merino, 2012). As far as peripheral tissues, CB1 is also expressed in heart, uterus, testis, liver and small intestine, as well as in immune cells (Maccarrone et al., 2001; Nong et al., 2001;Klein et al., 2003) and adipose tissue (Spoto et al.,2006).

CB2 was dubbed the “peripheral cannabinoid receptor” as a result of in situ hybridization study that showed high CB2 mRNA expression in spleen, where as no expression was observed in the brain (Shire et al., 1996; Griffin et al., 2000; Brown et al., 2002). Besides the cells of the immune and hematopoietic systems (e.g., leukocytes, spleen and tonsils), CB2 receptors were found also in other peripheral organs, such as muscle, liver, intestine and testis(Liuetal., 2009). However, CB2 receptor can be also detected in the central nervous system (CNS) (albeit at a lower expression level than CB1 receptors) (Núñez et al., 2004; Van Sickle et al., 2005), where its expression is significantly increased following a number of stressful conditions (Viscomi et al., 2009). In particular, CB2 receptor expression is foundin neurons with in the brainstem, microglia and astrocytes only after specific insults (e.g., neuroinflammation), whereas it cannot be detected in resting microglia (Van Sickle et al., 2005; Núñez et al., 2008; Cabral and Griffin-Thomas, 2009).

In the last decade, increasing evidence has shown that CB receptors may act as CB1-CB2 receptor heteromers in the brain (Callén et al., 2012). In fact, the expression of CB1-CB2 receptor heteromers was determined in a variety of brain regions, such as the nucleus accumbens, pineal gland and globuspallidus (Callén et al.,2012). Due to this tight functional interaction between CB receptors, the response to molecules acting as agonists or antagonists may be different when a CB receptor is engaged in hetero receptor complexes. Although the clinical relevance of this phenomenon is not entirely clear, additional studies are needed in order to shed further light on this important functional interaction.

eCBs after their actions are rapidly eliminated by cellular uptake and enzymatic hydrolysis. To this regard, AEA is mainly inactivated by fatty acid amide hydrolase (FAAH) (Cravatt et al., 1996; Dinh et al., 2002), whereas 2-AG is predominantly catalyzed by monoacylglycerol lipase (Dinh et al., 2002).

As previously reported, CB1 receptor expression is abundant in the CNS, where it seems to mediate the psychoactive effects of cannabis (Mackie, 2005). Therefore, the scarcity of CNS CB2 receptors makes CB2 selective drugs attractive as therapeutics as they would presumably invoke minimal psychoactive responses. In support of this hypothesis, CB2 knockout mice demonstrated typical behavioral responses to THC but lost their normal immune responsiveness to THC (Buckley et al., 2000). CB2 levels are also increased under certain conditions and disease states further adding to its attractiveness as a potential therapeutic target (Zhang et al., 2003; Wotherspoon et al., 2005; Yiangou et al., 2006).

Therefore, we will review the role of eCB system in two chronic neurodegenerative diseases, in which the neuroprotective effects following CB receptors modulation have been reported in different studies. Specifically, we will focus on the role of CB2 receptors and their agonists, as potential therapeutical targets in Alzheimer’s disease (AD) and Parkinson’s disease (PD).

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