JOURNAL OF NEUROCHEMISTRY | 2017 | 142 | 624–648 doi: 10.1111/jnc.14098

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*Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA †New York State Psychiatric Institute, New York City, New York, USA ‡Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York City, New York, USA §Department of Psychiatry, New York University Langone Medical Center, New York City, New York, USA

Abstract enzymes that catabolize these compounds, has been shown Most neurodegenerative disorders (NDDs) are characterized to contribute to the development of NDDs in several animal by cognitive impairment and other neurological defects. The models and human studies. In this review, we discuss the definite cause of and pathways underlying the progression of functions of the endocannabinoid system in NDDs and these NDDs are not well-defined. Several mechanisms have converse the therapeutic efficacy of targeting the endo- been proposed to contribute to the development of NDDs. cannabinoid system to rescue NDDs. These mechanisms may proceed concurrently or succes- Keywords: Alzheimer’s disease, CB1 receptors, Huntington’s sively, and they differ among cell types at different develop- disease, Loss of neurons, motor and memory behavior, mental stages in distinct brain regions. The endocannabinoid Parkinson’s disease. system, which involves cannabinoid receptors type 1 (CB1R) J. Neurochem. (2017) 142, 624–648. and type 2 (CB2R), endogenous cannabinoids and the

Cannabinoids are naturally occurring compounds found in the plant Cannabis sativa. Of over 500 different compounds Received April 6, 2017; revised manuscript received May 22, 2017; present in the plant, only approximately 85 are termed accepted June 2, 2017. cannabinoids (Brenneisen 2007). The most well-known Address for correspondence and reprint request to Dr Balapal S. among these compounds is delta-9-tetrahydrocannabinol Basavarajappa, Division of Analytical Psychopharmacology, Nathan (D9-THC) (Dewey 1986; Hollister 1986). D9-THC elicits Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, New York, NY 10962, USA. E-mail: basavaraj.balapal its psychoactive effects by binding to receptors on the cell @nki.rfmh.org membrane called cannabinoid receptors (CBRs) (Howlett Abbreviations used: 2-AG, 2-arachidonylglycerol; ABHD4, abhydro- et al. 1990). These receptors are present in both the central lase domain 4; AEA, arachidonylethanolamide (anandamide); AMPAR, nervous system (CNS) and the periphery and are classified as a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AMT, type 1 (CB1R) and type 2 (CB2R). Signaling downstream of AEA membrane transporter; BDNF, brain-derived neurotrophic factor; fi CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; these CBRs is signi cantly involved in a variety of standard DAGL, diacylglycerollipase; EC, endocannabinoid; FAAH, fatty acid functions as well as several pathophysiological functions of amide hydrolase; FAK, focal adhesion kinase; GABAA, gamma-amino the CNS. Signaling events of CB1R and CB2R are depicted butyric acid-A receptor; GDE1, glycerophosphodiesterase; GPCR, G in Figs 1 and 2 respectively. Discovery of the first endoge- protein coupled receptor; MAGL, monoacylglycerol lipase; MAPK, nous cannabinoid substance, anandamide (N-arachidonoyl mitogen-activated protein kinase; miRNAs, microRNAs; NAPE-PLD, N-acylphosphatidylethanolamine-specific phospholipase D; N-ArPE, ethanolamine, AEA) (Devane and Axelrod 1994), in the N-arachidonyl phosphatidylethanolamine; NAT, N-acyltransferase; NMDA, brain emphasized the importance of the cannabinoid receptor N-methyl-D-aspartate; PGH2, prostaglandin H2; PTPN22, phosphatase; and its endogenous ligands in the regulation of a wide variety VR1, vanilloid receptor type 1; D9-THC, delta-9-tetrahydrocannabinol.

624 © 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 Mechanisms of NDs 625 of biological functions (Pertwee 1997). Later, 2-arachidonoyl (Ohno-Shosaku et al. 1998, 2000, 2001, 2002; Wilson and glycerol (2-AG) was identified as a second endogenous Nicoll 2001, 2002; Wilson et al. 2001). The discovery of cannabinoid (Sugiura et al. 2006). These two endogenous ECs such as AEA and 2-AG and the widespread localization cannabinoids are derivatives of arachidonic acid (Fig. 3) and of CB1Rs in the brain have stimulated considerable excite- are synthesized and metabolized by different pathways ment regarding the role of the EC system in Alzheimer’s (Fig. 4a and b). Both AEA and 2-AG act on the CBRs to disease (AD). AD is the most devastating neurodegenerative elicit their biological activities; therefore, they are termed disorder in humans, and the most common symptom of AD endocannabinoids (ECs). ECs are lipophilic in nature and are is difficulty in retaining and recalling recently learned synthesized on demand from membrane phospholipids, and information. Cognitive deficits of AD patients correlate with they can readily partition into and diffuse throughout cellular cerebral disturbances in sensitive brain areas, largely in the membranes without storage in vesicles. After their release frontal cortex and the hippocampal region, areas that are rich from the post-synaptic neuron, ECs bind to CB1Rs located in CB1Rs (Glass et al. 1997; Biegon and Kerman 2001). AD on the pre-synaptic membrane to inhibit neurotransmitter pathology is characterized by the accumulation of b-amyloid release (Ohno-Shosaku et al. 2001; Berghuis et al. 2007; (Ab), neurofibrillary tangles consisting of hypophosphory- Harkany et al. 2008). ECs are removed from the synaptic lated tau, the loss of particular subsets of neurons, and junction after CB1R activation by process of cellular neuroinflammation resulting from glial activation. Although transport followed by hydrolysis. Anandamide is hydrolyzed the existence of familial AD, which shows early onset, has in post-synaptic neurons by fatty acid amide hydrolase been characterized, this form only accounts for a small (FAAH), thus terminating its action (Varvel et al. 2006, proportion of cases (Hardy 1996a,b; Campion et al. 1999; 2007). After CB1R activation, 2-AG is hydrolyzed in pre- Hardy and Selkoe 2002). The real cause of sporadic AD is synaptic neurons by monoacylglycerol lipase (MAGL) [see unknown, but numerous risk factors have been identified, recent reviews (Basavarajappa 2015; Lu and Anderson including hypercholesterolemia, ischemic stroke, hyperten- 2017)] (Fig. 4a and b). This retrograde signaling provides a sion, the ApoE4 allele and diabetes (Grammas 2011; mechanism for inhibitory feedback to regulate neurotrans- Carnevale et al. 2016; Hamel et al. 2016). mitter release in the brain. This unique function of ECs has Limited numbers of studies have reported reduced densi- provided a strong rationale for investigating them as ties of CB1Rs in aged animals (Mailleux and Vanderhaeghen therapeutic targets for autoimmune disease, stroke and some 1992a; Romero et al. 1998). ECs were shown to decrease other severe neurodegenerative diseases, including Alzhei- significantly with age in the mouse hippocampus and frontal mer’s disease (AD), Huntington’s disease (HD) and Parkin- cortex (Maroof et al. 2014). An autoradiographic examina- son’s disease (PD). We have recently reviewed the functions tion of sections of normal post-mortem brain suggested a no of EC system in the normal brain (Basavarajappa 2015; Lu significant reduction in CB1R binding with age (Ahmad and Anderson 2017); therefore, the current study aims to et al. 2014). Several investigators have studied the changes present the new understanding of the role and involvement of associated with the EC system during the progression of AD the EC system in neurodegenerative disorders (Tables 1 disease. Correlation analyses based on post-mortem cortical and 2). brain tissues (Brodmann area 10) from a cohort of neu- ropathologically confirmed AD patients indicated lower EC system and AD CB1R levels than in age-matched controls (Solas et al. The distribution of CB1Rs in the rodent adult brain is highly 2013). These lower CB1R levels correlated with hypophagia heterogeneous, with the highest densities of receptors present but not with any AD molecular markers or cognitive status in the basal ganglia, including the substantia nigra pars (Solas et al. 2013). The levels of AEA were reduced in the reticulata (SNr) and the globus pallidus, in the hippocampus, hippocampus of a mouse genetic model of AD (transgenic particularly within the dentate gyrus, and in the molecular mice overexpressing amyloid precursor protein, APP) layer of the cerebellum. Low levels of CB1Rs are also found (TgAPP-2576) (Kofalvi et al. 2016). The ECs acting through in the brainstem (Howlett 2002). There is a similar distribu- transient receptor potential cation channel subfamily V tion of CB1Rs in humans (Glass et al. 1997; Biegon and member 1 (TRPV1) were suggested to play a significant Kerman 2001). The highest densities are found in limbic role in Ab-induced cognitive impairment in D3 receptor KO cortices, with much lower levels observed within primary mice (Micale et al. 2010). sensory and motor regions, pointing an important role in Cannabinoid receptor agonists such as AEA and noladin motivational (limbic) and cognitive (Association) informa- ether have been shown to provide protection against the Ab- tion processing. CB1Rs have been shown to be localized pre- peptide induced neurotoxicity in neurons differentiated from synaptically on GABAergic interneurons and glutamatergic the human teratocarcinoma cell line NTERA-2/cl-D1 in a neurons (Katona et al. 1999, 2001, 2006), and this localiza- CB1R- and mitogen-activated protein kinase pathway- tion of CB1Rs is consistent with the proposed role of ECs in dependent manner (Milton 2002). In another study, the modulating GABA and glutamate neurotransmission injection of the CB1R antagonist SR141716A failed to

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Fig. 1 CB1R signaling pathway. Both endogenous and synthetic thought to be mediated by the G protein a subunits, while the bc subunits cannabinoids elicit their effects by binding to CB1Rs (Breivogel and activate GIRK and PI3K. The bc complex further activates the p38/JNK/ Childers 2000; Derkinderen et al. 2003; Mackie 2006; Mechoulam and ERK1/2 pathways, followed by phosphorylation of several downstream Parker 2013). CB1Rs are seven-transmembrane-domain, G protein- targets, such as cPLA2, ELK-1, c-fos, c-Jun, and CREB, leading to the coupled receptors located in the cell membrane (Howlett 1995). CB1R expression of target genes such as krox-24 and BDNF (Derkinderen et al. signaling leads to inhibition of adenylate cyclase (AC) activity (Childers 2003; Graham et al. 2006). PI3K mediates the AKT-induced inhibition of et al. 1994; Pinto et al. 1994; Howlett and Mukhopadhyay 2000), N-type CREB activation (Graham et al. 2006). Inhibition of AC and the subse- voltage-gated calcium channels (Caulfield and Brown 1992; Mackie and quent decrease in cAMP reduces the activation of cAMP-dependent Hille 1992; Pan et al. 1996; Nogueron et al. 2001), N-type and P/Q-type protein kinase (PKA), resulting in reduced phosphorylation of K+ channels calcium channels and D-type potassium channels (Howlett and (Ozaita et al. 2007; Basavarajappa and Arancio 2008; Mechoulam and Mukhopadhyay 2000; Howlett et al. 2002) and activate A-type and Parker 2013). Inhibition of ERK1/2 activation followed by inhibition of inwardly rectifying potassium channels (GIRKs) (Mu et al. 1999). CB1Rs CaMKIV and CREB phosphorylation has also been found under certain also participate in the regulation of neurotransmitter release (Howlettet al. conditions in vivo, leading to inhibition of Arc expression (Basavarajappa 2002; Freund et al. 2003) and inhibit synaptic transmission (Howlett et al. and Subbanna 2014; Basavarajappa 2015). Stimulatory effects are 2002; Freund et al. 2003). The actions on Ca2+ channels and AC are shown by (?) arrows and inhibitory effects by (⊥) arrows. provide protection against Ab-induced amnesia (Mazzola activity decreased in nucleus basalis of Meynert at et al. 2003). However, in a triple mouse model of AD (3xTg- 15 months of age (Manuel et al. 2016). AD), the activity of CB1R was found to be up-regulated in It has been found that senile plaques in AD patients the anterior thalamus at the age of 4 months while the express CB1R and CB2R and are associated with markers of

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

et al. 2005). However, CB2R levels were found enhanced in AD patients and well-correlated with two relevant AD molecular markers (Ab-42 levels and senile plaque score) but not with cognitive status (Solas et al. 2013). Additionally, in AD brains, the nitration of CB1R and CB2R proteins was elevated (Ramirez et al. 2005). It has been reported that AD- like pathology and learning and memory impairments induced by Ab administration in rats was rescued by WIN- 55,212-2 (CB1R agonist) (Ramirez et al. 2005). Addition- ally, cannabinoids (HU-210, WIN-55,212-2, and JWH-133) prevented Ab-induced microglial activation in cultured glial cells (Ramirez et al. 2005). Furthermore, Ab-induced CD40- mediated microglial phagocytosis was inhibited by the CB2R agonist JWH-015 (Ehrhart et al. 2005). Similarly, treatment with WIN, 2-AG, or methanandamide prevented the hemichannel activity and inflammatory profile induced by Fig. 3 The AEA and 2-AG chemical structures. Ab in astrocytes; excitotoxic glutamate release and neuronal damage in hippocampal slices treated with Ab (Gajardo- microglial activation. CB1R-enriched neurons were signifi- Gomez et al. 2017). Notably, CB2R and the AEA-hydro- cantly reduced in areas of microglial activation (Ramirez lyzing enzyme FAAH have been shown to be selectively et al. 2005). Also, G-protein coupling and CB1R protein expressed in astrocytes and microglia associated with neuritic expression are significantly reduced in AD brains (Ramirez plaques (Benito et al. 2003); however, these AD patients

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Fig. 4 The schematic enzymatic pathway that regulates catabolism of for removing endocannabinoids from the synaptic cleft to ensure rapid AEA (a) and 2-AG (b). (a) Stimulation of AC and PKA potentiates the N- signal inactivation: re-uptake or enzymatic degradation. AEA is inacti- acyltransferase (Ca2+-dependent transacylase, CDTA). An arachidonic vated by reuptake (Beltramo and Piomelli 2000; Bisogno et al. 2001) via acid chain is transferred by CDTA from the sn-1 position of a an uncharacterized membrane transport molecule, the ‘AEA membrane phospholipid to the primary amine of phosphatidylethanolamine, in transporter’ (AMT) (Beltramo et al. 1997; Hillard et al. 1997; Maccarrone aCa2+-dependent manner, forming N-arachidonoyl phos- et al. 1998; Beltramo and Piomelli 2000; Hillard and Jarrahian 2000; phatidylethanolamine (N-ArPE), an intermediate. This N-ArPE is then Giuffrida et al. 2001; Basavarajappa et al. 2003), and subsequently, hydrolyzed by a phospholipase D (PLD)-like enzyme to yield anan- undergoes intracellular enzymatic degradation. FAAH metabolizes AEA damide (AEA) (Natarajan et al. 1981; Schmid et al. 1983; Di Marzo et al. to arachidonic acid, and ethanolamine leading to rapid clearance of AEA 1994). It is not clear whether the N-acyltransferase (NAT) or the N- from extracellular compartments (Deutsch et al. 2001; Glaser et al. acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) 2003). B. Intracellular Ca2+ initiates 2-AG biosynthesis by activating the controls the rate-limiting step of AEA synthesis (Di Marzo 1998; Hansen process of formation of diacylglycerol (DAG) (Prescott and Majerus et al. 2000; Sugiura et al. 2002). NAPE-PLD knockout mice exhibit 1983; Sugiura et al. 1995) in the membrane by stimulating the normal AEA biosynthesis, suggesting the involvement of other enzymes phosphatidyl-inositol-phospholipase C (PI-PLC) pathway. 2-AG is the (Leung et al. 2006). Another pathway that regulates the conversion of product of DAG-lipase (DAGL) acting on DAG (Bisogno et al. 1999b;

NAPE into 2-lysol-NAPEs by the activity of secretory PLA2 (sPLA2) has Carrier et al. 2004). The second route involves hydrolysis of phos- also been proposed. 2-Lysol-NAPEs by the action of selective phatidylinositol (PI) by phospholipase A1 (PLA1) and hydrolysis of the lysophospholipase D (lyso-PLD) (Sun et al. 2004) is then converted resultant lyso-PI by a specific lyso-PLC (Sugiura et al. 1995). 2-AG is into N-acyl-ethanolamides, including AEA. 2-Lysol-NAPEs, through the also synthesized through the conversion of 2-arachidonyl lysophospha- action of abhydrolase domain 4 (ABHD4) (Liu et al. 2008), are turned tidic acid (LPA) by phosphatase (Nakane et al. 2002). 2-AG activates into glycero-p-AEA, which is then converted by glycerol phosphodi- CB1Rs with greater efficacy than does AEA. Like AEA, 2-AG is esterase (GDE1) (Simon and Cravatt 2008) into AEA. A recent study inactivated by reuptake (Beltramo and Piomelli 2000; Bisogno et al. using mouse brain and RAW264.7 macrophages proposed the exis- 2001) via the AMT (Beltramo et al. 1997; Hillard et al. 1997; Maccarrone tence of an analogous pathway where NAPE converted into pAEA by the et al. 1998; Beltramo and Piomelli 2000; Hillard and Jarrahian 2000; action of PLC. The pAEA is subsequently dephosphorylated by a protein Giuffrida et al. 2001; Basavarajappa et al. 2003) and subsequently tyrosine phosphatase (PTPN22) (Liu et al. 2006). As a putative undergoes intracellular enzymatic degradation (Di Marzo et al. 1994; neuromodulator, AEA that is released into the synaptic cleft is expected Day et al. 2001; Deutsch et al. 2001) by monoacylglycerol lipase to be rapidly inactivated. In general, there are two known mechanisms (MAGL). showed no difference in CB1R expression in the neuritic et al. 2012) and decreased FAAH activity in cortical plaques (Benito et al. 2003). Other studies have reported membrane tissues of AD patients (Pascual et al. 2014). increased FAAH gene expression and decreased DNA Other studies have reported increased DAG lipase alpha methylation at the FAAH gene promoter in peripheral blood (DAGLa) in the hippocampus of AD patients (Farooqui mononuclear cells from late-onset AD patients (D’Addario et al. 1988) and increased DAGLa followed by enhanced

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Table 1 Changes in the endocannabinoid system in neurodegenerative disease

Study model Changes in EC system References

Changes in the EC system components in Alzheimer diseases Preclinical studies AbPPswe/PS1DE9 model of AD CBR/effector coupling TgAPP-2576 mice DAGLa, DAGLb and 2-AG in hippocampus Mulder et al. (2011) 3xTg-AD mice >CB1R activity in anterior thalamus at 4 months Manuel et al. (2016) CB2R expression in frontal cortex Nitrated CB1R and CB2R protein levels in whole brain >FAAH protein Benito et al. (2003) >CB2R in neuritic plaque-associated astrocytes and microglia CB1R unchanged in whole brain Peripheral blood mononuclear cells >FAAH gene and protein and its activity D’Addario et al. (2012) (PBMCs) with late-onset AD patients AD patients 2AG in cortex AEA in cortex HD mouse model 2AG AEA in substantia nigra

Post-mortem samples from high AEA levels HD patients

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Table 1 (continued)

Study model Changes in EC system References

Changes in the EC system components in Parkinson’s diseases Pre-clinical studies Reserpine treated rats >2-AG in globus pallidus Di Marzo et al. (2000) Impaired locomotion >AEA in globus pallidus & substantia nigra 2-AG in striatum & substantia nigra van der Stelt et al. (2005) >AEA in striatum & globus pallidus Rats treated with L-DOPA >AEA in basal ganglia Ferrer et al. (2003) 6-OHDA-lesioned rats CB1Rs in substantia nigra Gonzalez et al. (2006) MPTP-lesioned mice >2-AG in substantia nigra Mounsey et al. (2015) >TH+ neurons MPTP-lesioned marmosets treated with L-DOPA >CB1R binding in Caudate nucleus & putamen Lastres-Becker et al. (2001a) 6-OHDA-lesioned rats treated with L-DOPA >CB1R mRNA expression in Denervated striatum Zeng et al. (1999) >AEA in striatum Maccarrone et al. (2003) CB1R-mRNA & CB1R binding in older age MPTP-lesioned mice treated with Anti-inflammatory cytokines (2002b, 2003) and Price et al. (2009) MPTP-lesioned CB2R KO mice >Microglial activation Price et al. (2009) Exacerbation of PD pathology LPS-lesioned mice >CB2R in striatum & substantia nigra Garcia et al. (2011), Gomez-Galvez et al. (2016) and Price et al. (2009) LPS-lesioned CB2R KO mice >CD68 immunostaining in striatum Garcia et al. (2011), Gomez-Galvez et al. (2016) and Price et al. (2009) Post-mortem brain tissue from dopamine external segment of globus pallidus agonists treatment LRRK2-transgenic mice >Motor deficits Palomo-Garo et al. (2016) Inflammation-driven PD rat model >CB2R expression Concannon et al. (2016) Clinical studies Cerebrospinal fluid of PD patients >ECs Pisani et al. (2005) Brain tissues from PD patients >CB2R in microglial cells Garcia et al. (2011), Gomez-Galvez et al. (2016) and Price et al. (2009)

Symbols used, <, decreased, >, increased. AD, Alzheimer diseases; HD, Huntington diseases; PD, Parkinson’s disease; Tg mice, transgenic mice; CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; 2-AG, 2-arachidonoylglycerol; AEA, N-arachidonoyl ethanolamine; FAAH, fatty acid amide hydrolase; NAPE-PLD,N- acyl phosphatidylethanolamine phospholipase D; DAGL, diacylglycerol lipase; 3-NP, 3-nitropropionic acid; MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; L-DOPA, 3,4-dihydroxy-L-phenylalanine; 6-OHDA, 6-hydroxydopamine; LPS, lipopolysaccharide; TH, tyrosine hydroxylase; PARK, genes associated with the development of Parkinson’s disease in humans [PARK1 (alpha-synuclein); PARK2 (parkin) or PARK6 (PINK1)];

ECs, endocannabinoids; NO, nitric oxide; iNOS, inducible NO synthase; ROS, reactive oxygen species; KO, knock out; A2AR, adenosine A2A receptor; LRRK2, leucine-rich repeat kinase 2.

2-AG levels in the hippocampus of Ab peptide-treated mice but exhibited enhanced cannabinoid receptor/effector rodents. Eight-month-old AbPPswe/PS1DE9 mice displayed coupling (Maroof et al. 2014). Superfusion of mouse significantly lower levels of striatal 2-AG than wild-type hippocampi with Ab was reported to significantly prolong

© 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 Mechanisms of NDs 631 depolarization-induced suppression of inhibition leading to Ab and neuroinflammation by inhibiting MAGL was synapse silencing in AD (Mulder et al. 2011). Also, early blocked by PPARc antagonism. Also, BACE1 suppression administration of an EC cellular reuptake inhibitor (VDM11) by 2-AG and PPARc activation was eliminated by knock- rescued both hippocampal damage and loss of memory down of NF-jB, and improved synaptic and cognitive retention in rats (van der Stelt et al. 2006). Thus, increased 2- function in TG mice was prevented by 2-AG signaling AG signaling, particularly near the senile plaques, can (Zhang et al. 2014). APP/PS1 mice lacking CB2R exhibit exacerbate synaptic failure in AD (Mulder et al. 2011). In increased Ab deposits in cerebral cortex, hippocampus, and another study (Tanveer et al. 2012), it was reported that cortical Ab40 soluble levels in the early symptomatic phase AEA up-regulates Notch-1 signaling in cultured neurons. (6 months) but not in the pre-symptomatic phase (3 months) Exposure of cultured neurons to Ab (1-42) increases (Koppel et al. 2014; Aso et al. 2016). However, lack of expression of the endogenous inhibitor of Notch-1, numb CB2R (CB2RKO) does not accelerate the memory impair- (Nb), leading to impaired Notch-1 signaling. The addition of ment in APP/PS1 mice, even though CB2RKO mice AEA and 2-AG prevented Nb expression and enhanced themselves exhibit memory impairments (Garcia-Gutierrez Notch-1 signaling. The stimulatory effects of AEA on Notch- et al. 2013; Li and Kim 2016a,b). These findings together 1 signaling persisted in the presence of Ab (1-42). Through demonstrate that CB2Rs may assist in Ab processing and Notch-1 signaling, AEA may be able to help restore thereby prevent neuroinflammation in AD (Koppel et al. neurogenesis and cognition in AD (Tanveer et al. 2012). 2014; Schmole et al. 2015). The treatment of APP/PS1/ Interestingly, elevation of 2-AG through pharmacological CB2R KO and APP/PS1/CB2R WT mice with D9-THC and inhibition of MAGL significantly reduced Ab-induced cannabidiol (CBD) at a therapeutic dose are effective in neurodegeneration via CB1R-dependent suppression of rescuing the memory and learning impairments, Ab42 ERK1/2, NF-jB phosphorylation and cyclooxygenase contents in plaques, and astroglial reactivity (Aso et al. (COX-2) expression in cultured hippocampal neurons (Chen 2015), irrespective of the presence or lack of CB2Rs. et al. 2011). In another study (Yan et al. 2016), increasing 2- Furthermore, pre-treatment with CBD was found to suppress

AG via inhibiting MAGL prevented prostaglandin (PGE2) the expression of proteins involved in tau phosphorylation production, neuroinflammation-associated Ab42 accumula- and Ab production in Mesenchymal stem cells derived from tion, and neurodegeneration in C57BL/6J and APP/PS1 mice gingiva (GMSCs) (Libro et al. 2016). In contrast, admin- [Double transgenic mice over expressing human amyloid istration of D9-THC + CBD in APP/PS1/CB2 KO mice has precursor protein (APP) and a mutant human presenilin 1 no effect on the microglial reactivity or tau phosphorylation

(PS1)] exposed to NO2 inhalation, which promotes patho- around Ab plaques. These findings indicate that signaling logical abnormalities and cognitive defects related to AD pathways other than those associated with CB2R are (Yan et al. 2016). Furthermore, inhibition of MAGL signif- responsible for the beneficial effects of D9-THC and CBD icantly suppressed the production and accumulation of Ab by in APP/PS1 mice (Aso et al. 2015, 2016). Activation of reducing the expression of b-site amyloid precursor protein CB1Rs or inhibition of endocannabinoid-degrading cleaving enzyme 1 (BACE1) in a mouse model of AD (Chen enzymes [FAAH, MAGL, and alpha/beta-Hydrolase domain et al. 2012). MAGL inhibition also prevented neuroinflam- containing 6 (ABHD6)] was shown to enhance Ab clear- mation and decreased neurodegeneration by suppressing ance across the blood-brain barrier through increased microglial and astrocytic activation. Inhibition of MAGL expression of the low-density lipoprotein receptor-related also maintained the integrity of hippocampal synaptic protein 1 (LRP1) (Shibata et al. 2000). LRP1 has been structure and function, improved long-term synaptic plas- demonstrated to function in the brain-to-blood transport of ticity, spatial learning, and memory (Chen et al. 2012). Ab (Shibata et al. 2000). Infact, LRP1 levels in the brain Expression of the non-coding small RNA miR-188-3p, and plasma were elevated following activation of CB1Rs which targets BACE1, was demonstrated to be significantly (Bachmeier et al. 2013). Together, these findings provide reduced in the AD postmortem brains and APP transgenic insight into the additional mechanisms by which cannabi- (TG) mice (Zhang et al. 2014), a mouse model of AD, and noid-based strategies help to reduce Ab deposition in the MAGL inhibition restored the decreased miR-188-3p AD brain. Exposure to a low concentration of D9-THC expression. Over-expression of miR-188-3p in the hip- reduced Ab levels in N2a-variant Ab protein precursor pocampus reduced the levels of BACE1, Ab, and neuroin- (AbPP) cells and inhibited Ab aggregation by directly flammation and prevented impairments in hippocampal interacting with Ab peptide (Cao et al. 2014). D9-THC basal synaptic transmission, long-term potentiation, learn- competitively binds to the peripheral anionic site of ing, and memory in TG mice. MiR-188-3p loss of function acetylcholine esterase (AChE) and prevents AChE-induced prevented 2-AG-induced suppression of BACE1. Moreover, Ab-peptide aggregation (Eubanks et al. 2006). D9-THC 2-AG or peroxisome proliferator-activated receptor-c attenuates Ab accumulation in a human CNS cell line (PPARc) agonists and PPARc antagonism or NF-jB (MC65 cells) that is induced to express Ab proteotoxicity activation up-regulated miR-188-3p expression. Reducing that initiates inflammatory responses (Currais et al. 2016). It

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Table 2 EC system targeted pharmacological compounds treating neurodegenerative diseases

Study model Drugs Effects References

EC system targeted pharmacological compounds treating Alzheimer diseases Pre-clinical studies Ab injected rats WIN-55, 212 22 Endocannabinoid levels reversed van der Stelt et al. (2006) the Ab- peptide (1–42) (BAP) hippocampal damage in rats Ab- peptide (1–42) treated JWH-015 Suppressed IFN-c-induced CD40 Ehrhart et al. (2005) microglial cells expression, attenuated CD40-mediated inhibition of microglial phagocytosis of

Ab1–42 peptide Cultured hippocampal neurons Exogenous 2-AG Protection against Ab peptide-induced Chen et al. (2011) neurodegeneration >2-AG,

APP/PS1 mice exposed to NO2 MiR188-3 expression, mitochondrial function Cao et al. (2014) Human neuron D9 THC Attenuates Ab accumulation Currais et al. (2016) cells, MC65 cell line TG APP2576 mice WIN 55, 212 22, Rescued neuroinflammation Martin-Moreno et al. (2012) JWH-133 Reduced Ab levels Improves cognitive performance Ab injected rats WIN55212-2 Up-regulated PARP signaling Fakhfouri et al. (2012) Attenuate Ab-induced neuroinflammation, neurodegeneration Improves spatial memory Ab evoked Neuroblastoma 2-AG, CBD Direct neuroprotective against Ab toxicity Janefjord et al. (2014) (SH-SY5Y)cells BV-2 cells in conditioned media JWH015, THC, Reduced Ab fibrils and their aggregation CBD, O-1602 Human macrophage JWH-015 Cleared native Ab peptide Tolon et al. (2009) (THP-1) cell line

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Table 2 (continued)

Study model Drugs Effects References

Ab injected rats Piperidine (MDA7) Ameliorated CD11b and GFAP Wu et al. (2013) Ab-induced astrocytic proliferation Esposito et al. (2007) C6 rat glioma cells APP/PS1 mice JWH133 Cognitive performance Streptozotocin & 1-phenylisatin Improved learning & memory Jayant et al. (2016) aluminum trichloride + nabilone or dronabinol) Nabilone Cannabinor, Hypokinesia de Lago et al. (2004)

(continued)

© 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 634 B. S. Basavarajappa et al.

Table 2 (continued)

Study model Drugs Effects References

HD patients Nabilone Little changes in motor skill Consroe et al. (1991) Chorea and cognition Nabilone DA neuron survival in substantia nigra Cerri et al. (2014) >astrocyte cell density AM251 Antiparkinsonian effects Fernandez-Espejo et al. (2005) D9-THC >Dopamine content, >TH activity & >TH Lastres-Becker et al. (2005) mRNA in striatum & substantia nigra CBD >Dopamine content, >TH activity & >TH Lastres-Becker et al. (2005) mRNA in striatum & substantia nigra CBD Neuroprotection when administered Garcia-Arencibia et al. (2007) immediately after the lesion MSX-3 TH+ neurons Garcia et al. (2011) AM404 Prevented DA depletion, >TH+ Garcia-Arencibia et al. (2007) neurons, Antiparkinsonian effect Cao et al. (2007) rhesus monkeys 6-OHDA-lesioned rats WIN 55,212-2 Survival of DA neurons in substantia Chung et al. (2011) nigra & striatum >Dopamine levels TH+ neurons in substantia nigra & dorsal Price et al. (2009) striatum >Dopamine & 3,4-dihydroxyphenylacetic acid Survival of DA neurons in substantia Chung et al. (2011) nigra & striatum >Dopamine levels

(continued)

© 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 Mechanisms of NDs 635

Table 2 (continued)

Study model Drugs Effects References

MPTP-lesioned mice URB597 NO release Ehrhart et al. (2005), Klegeris co-incubated with LPS et al. (2003) and Molina Holgado et al. (2002b) HU210 IL-1ra release Molina-Holgado et al. (2003) LPS-lesioned mice HU-308 TH+ neurons and Garcia et al. (2011) TH+ neurons Garcia et al. (2011) Prevented neurodegeneration Rotenone-lesioned rats b-caryophyllene Antioxidant enzyme activity >Survival of DA neurons Post-mortem brain WIN 55,212-2 >CB1R binding Lastres-Becker et al. (2001a) of humans affected by PD

Symbols used: <: decreased, >: increased. AD, Alzheimer diseases; Ab, beta amyloid; HD, Huntington diseases, Tg mice, transgenic mice; 3-NP, 3-nitropropionic acid; SOD, superoxide dismutase; ROS, reactive oxygen species; GFAP, glial fibrillary acidic protein; CC3, cleaved caspase-3; AChE, acetylcholinesterase; CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; L-DOPA, 3,4-dihydroxy-L- phenylalanine; 6-OHDA, 6-hydroxydopamine; LPS, lipopolysaccharide; WIN-55, 212 2, CB1R and CB2R agonist; HU-210, CB1R and CB2R agonist; JWH-133, selective CB2R agonist; AEA, N-arachidonoylethanolamine; VDM-11, potent cannabinoid reuptake inhibitor; JWH015, selective CB2R agonist; 2-AG, 2-arachidonoylglycerol; MAGL, monoacylglycerol lipase; URB602, selective MAGL inhibitor; JZL184, irreversible MAGL inhibitor; GW9662, selective PPAR antagonist, O-1602, synthetic compound most closely related to abnormal cannabidiol; MDA7, selective CB2R agonist; SR144528, selective CB2R antagonist; HU308, Selective CB2R agonist; CP 55 940, synthetic cannabinoid; Quinpirole, D2 dopamine receptor agonist; Cl-APB, R-()-3-allyl-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; D1 dopamine recep- tor agonist; SR141716A, CB1R antagonist; LID, levodopa-induced dyskinesia; NO, nitric oxide; IL-1ra, IL-1 receptor antagonist; DA, dopaminergic; TH, tyrosine hydroxylase; D9-THC, (-)-trans-D9-tetrahydrocannabinol; CB1R and CB2R agonist; CBD, cannabidiol; CB1R and CB2R antagonist; CE, 1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide benzene- sulfonate; CB1R antagonist; MSX-3, 3,7-dihydro-8-[(1E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-3-[3-(phosphonooxy)propyl-1-(2-propynyl)-1H- purine-2,6-dione disodium salt; selective adenosine/P2 nucleotide receptor antagonist; THP-1, human monocytic cell line; IFN-c, interferon-c; D9-THCV, D9-tetrahydrocannabivarin; CB1R and CB2R antagonist; AM251, CB1R antagonist; AM404, N-arachidonoylaminophenol; AEA transport inhibitor; URB597, fatty acid amide hydrolase inhibitor; b-caryophyllene, CB2R agonist; VCE-003.2, cannabigerol quinone derivative.

© 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 636 B. S. Basavarajappa et al. has been shown that prolonged oral administration of two Inhibition of MAGL decreased the astroglial reaction to Ab different cannabinoid agonists (WIN 55,212-2 and JWH- plaques in 5xFAD mice lacking CB2R [54]. In contrast, 133) rescues neuroinflammation, reduces Ab levels and natural cannabinoids such as THC+CBD failed to reduce the improves cognitive performance in Tg APP 2576 mice Ab plaques and rescue memory deficits in APP/PS1 mice (Martin-Moreno et al. 2012). lacking CB2R (Aso et al. 2016). The non-selective CBR A previous report showed that the activation of CB1R and agonist WIN-55,212-2 inhibited Ab-induced tau hyperphos- CB2R up-regulates PPARc signaling and attenuates Ab- phorylation via CB1R but not CB2R in PC12 neuronal cells induced neuroinflammation, neurodegeneration, and spatial (Esposito et al. 2006). In another study, D9-THC reduced memory impairment in animals (Fakhfouri et al. 2012). In phosphorylated tau in N2a/APPswe cells (Cao et al. 2014). another study (Janefjord et al. 2014), 2-AG and CBD The CB2R agonist JWH-133 decreased tau phosphorylation provided protection against Ab-evoked loss of SH-SY5Y at Thr181 and also decreased the expression of the active cell viability, whereas JWH-015, D9-THC, CBD, abnormal- forms of GSK3b, p38 and SAPK/JNK in APP/PS1 mice cannabidiol (Abn-CBD), and O-1602 (GPR18/GPR55 (Aso et al. 2013). Furthermore, the lack of CB2R failed to ligands) all protected SH-SY5Y cells from BV-2 conditioned alter tau phosphorylation in mice (Aso et al. 2016). The lack media activated via lipopolysaccharide (LPS, microglial of CB2R reduced total tau without any effect on tau activation). While cannabinoid ligands variably altered the phosphorylation in J20APP mice (Koppel et al. 2014). In morphology of Ab fibrils and aggregates, there was no clear other studies, JWH-133 decreased the levels of superoxide correlation between effects on Ab morphology and neuro- dismutase (SOD) 1 and 2 around plaques in APP/PS1 mice protective actions. These findings indicate a neuroprotective (Aso et al. 2013). In line with these findings, CBD prevented activity of cannabinoid ligands via actions at microglial and Ab-induced reactive oxygen species production, lipid per- neuronal cells (Janefjord et al. 2014). In another animal oxidation, caspase-3-mediated apoptosis, and elevation of the model of AD (APP/PS1) mice, deletion of CB2R reduced intracellular calcium concentration in PC12 neuronal cells microglial activation and infiltration of macrophages. Fur- (Iuvone et al. 2004). In a mouse model of tauopathy exposed thermore, these mice expressed low levels of pro-inflamma- to Sativex, a mixture of D9-THC and CBD, both reactive tory chemokines and cytokines in the brain, as well as oxygen species levels and mitochondrial activity were decreased concentrations of soluble Ab 40/42 (Schmole decreased (Casarejos et al. 2013). In a published case report, et al. 2015). Activation of CB2R with a lower dose of JWH- treatment with an analog of D9-THC (nabilone or dronabinol) 015 was shown to remove native Ab from human tissue improved the behavior and food intake in AD patients after sections as well as to clear synthetic pathogenic Ab peptide 6 weeks of treatment (Volicer et al. 1997). Similarly, the use from a human macrophage cell line (THP-1) but not from of nabilone improved reduced agitation and aggressiveness U373MG astrocytoma cells. This effect was reversed by the exhibited by advanced AD patients (Passmore 2008). Up- selective CB2R antagonist SR144528 (Tolon et al. 2009). regulation of CB2R and its preferential distribution near Ab Furthermore, a novel CB2R agonist (MDA7) provided plaques has been reported in several animal models of AD protection against Ab fibril-induced microglial and astrocyte and in post-mortem patients. However, in a study conducted activation, normalized CB2R expression, promoted Ab by Ahmad et al. 2016 it was found that in vivo availability of clearance, attenuated synaptic plasticity deficits, learning CB2R is decreased in AD patients compared to healthy and memory impairments (Wu et al. 2013). individuals (Ahmad et al. 2016). CB2R activation has been reported to transform microglial cells from the M1 to the M2 phenotype (Orihuela et al. EC system in Huntington’s disease 2016) and to favor phagocytosis (Mecha et al. 2015). In an Huntington’s disease (HD) is life-threatening and inherited in vitro experiment, selective CB2 agonists prevented the progressive and neurodegenerative disorder caused by the Ab-induced release of proinflammatory cytokines by extension of an unstable trinucleotide (cytosine-adenine- decreasing the intracellular calcium concentration and guanine, CAG) repeat in the Huntingtin gene (Htt) to more enhanced phagocytosis in microglial cells (Martin-Moreno than 36 repeats, resulting in a polyglutamine (polyQ) et al. 2011). CB2R activation by JWH-015 increased Ab- expansion in the N-terminus of Huntingtin. HD is charac- induced astrocytic proliferation in cell culture (Esposito et al. terized by progressive motor abnormalities (chorea) and 2007). Administration of the CB2R agonist JWH-133 has cognitive deterioration (dementia) accompanied by neuronal been shown to prevent the activation of microglial cells and death in some basal ganglia structures, such as the striatum, the release of proinflammatory cytokines in the vicinity of globus pallidus, and SN, and to a lesser extent, the cerebral Ab deposits in APP transgenic mice (Aso et al. 2013). cortex. The mechanism of disease progression remains Treatment with 1-phenylisatin, selective modulator of CB2R, unknown, and there is currently no successful treatment prevented streptozotocin and aluminum trichloride d- available to prevent or slow the disease. Although consid- galactose induced impairment of learning-memory and brain erable research suggests that there is apoptotic neuron loss in damage in mouse model of AD (Jayant et al. 2016). HD (Hickey and Chesselet 2003), the molecular mechanisms

© 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 Mechanisms of NDs 637 responsible for such a loss of neurons remains unknown. (Battista et al. 2007). These findings clearly suggest that Changes in protein aggregation (Arrasate and Finkbeiner endocannabinoids are dysregulated in different brain regions of 2012), mitochondrial function (Quintanilla and Johnson HD animal models. 2009), oxidative stress (Browne et al. 1999), and glial It is very clear that cannabinoid signal becomes hypo- activation leading to inflammatory and cytotoxic events (Tai functional in the basal ganglia in HD. However, it has also et al. 2007) have been suggested to play important roles in been suggested that loss of CB1R may be initially related to causing neuronal loss and disease onset. ECs, their synthe- the progressive and selective loss of medium spiny sizing and degrading enzymes, and their receptors are GABAergic neurons in the striatum, where these receptors particularly abundant in basal ganglia structures (Herkenham are abundant (Rikani et al. 2014). Studies using R6/2 mice at et al. 1991; Mailleux and Vanderhaeghen 1992b; Bisogno presymptomatic ages showed impairment of the sensitivity of et al. 1999a). The abundance of the EC system in the basal striatal GABA synapses to cannabinoid stimulation (Cen- ganglia suggests that the activation or inhibition of EC tonze et al. 2005). It has been shown that loss of CB1Rs signaling system might have a significant influence on motor function contributes to the progression of HD, the aggrava- responses. Interestingly, most post-mortem studies of HD tion of HD symptoms and neuropathology in a mouse model patients published to date have reported a massive loss of that expresses human mutant Huntingtin exon 1 and lacks CB1R in various basal ganglia structures. A dramatic loss of CB1R (Blazquez et al. 2011). It has also been shown that CB1R immunoreactivity in the globus pallidus was observed lack of CB1R in N171-82Q transgenic mice worsens motor in human HD brain (Richfield and Herkenham 1994). function, increases mouse susceptibility to 3-NP, and con- Quantitative autoradiography of tissue sections from post- tributes to the physiological development of HD (Mievis mortem HD brain showed a greater loss of CB1Rs in the lateral et al. 2011). A marked loss of CB1R immunoreactivity in pallidum and SNr (Glass et al. 1993). Studies using various HD the globus pallidus has been associated with the up- animal models have also shown similar patterns of decrease in regulation of GABA (A and B) receptor in human HD brain CB1R expression (Glass et al. 2000; Bisogno et al. 2008; (Allen et al. 2009). It has also been shown that the severity Dowie et al. 2009). For example, HD R6/1 mice showed of HD pathology was associated with increased numbers of reduced CB1R mRNA and CB1R ligand binding in the striatum progenitor cells with functional CB1Rs (Curtis et al. 2006). (Dowie et al. 2009). In another study, a progressive decline in These findings suggest that CB1R agonists or inhibitors of CB1R with significant decreases in AEA and 2-AG levels was EC inactivation have the potential therapeutic value in observed in the striatum of transgenic HD R6/2 mice with 150 treating various forms of HD. CAG repeats (Bisogno et al. 2008). Interestingly, HD mice In late-onset HD, the loss of CB1R is accompanied by showed loss of CB1R mRNA in the lateral striatum, cortex, and increased expression of CB2R, particularly in glial cells, hippocampus in the early onset of disease suggesting that during striatal degeneration (Fernandez-Ruiz et al. 2007, decrease in the CB1R mRNA is a hallmark in the initial phase of 2008). In a rat model of HD (intrastriatal injection of the the HD disease (Denovan-Wright and Robertson 2000; McCaw mitochondrial complex II inhibitor malonate), the selective et al. 2004). Also, it was found that CB1R protein and its mRNA CB2R antagonist SR144528 protected striatal projection levels decreased with the motor hyperkinesia in the caudate neurons from malonate-induced death through a mechanism putamen of rats injected with 3-nitropropionic acid (3-NP) involving glial cells (Sagredo et al. 2009). The CB2R (Lastres-Becker et al. 2002). Also, 3-NP injected HD rats expression has been shown to increase in striatal microglia showed reduced CB1R binding, GTPcS binding, AEA and 2- in a transgenic mouse model of HD and also in patients AG in the SN but not in the cerebral cortex (Lastres-Becker et al. (Palazuelos et al. 2009). Furthermore, another study demon- 2001b). However, investigations have shown significant strated that the genetic ablation of CB2R exacerbated HD decreases in the AEA and 2-AG levels in the striatum (Bisogno and that administration of CB2R-selective agonists reduced et al. 2008), a significant reduction in 2-AG levels and increase striatal neurodegeneration through microglial activation in AEA levels in the cortex with no significant difference in the (Palazuelos et al. 2009). Along with CB1R, adenosine hippocampus in the late phase of HD (Bisogno et al. 2008). A2A receptor (A2AR) plays an important role in the control These observations suggest that impairment of the EC system in of neuronal excitability. The A2AR-CB1R form heteromeric HD is region-specificaswellasstage-specific. In contrast, complexes and recent studies revealed that the complex another study showed that 2-AG was increased and AEA was becomes dysfunctional in caudate putamen of advanced HD decreased significantly in R6/1 mice (Dowie et al. 2009). Also, patients (Moreno et al. 2017). reductions in the activity of N-acylphosphatidylethanolamine- One study in HD rats demonstrated that D9-THC treatment specific phospholipase D (NAPE-PLD) and DAGL as well as in provided neuroprotection against 3-NP-induced toxicity cannabinoid binding with increased 2-AG levels were observed (Lastres-Becker et al. 2004). However, in the malonate- in the striatum of the R6/2 mouse model of HD (Bari et al. 2013). injected rat model of HD, D9-THC exacerbated malonate- FAAH activity was dramatically decreased along with a sixfold induced striatal pathology (Lastres-Becker et al. 2004). Also, increase in AEA levels in the lymphocytes of HD patients SR141716 has also been reported to exacerbate malonate-

© 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 638 B. S. Basavarajappa et al. induced striatal pathology (Lastres-Becker et al. 2003). the function of the cannabinoid system in HD because there Consistent with this observation, another study suggests that is substantial evidence that CB1Rs regulate motor function. D9-THC inhibited CB1R signaling by increasing b-arrestin expression and exacerbating neuronal loss in a cell culture EC system in Parkinson’s disease model of HD. However, CBD treatment prevented the D9- Parkinson’s disease (PD) is the second most common THC-induced loss of CB1R and rescued neuronal loss neurodegenerative disease and is characterized by the (Laprairie et al. 2016). In another study, CBD completely progressive loss of dopamine (DA)-containing neurons of reversed 3-NP-induced toxicity in HD rats, and this effect the SN, leading to basal ganglia circuit deficits. The was not reversed by SR141716, suggesting that CBD effects irreversible loss of the DA-mediated control of striatal are independent of CB1Rs (Sagredo et al. 2007). Similarly, function leads to bradykinesia, tremor, and rigidity in PD (de WIN55,212-2 administration has a protective effect on the 3- Lau and Breteler 2006; Branchi et al. 2008, 2010; Bartels NP-induced striatal neurotoxicity in rat model of HD which and Leenders 2009). The striatum is a major forebrain could be related to endocannabinoid signaling stimulation nucleus that interconnects cortical and thalamic circuits and (ECS) stimulation and induction of NMDA receptor hypo- acts as the input nucleus of the basal ganglia. Striatal function (Maya-Lopez et al. 2017). VCE-003.2, a cannabi- projection neurons send information to the SN pars reticulata gerol quinone derivative, inhibited the up-regulation of (direct pathway) or the lateral globus pallidus (indirect proinflammatory markers and improved antioxidant defenses pathway). Deficits in the neural activity of these two in 3NP-injected mice brain (Diaz-Alonso et al. 2016). pathways have been suggested to cause the motor deficits Administration of WIN-55,212-2 dose-dependently and in observed in PD. However, the differences in the cellular and a CB1R-dependent manner decreased the extracellular synaptic mechanisms of these circuits are not well-under- glutamate and attenuated the striatal damage induced by stood. PD progression has been shown to be associated with quinolinic acid in rat experimental models of HD (Pintor multiple molecular changes in the brain. For instance, et al. 2006). Administration of AEA to HD rats caused inflammation through activation of microglia in the SN hypokinesia and decreased nigrostriatal dopaminergic activ- (McGeer et al. 1988) and an increase in TNF-a, IL-1b, IL-2, ity, but this effect was mediated through activation of IL-4, and IL-6 (Ouchi et al. 2005; Gerhard et al. 2006; vanilloid-like receptor rather than CB1R (de Lago et al. Taylor et al. 2013), have been suggested to be significant 2004). Cannabis sativa and its components have been shown pathogenic factors in sporadic PD, in which they lead to loss to provide protection against many movement disorders, of dopaminergic (DA) neurons in the SN and thus to the DA such as tremor (Gapen 1982; Clifford 1983; Consroe et al. denervation in the striatum. Missense mutations in the a- 1997), dystonia (Consroe et al. 1986; Sandyk et al. 1986), L- synuclein (a-syn) gene have been shown to cause autosomal 3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia dominant familial PD (Polymeropoulos et al. 1997; Kruger (LID) in Parkinson’s disease (PD) (Sieradzan et al. 1998), et al. 1998; Zarranz et al. 2004), and it has been suggested and Gilles de la Tourette syndrome (TS) (Muller-Vahl et al. that a-syn causes the microglia-mediated inflammatory 1999a,b). However, in several clinical trials, cannabinoids response in PD (Zhang et al. 2005; Austin et al. 2006; failed to provide protection against HD. In a case report of a Thomas et al. 2007; Gao et al. 2008; Klegeris et al. 2008; female HD patient with irritability, cannabis improved motor Reynolds et al. 2008a,b; Aureli et al. 2014). Current treat- skills and cognitive behavior, and these improvements were ments such as dopaminergic replacement therapy have been maintained by treatment with nabilone (Curtis and Rickards proposed to alleviate some of the symptoms of PD, but there 2006). In another pilot study with HD patients, treatment are no existing therapies that can rescue any of the with nabilone improved motor skills, chorea, and cognition underlying pathological conditions of PD (Calne et al. to moderate levels (Curtis et al. 2009). In a double-blind, 2005; Trapani et al. 2011; Denora et al. 2012; Di Gioia randomized, placebo-controlled, cross-over pilot clinical et al. 2015). Together, these findings suggest that both trial, no significant differences on motor, cognitive, behav- environmental and genetic factors may contribute to the ioral, and functional scores were detected among HD patients initiation of neurodegeneration followed by neuroinflamma- treated with Sativex and placebo (Lopez-Sendon Moreno tion leading to PD pathology. et al. 2016). Furthermore, in a controlled clinical trial, CBD Several mechanisms have been shown to play significant failed to provide any symptomatic protection against chorea roles in the selective DA neuron degeneration observed in in 15 neuroleptic-free HD patients (Consroe et al. 1991). In PD, such as mitochondrial dysfunction, oxidative stress, and contrast, in an uncontrolled clinical trial, administration of a excitotoxicity. Enhanced EC tone in the globus pallidus has single dose of nabilone in one patient with HD resulted in a been shown to cause Parkinsonian symptomology (Maneuf marked increase in choreatic movements (Muller-Vahl€ et al. et al. 1996). Although CB1Rs are not abundant in DA 1999). Taken these findings, it can be speculated that CBR neurons of the SN, the alleged involvement of the ECs in DA antagonists might have potential therapeutic value in treating neuron degeneration is apparent in many studies. A study HD. Further mechanistic studies are warranted to investigate demonstrated increased 2-AG in the globus pallidus of rats

© 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 Mechanisms of NDs 639 treated with reserpine (Di Marzo et al. 2000). EC signaling amplitude of glutamate-induced spontaneous excitatory post- was also shown to contribute to the pathophysiology of synaptic currents were augmented in striatal spiny neurons parkinsonism and LID in 1-methyl-4-phenyl-1,2,3,6-tetrahy- recorded from PD rats (Maccarrone et al. 2003). Chronic dropyridine (MPTP)-lesioned, non-human primate models of treatment of PD rats with L-DOPA rescued both deficits in PD (van der Stelt et al. 2005). The impairments in EC the EC system and glutamatergic activity (Maccarrone et al. transmission may contribute to LID which may be alleviated 2003). Blockade of CB1R by injections of SR141716A into by the activation of CB1Rs (Ferrer et al. 2003). However, the striatum, globus pallidus, and to a lesser extent, the enhanced AEA levels have also been shown in rat models of subthalamic nucleus, reduced motor asymmetry in PD rats PD (Di Marzo et al. 2000; Gubellini et al. 2002). In the (El-Banoua et al. 2004). Administration of SR141716A in reserpine-treated rodent model of PD, impaired locomotion is PD rats with very severe nigral degeneration was shown to associated with a sevenfold increase in the levels of the 2-AG exert antiparkinsonian effects (Fernandez-Espejo et al. in the globus pallidus, but no such change was observed in 2005). Daily administrations of D9-THC or cannabidiol the other five brain regions analyzed (Di Marzo et al. 2000). (CBD) for two weeks rescued the 6-OHDA-induced (PD In this model, stimulation of locomotion in the reserpine- model) reduction in dopamine contents and the decrease in treated rat with quinpirole (D2 dopamine receptor agonist) tyrosine hydroxylase (TH) activity in the lesioned striatum, and R-()-3-allyl-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5- and those effects were accompanied by a decrease in TH- tetrahydro-1H-3-benzazepine hydrobromide (Cl-APB) (D1 mRNA levels in the SN (Lastres-Becker et al. 2005). dopamine receptor agonist) results in decreased levels of Increased density of CB1R in the SN was observed in a rat both AEA and 2-AG in the globus pallidus (Di Marzo et al. model of PD induced by an intracerebroventricular injection 2000). Co-administration of quinpirole and SR141716A of 6-OHDA (Gonzalez et al. 2006). Also, a low dose of (CB1R antagonist) rescued deficits in locomotion in the SR141716A attenuated hypokinesia associated with nigral reserpine-treated rat (Di Marzo et al. 2000). However, cell death in this model (Gonzalez et al. 2006). Administra- reserpine treatment caused a decrease in CB1R mRNA tion of the CB1R selective antagonist, CE (1-[7-(2- expression in the rat striatum (Silverdale et al. 2001). chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]- Consistent with these data from animal models, higher levels [1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid of ECs were also found in the cerebrospinal fluid of PD amide benzenesulfonate) to L-DOPA-primed MPTP-treated patients (Pisani et al. 2005). Increased 2-AG levels were rhesus monkeys with moderate and severe parkinsonism observed in a time- and region-specific manner following increased responses to L-DOPA (Cao et al. 2007). In models MPTP administration in mice (Mounsey et al. 2015). of PD, EC-mediated long-term depression is absent from the URB597, an inhibitor of FAAH, exhibited protective effects indirect pathway, but this could be rescued by a D2 recep- by inhibiting dopaminergic neuronal death, decreased tor agonist or inhibitors of endocannabinoid degradation. microglial immunoreactivity, and improving motor alter- Co-administration of these drugs in vivo reduces parkinso- ations in MPTP-lesioned mice (Celorrio et al. 2016; nian motor deficits. These observations suggest that EC- Viveros-Paredes et al. 2017). It has also been reported that mediated depression of synapses in the indirect pathway CB1R binding and the activation of G proteins by cannabi- plays a significant role in the control of movement (Kreitzer noid agonists were significantly increased in the PD post- and Malenka 2007). In genetic models of PD (various mouse mortem basal ganglia brain region and that this increase mutants generated by deletion of specific genes associated could be rescued by chronic L-DOPA therapy (Lastres- with the development of PD in humans [PARK1 (alpha- Becker et al. 2001a). Enhanced levels of CB1Rs were also synuclein), PARK2 (parkin), or PARK6 (PINK1)], CB1Rs found in MPTP-treated marmosets, a primate PD model have been reported to exhibit a biphasic response, with losses (Lastres-Becker et al. 2001a). Blockade of CB1Rs with at early stages, during which the dopaminergic dysfunction is lower doses of SR141716A partially prevented the hyperki- possibly the major event, followed by up-regulation at nesia in a rat model of PD (Gonzalez et al. 2006). However, advanced stages, which are characterized by the presence of in post-mortem brain tissues derived from healthy subjects nigrostriatal pathology including neuronal death (Garcia- and PD patients, the level of CB1R mRNA was reduced in Arencibia et al. 2009). Acute injections of L-DOPA or the caudate nucleus, anterior dorsal putamen and in the outer rimonabant produced similar improvements in contralateral segment of the globus pallidus but no changes were observed forepaw stepping in rats with unilateral 6-OHDA lesions, and in the other brain areas examined (Hurley et al. 2003). their co-administration enhanced stepping more than either Chronic L-DOPA treatment of 6-hydroxydopamine (6- drug alone (Kelsey et al. 2009). Rats with 6-OHDA injected OHDA)-lesioned rats significantly increased CB1R mRNA into the striatum exhibit emotional and cognitive alterations expression in the denervated striatum (Zeng et al. 1999). that were rescued by acute injection of SR141716A Also, enhanced levels of AEA in the striatum and decreased (Tadaiesky et al. 2010). Blockade of CB1R was shown to activity of FAAH was reported in a rat model of PD (induced protect nigrostriatal dopaminergic neurons against MPTP by unilateral nigral lesion with 6-OHDA). The frequency and neurotoxicity by inhibiting microglial activation (Chung

© 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 640 B. S. Basavarajappa et al. et al. 2011). Rats with unilateral intrastriatal 6-OHDA (Palomo-Garo et al. 2016). In recent study, up-regulation of lesions treated chronically with MSX-3/or rimonabant the CB2R was shown in inflammation-driven PD rat model showed rescue of dopaminergic cell death and neuroinflam- (Concannon et al. 2016). Although more studies are neces- mation in the SN pars compacta (Cerri et al. 2014). In a sary, these findings suggest that CB2Rs function in the primate model of PD, SR141716A failed to ameliorate the pathophysiology of PD. Use of CB2R selective agonists motor deficits of parkinsonism (Meschler et al. 2001). without the psychoactive effects may provide neuroprotection Together, these findings suggest a direct link between EC against the neurodegenerative processes of PD. signaling and symptoms of Parkinson’s disease and suggest that modulation of the EC signaling system might prove Conclusion useful in treating PD. Several lines of research imply that inflammation plays a Several lines of evidence suggest a primary function of significant role in the neurodegenerative process, and endocannabinoids, CBRs, and other components of EC because cannabinoids possess anti-inflammatory and neuro- system in the degenerative process. Various investigators protective actions, recent pre-clinical research provides much using a variety of pre-clinical models have discovered the evidence suggesting that CB2Rs play a major role in limiting therapeutic intervention strategies modulating EC system. the inflammatory responses secondary to microglial activa- Furthermore, current approaches to the development of novel tion. Pharmacological activation of microglial CB2Rs in the therapeutic strategies for neurodegenerative diseases have MPTP mouse model of PD led to reduced microglial focused not only on their neuroprotective properties but also activation and functional deficits (Price et al. 2009), reduced on alleviating symptoms of the neurodegenerative diseases. the release of pro-inflammatory cytokines (Molina-Holgado These approaches are based on the well-characterized role of et al. 2002b; Klegeris et al. 2003; Ehrhart et al. 2005), and cannabinoids that have the ability to control both anti- increased the levels of anti-inflammatory cytokines (Molina- inflammatory and neuroprotective functions. Therefore, the Holgado et al. 2003). Consistent with these observations, use of CB2R agonists and CB1R antagonists endeavor an CB2R knockout (KO) mice exhibited enhanced microglial interesting, unique, and potential therapeutic advance for activation and exacerbation of the PD pathology with neural neurodegenerative disorders. alterations and functional deficits (Molina-Holgado et al. 2003). Similar changes have also been reported in other PD Acknowledgments and conflict of interest models, such as MPTP-lesioned and LPS-injected mice disclosure (Price et al. 2009; Garcia et al. 2011; Gomez-Galvez et al. 2016). Also, over-expression of CB2R provides protection This study was partially supported by a grant from the National against 6-OHDA-induced nigrostriatal lesions in mice (Ter- Institute of Alcohol and Alcoholism (RO1-AA019443) to B.S.B. nianov et al. 2012). Activation of CB2R with selective The authors declare no competing financial interests. agonists improved function in MPTP-lesioned mice (Price et al. 2009) and LPS-injected mice (Garcia et al. 2011) but References not in 6-OHDA-lesioned rats (Garcia-Arencibia et al. 2007). For example, the selective CB2R agonist HU-308 rescued Ahmad R., Goffin K., Van den Stock J. et al. (2014) In vivo type 1 ’ the LPS-induced decrease in TH-positive neurons. Increased cannabinoid receptor availability in Alzheimer s disease. Eur. Neuropsychopharmacol. 24, 242–250. CD68 immunostaining in the striatum (activated microglia Ahmad R., Postnov A., Bormans G., Versijpt J., Vandenbulcke M. and and infiltrated peripheral macrophages) was also observed Van Laere K. (2016) Decreased in vivo availability of the (Gomez-Galvez et al. 2016). Also, HU-308 significantly cannabinoid type 2 receptor in Alzheimer’s disease. Eur. J. Nucl. rescued striatal iNOS gene expression after LPS injection Med. Mol. 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