Biochemical Society Transactions


Cannabinoids and PPARα signalling

Y. Sun, S.P.H. Alexander, D.A. Kendall, A.J. Bennett


Cannabinoids have been shown to possess anti-inflammatory and neuroprotective properties, which were proposed to occur mainly via activation of the G-protein-coupled receptor CB1 (cannabinoid receptor 1). Recently, certain cannabinoids have been reported to be ligands for members of the nuclear receptor transcription factor superfamily known as PPARs (peroxisome-proliferator-activated receptors). This review summarizes the evidence for cannabinoid activation of PPARs and identifies a new intracellular target for cannabinoids as therapeutic agents for neuroprotective treatment.

  • cannabinoid receptor (CB receptor)
  • central nervous system (CNS)
  • G-protein-coupled receptor (GPCR)
  • middle cerebral artery occlusion
  • neuroprotection
  • peroxisome-proliferator-activated receptor (PPAR)

THC (Δ9-tetrahydrocannabinol) is the main psychoactive ingredient in cannabis, and in the brain it acts on the CB1 receptor (cannabinoid receptor 1), identified in 1990 by Matsuda and co-workers [1]. The CB1 receptor is by far the most abundant G-protein-coupled receptor in the CNS (central nervous system) and it is also expressed on peripheral neurons and other cell types. CB2 receptors seem to be expressed primarily in the immune system, although their presence in the CNS has also been identified recently [1a]. Following the discovery of CB receptors, a structurally diverse range of subtype-selective and -non-selective receptor ligands (cannabinoids) have been generated, including potent agonists (such as Win 55212-2) and antagonists (such as rimonabant) [2]. Subsequently, endogenous activators of CB receptors (endocannabinoids) were identified, the first of which, anandamide, was discovered in 1992 [2]. The CB1-utilizing endocannabinoid system regulates synaptic neurotransmission in excitatory and inhibitory circuits. The endocannabinoids act as retrograde modulators in many circumstances, being synthesized postsynaptically in response to Ca2+-mobilizing stimuli, thereafter causing presynaptic inhibition of neurotransmitter release (Figure 1). Using both in vitro and in vivo models, cannabinoids have been observed to display neuroprotective effects [3].

Figure 1 Putative neuroprotection mechanism of cannabinoids

Cannabinoids act on CB1 receptor, which mediates inhibition of neurotransmitter release with consequent prevention of Ca2+-induced neurotoxicity. Cannabinoids also act on PPARα and trigger some anti-inflammatory pathways such as IκBα.

Although many of the physiological responses to cannabinoids, such as alterations in cognition and memory, euphoria, immobility, analgesia, hypothermia and sedation, are generally thought to be due to action at the CB1 and CB2 receptors, studies in CB1, CB2 or double-knockout mice have revealed non-CB1/CB2 receptor-mediated responses to cannabinoids, both in the CNS and periphery [2]. One potential candidate for CB1/2-independent effects of cannabinoids is the PPAR (peroxisome-proliferator-activated receptor) family of nuclear receptor transcription factors. The PPARs were originally identified as being involved in the regulation of lipid metabolism but more recently have been implicated in a wide variety of biological processes including inflammation [4]. In particular, activation of the PPAR α and γ isoforms has been shown to have anti-inflammatory effects in a variety of tissues. Recently, THC was found to activate one member of the PPAR family, PPARγ, in a concentration-dependent manner in transactivation assays in HEK-293 (human embryonic kidney) cells [5]. It also stimulated adipocyte differentiation in 3T3L1 cells, a well-accepted property of PPARγ ligands. It has also been demonstrated that THC can cause vasorelaxation through activation of PPARγ [5]. The structurally diverse endocannabinoid anandamide has also been found to induce transcriptional activation of PPARγ in a concentration-dependent manner. The direct binding of anandamide with PPARγ was confirmed by competition binding experiments and anandamide also induced 3T3-L1 fibroblast differentiation into adipocytes [6]. The synthetic cannabinoid ajulemic acid is also a selective activator of PPARγ [3]. The N-acyl ethanolamine OEA (oleoylethanolamide), a naturally occurring lipid derivative structurally related to anandamide, shares the anorectic property of other cannabinoids. Although OEA is a (albeit relatively low-affinity) CB receptor agonist and could enhance the activity of other endocannabinoids via an ‘entourage’ effect by inhibiting the metabolism of other endocannabinoids, its regulation of feeding behaviour in rats appears to be due to activation of the nuclear receptor PPARα [7]. In vivo, OEA regulates feeding and body weight via a PPARα-dependent mechanism. OEA reduced body weight gain and triacylglycerol content in liver and adipose tissues in subchronic treatments of diet-induced obese mice, but not in PPARα-knockout mice. Similarly, OEA induced lipolysis in both rats and wild-type mice but not in PPARα-knockout mice [8]. Other cannabinoids, in addition to OEA, may be PPAR ligands. PEA (palmitoylethanolamide), a saturated analogue of OEA and anandamide, reduces pain and inflammation without directly acting on CBs [9]. PEA was found to activate PPARα in cultured cells and to induce the expression of PPARα. In vivo, PEA attenuates inflammation in wild-type mice but not in PPARα-knockout mice [10]. Using a CPA (cis-parinaric acid)-based ligand-binding system and a transient transfection system, selected cannabinoids, including synthetic cannabinoid (Win 55212-2) and endocannabinoids (OEA, anandamide, noladin ether and virodhamine), were found to have PPARα binding and transcription activity (Table 1).

View this table:
Table 1 Effects of selective cannabinoids on mouse PPARα

Data are mean potency [pEC50=−log10(EC50)] for reduction of CPA binding to a fusion protein of GST with a truncated mPPARα (mouse PPARα) containing the LBD (ligand-binding domain) (GST–mPPARα-LBD), and fold enhancement of the luciferase activity (the ratio of luciferase activity/mg of protein to vehicle only) in HeLa cells transiently transfected with mPPARα–PPRE (PPAR-responsive element)–RXR (retinoid X receptor)–luciferase constructs.

The neuroprotective actions of the selective PPARα agonist fenofibrate have been identified as being PPARα-dependent, since fenofibrate did not protect against cerebral injury in PPARα-deficient mice [7]. In a mouse model of cerebral ischaemia [MCAO (middle cerebral artery occlusion)], both fenofibrate and OEA treatments were found to significantly reduce infarct volume. The neuroprotection afforded by OEA has also been found to be PPARα-dependent, since the infarct volume of MCAO mice was not changed after OEA treatment in PPARα-null animals. The neuroprotective effect of PPARα activation was suggested to be independent of its well-known lipid-lowering property, since fenofibrate still reduced infarct size in hypercholesterolaemic ApoE (apolipoprotein E)-deficient mice without significantly altering plasma lipid levels. Since PPARα activation was found to be neuroprotective, the involvement of two PPARα-regulated genes known to be involved in the control of inflammation was investigated [11]. The NF-κB (nuclear factor κB) pathway, which plays an important role in the immune system and was previously shown to be regulated by PPARα, was assessed by measuring the expression of its inhibitory protein IκBα (inhibitory κBα) by Western blotting. The cerebral cortices of mice treated for three days with OEA (10 mg/kg) were found to express significantly more IκBα than tissue from vehicle-treated animals. Increased expression of IκBα would be expected to lead to the association of more NF-κB with IκBα proteins in the cytoplasm, thus decreasing the transcription of NF-κB target genes. Although the role of NF-κB in neuroprotection in the model of ischaemic stroke is unclear, an increase in constitutive NF-κB activation is generally thought to exacerbate brain damage and inhibition of the NF-κB pathway should, consequently, reduce ischaemic damage [12,13]. The genes regulated by NF-κB in brain include iNOS (inducible nitric oxide synthase), neural cell adhesion molecules, μ-opioid receptor, amyloid precursor protein, brain-derived neurotrophic factor, Mn-SOD (superoxide dismutase), COX-2 (cyclo-oxygenase 2) and Ca2+/calmodulin-dependent protein kinase II. The expression of COX-2 in cerebral cortex was found to be reduced significantly by OEA treatment. Following cerebral ischaemia, COX-2 expression is frequently found to be up-regulated in ischaemic areas [14,15] and inhibition of the enzyme has been found to reduce the infarct volume and neuronal damage in stroke models [16]. These observations suggest that the synthesis of COX-2 products contributes to the ischaemic damage. In addition to COX-2 modulation, changes in expression of other NF-κB-regulated genes in the brain could be involved in OEA-induced neuroprotection. For example, iNOS mRNA, protein and enzymatic activities are increased following permanent or transient MCAO, and expression of iNOS is generally thought to contribute to the evolution of brain injury (Figure 1).

In summary, there is strong evidence to suggest that some cannabinoids are PPARα and PPARγ agonists. In addition to its well-recognized role in lipid metabolism, PPARα activation showed obvious beneficial effects on ischaemic brain damage, which are likely to be connected with its antiinflammatory action through the NF-κB pathway. These discoveries not only broaden the potential usage of cannabinoids as therapeutic agents, but also support PPARα as a target for neuroprotective treatment.


  • Nuclear Receptors: Structure, Mechanisms and Therapeutic Targets: A Focus Topic at BioScience 2006, held at SECC Glasgow, U.K., 23–27 July 2006. Edited by C. Bevan (Imperial College London, U.K.), D. Black (Organon, U.K.) and I. McEwan (Aberdeen, U.K.).

Abbreviations: CB receptor, cannabinoid receptor; CNS, central nervous system; COX-2, cyclo-oxygenase 2; IκBα, inhibitory κBα; iNOS, inducible nitric oxide synthase; MCAO, middle cerebral artery occlusion; NF-κB, nuclear factor κB; OEA, oleoylethanolamide; PEA, palmitoyl-ethanolamide; PPAR, peroxisome-proliferator-activated receptor; THC, Δ9-tetrahydrocannabinol


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