**Abstract**

Progressive neuronal loss is a typical characteristic of neurodegenerative diseases. In Parkinson's disease, the loss of dopaminergic neurons in the basal ganglia results in impaired mobility and flawed muscle control. The loss of cholinergic neurons largely in the basal forebrain contributes to memory and attention deficits and the overall cognitive impairment in Alzheimer's disease. This being said, neuroprotective drugs should be expected to preserve and/or restore the functions affected by neuronal loss, and substantially prevent cell death. The endocannabinoid system, comprising lipid mediators able to bind to and activate cannabinoid receptors, has emerged as a therapeutic target of potential interest in a variety of central nervous system diseases. Palmitoylethanolamide (PEA) is one of the most important endocannabinoids, which has a key role in modulating oxidative stress and inflammatory response with neuroprotective potential in neurological disorders. Neurodegenerative diseases undergo varied, progressive stages. The current therapeutical approaches are beginning to fall short when it comes to meet the expected results, urging to either develop or identify or develop new effective treatments. This chapter discusses the neuroprotective potential of new drugs, aiming to shed some light on their proposed mechanism of action and their effect in cellular and animal models of neurodegeneration.

**Keywords:** Parkinson's disease, Alzheimer's disease, endocannabinoids, palmitoylethanolamide (PEA), dopaminergic neurons

## **1. Introduction**

The palmitoylethanolamide (PEA) is an endogenous biologically active lipids belonging to the family of the endogenous cannabinoid. PEA has many uses in a range of therapeutics areas, such as: neurological diseases, neurodegeneration, and pain.

Several studies have been carried out to define the molecular mechanism of PEA. However, at time, it was proposed that the existence of a mechanism

#### **Figure 1.**

*Scheme of the performance of the PEA through the union to its different receptors. The PEA, through PPARα, mainly performs metabolic functions such as the regulation of lipid metabolism and exerts neuroprotective functions due to the reduction of transcription of various proinflammatory cytokines. After the binding of PEA to PPARα in the nucleus, it heterodimerizes with the RXR receptor, to then join specific DNA sequences called PPRE. These PPRE modulate transcription of target genes that control a wide variety of activities metabolic and physiological. On the other hand, it has been hypothesized that the PEA can also exercise its biological functions through different transmembrane receptors like GPR55, GPR119, and TRPV1, although this issue is still controversial.*

receptor-dependent, and several studies demonstrated that PEA can act via direct activation of two different receptors: the orphan GPCR 55 (GPR55) [1] and the PPAR-α [2]. It was discovered that there is a wide variety receptors capable of interacting with PEA. All of them are belonged to these two receptors families, **Figure 1.**

Other supposition postulated that PEA could also be a cannabinoid receptor type 2 (CB2) receptor agonist; however, studies suggested that it has very weak affinity for this receptor [3]. In other hand, the transient receptor potential vanilloid receptor type 1 (TRPV1) channels can be activated for PEA in an indirectly way, **Figure 1**. These receptors are important targets of many endocannabinoids.

All data, which will be shown in this chapter, suggest that the action mechanism of PEA operates for several different ways. In the central and the peripheral nervous system, these mechanisms have collaborative interactions essential for the most important therapeutic effects of PEA.

#### **2. Receptors of PEA**

GPR55 and PPAR-α are the two most important receptors for PEA. GPR55 is a receptor belongs to the large family of GPCRs. It is expressed in brain areas, including the hippocampus, striatum, cortex, forebrain, and cerebellum. It has been reported that GPR55 utilizes the high concentration of intracellular to trigger a cascade of signalling events [4]. NF-κB, cAMP, MAPK, ERK1/2, and transcriptional regulators such as nuclear factor of activated T-cells (NFAT) are involved to GPR55 activation [5]. Other receptor belongs to the family of GPCR is GPR119, which can recognize oleoylethanolamide (OEA) and PEA. However, these two acylethanolamides do not interact with classical cannabinoid receptors such as CB1 and CB2 [6].

PPAR-α belongs to the family of PPARs and acts as a nuclear receptor protein. PPAR-α is present in many tissues and organs; liver, intestine, heart, muscle,

**5**

*Neuroprotective Properties of Cannabinoids in Cellular and Animal Models: Hypotheses and Facts*

Both receptors have recently emerged as a putative target for the treatment of

TRPV1 channel belongs to a subfamily of transient receptor potential channels (TRP channels). It is called 'the capsaicin receptor.' This is conformed by intramembrane loop linking the transmembrane domains, forming the pore channel region [9]. TRPV1 is present in sensory nerve fibres and dorsal root ganglia, keratinocytes, in brain neurons, and other cell types [10–13]. TRPV1 is activated by stimulation of the non-selective ion channel, permeable to cations. Also, it is activated by exog-

The changes in the phosphorylation state of TRPV1 induced by regulatory proteins (including PKA, PKC, ATP, phosphorinositide binding protein (PIRT) and phosphatidylinositol 4,5-bisphosphate (PIP2)) influent in the function of the receptor [15, 16]. The changes in the phosphorylation state produce an activation of TRPV1, then this trigger the signaling cascade to pain transmission, neurotoxicity, and inflammation [13, 17]. The high concentration of intracellular Ca2+ produces the stimulation of two processes very important. On the one hand, the stabilization of the channel by locked conformational. On the other hand, the inactivation of TRPV1 channel by Ca2+-dependent phosphatases, such as calcineurin, which dephosphorylate it [15, 16]. This process contributes to the anti-inflammatory and

There are many hypotheses about the mechanisms for the action of PEA with TRPV1 channels. One of them proposes that TRPV1 channels can be indirectly activate via PPAR-α due the action of PEA. Other mechanism proposes an indirectly activation of TRPV1 through the allosteric effects produce for PEA. It could increase AEA - or 2-AG induced activation and desensitization at TRPV1 channels

The cannabinoid receptors types 1 and 2 (CB1 and CB2) are members of the G protein coupled receptor (GPCR) family that were identified over 20 years ago. [20, 21]. The CB1 receptor is often expressed in the brain, in the peripheral nervous system and presynaptic terminals. Also, it is expressed in almost all mammalian tissue and organs [22]. Its activation usually inhibits neurotransmitter release; the CB1 activation inhibits adenylate cyclase activity with the subsequent stimulates MAPK activity or reduction of intracellular levels of cAMP [23]. Consequently to the coupling of CB1 to PKB (Akt), phosphoinositide 3-kinase and PLC/inositol1,

The CB2 receptors are involved in the activated astrocytes and microglia in the brain, where are expressed in low concentration [26]. However, this receptor is expressed in peripheral organs and cells of the immune system [16, 27–29]. One of the most important functions of the CB2 receptor is controlling the inflammatory responses [16, 30]. The CB2 receptor activation promotes MAPK activity and

4,5-trisphosphate/PKC (PLCβ/IP3/PKC) pathways [24, 25].

**3. Other components involved indirectly in the mechanism of PEA**

brain, kidney, and adipose tissue. Also, this receptor is present in cells of the immune system PPAR-α. Their main functions are involved in the control of inflammatory processes and in the transcription factor regulating gene expression. In the same way, it is accepted that the binding of PEA to PPAR-α induces a heterodi-merization event with the retinoic acid receptor (RXR), forming the activated receptor complex, which decrease the transcription of pro-inflammatory

*DOI: http://dx.doi.org/10.5772/intechopen.90761*

pain, inflammation, and neurodegenerative diseases [8].

enous or endogenous chemical compounds [9, 14].

analgesic actions of TRPV1 [16, 17].

inhibits adenylate cyclase activity [31].

[10, 18, 19].

genes [7].

*Neuroprotective Properties of Cannabinoids in Cellular and Animal Models: Hypotheses and Facts DOI: http://dx.doi.org/10.5772/intechopen.90761*

brain, kidney, and adipose tissue. Also, this receptor is present in cells of the immune system PPAR-α. Their main functions are involved in the control of inflammatory processes and in the transcription factor regulating gene expression. In the same way, it is accepted that the binding of PEA to PPAR-α induces a heterodi-merization event with the retinoic acid receptor (RXR), forming the activated receptor complex, which decrease the transcription of pro-inflammatory genes [7].

Both receptors have recently emerged as a putative target for the treatment of pain, inflammation, and neurodegenerative diseases [8].
