Progress in Neuro-Psychopharmacology and Biological Psychiatry
Potential of the cannabinoid CB2 receptor as a pharmacological target against inflammation in Parkinson's disease
Introduction
Cannabinoids have important anti-inflammatory properties that may preserve neuronal homeostasis and survival in different neuroinflammatory/neurodegenerative disorders (Chiurchiù et al., in press). These effects are preferentially exerted by the activation of the cannabinoid type-2 (CB2) receptor (Fernández-Ruiz et al., 2007), although recent studies also situate the cannabinoid type-1 (CB1) receptor (Chung et al., 2011, de Lago et al., 2012) and even the nuclear receptors of the peroxisome proliferator-activated receptor (PPAR) family (Fidaleo et al., 2014) as additional potential targets for the anti-inflammatory action of certain cannabinoids. The anti-inflammatory properties of compounds activating the CB2 receptors are facilitated by the presence of these receptors in glial cells, mainly astrocytes and microglial cells, and the up-regulatory response that they experience when these cells become reactive in inflammatory, excitotoxic, oxidative or infectious conditions (Fernández-Ruiz et al., 2007, Fernández-Ruiz et al., 2010). Frequently, glial CB2 receptors may work alone but they can also work in conjunction with CB1 receptors, for example in the regulation of astrocyte activity in conditions of brain damage (reviewed by Stella, 2010). Irrespective of the cannabinoid receptor type involved, the benefits that cannabinoids may provide appear to be associated with the trophic role exerted by these glial cells, including improvements in the supply of metabolic substrates to neurons (lactate or ketone bodies: Duarte et al., 2012). They could act: (i) by enhancing the generation of neurotrophins or anti-inflammatory/pro-survival mediators that could potentially rescue damaged neurons, e.g., interleukin-10 (IL-10), IL-1 receptor antagonists, transforming growth factor-β (TGF-β) (Molina-Holgado et al., 2003, Smith et al., 2000), and/or (ii) by inhibiting the production of chemokines by astrocytes, e.g., fractalkine (Sheng et al., 2009). In contrast to astrocytes, the effects of cannabinoids on microglial cells are much more dependent on CB2 receptor function. Indeed, CB2 receptors appear to play an important role in the proliferation and migration of these cells at lesion sites (Carrier et al., 2004, Walter et al., 2003). In addition, the activation of CB2 receptors dampens the generation of a variety of neurotoxic factors by microglial cells (Fernández-Ruiz et al., 2007, Fernández-Ruiz et al., 2010), for example tumor necrosis factor-α (TNF-α), a major contributor to the pathophysiology of brain injury (reviewed by Stella, 2010). Activation of CB2 receptors apparently inhibits the production of TNF-α by inhibiting NFκB (Oh et al., 2010), a transcription factor that plays a key role in the regulation of pro-inflammatory responses.
Therefore, the presence of CB2 receptors in reactive microglia and also in activated astrocytes, places these receptors in a promising position for their use as a target for neuroprotection (Fernández-Ruiz et al., 2010). An important advantage of compounds targeting these receptors is that they do not provoke the frequent psychotropic side effects elicited by cannabinoids that activate the CB1 receptor, indicating that they may be safe and well-tolerated in clinical applications. In addition, such pharmacological manipulations may be the best way to reproduce the endogenous response provoked by these receptors, which, as mentioned above, are up-regulated in activated astrocytes and, in particular, reactive microglia in response to inflammatory, excitotoxic and traumatic insults, such as those that occur in most of neurodegenerative disorders including Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and others (reviewed in Fernández-Ruiz et al., 2007, Fernández-Ruiz et al., 2010). This response, which had remained elusive for years, has been also identified in Parkinson's disease (PD) in a couple of recent studies. Thus, Price et al. (2009) described an elevation of CB2 receptors in microglial cells recruited at the lesion sites in mice intoxicated with MPTP, a model with a modest glial response. In addition, these authors found that targeting these receptors reduced the damage of nigrostriatal neurons (Price et al., 2009), although a recent study showed that the inhibition of microglial activation and the preservation of nigrostriatal dopaminergic neurons in MPTP-lesioned mice involved surprisingly the activation of CB1 receptors (Chung et al., 2011). In our laboratory, we studied this issue in a more inflammatory model of nigrostriatal damage consisting in intrastriatal injection of lipopolysaccharide (LPS) (García et al., 2011). We found elevated levels of CB2 receptors in the striatum of LPS-lesioned mice, although we did not investigate the cell substrates in which this response is occurring (García et al., 2011). In addition, we found that CB2 receptor-deficient mice were more vulnerable to LPS lesion than wild-type animals, a difference that was not found in mice lesioned with 6-hydroxydopamine, a model with poor inflammatory responses and in which the death of dopaminergic neurons is directly related to mitochondrial dysfunction and oxidative damage (García et al., 2011). In agreement with this difference, LPS-lesioned mice responded to compounds targeting the CB2 receptor (García et al., 2011), whereas 6-hydroxydopamine-lesioned mice did not (García-Arencibia et al., 2007), although other authors described that mice overexpressing CB2 receptors were more protected against 6-hydroxydopamine-induced nigrostriatal damage (Ternianov et al., 2012). All this evidence supports that CB2 receptor may be also a promising pharmacological target in PD, although more specifically in those conditions having greater glial activation and inflammatory events. In the present study, we wanted to further explore the issue by addressing some unexplored objectives: (i) to elucidate whether such up-regulatory response of CB2 receptors also occurs in PD patients using postmortem tissues provided by two biobanks; (ii) to quantify the magnitude of such response in LPS-lesioned mice and the differences between wild-type and CB2 receptor-knockout mice; and (iii) to investigate some molecular substrates presumably controlled by the selective activation of these receptors in LPS-lesioned mice.
Section snippets
Human samples
We used post-mortem human substantia nigra from control subjects and patients with diagnosis of PD that were obtained from two biobanks: “Fundación CIEN”, Madrid, Spain, and “Banc de Teixits Neurològics, Universitat de Barcelona-Hospital Clínic”, Barcelona, Spain. All material has been collected from donors for and from whom a written informed consent for a brain autopsy and the use of material and clinical information for research purposes had been obtained from both biobanks. Our study was
CB2 receptors are elevated in microglial cells in the substantia nigra of PD patients
Our first objective in the present study was to elucidate whether the up-regulatory response of CB2 receptors found previously in MPTP-intoxicated mice (Price et al., 2009) and in LPS-lesioned mice (García et al., 2011) also occurs in PD patients, an issue still unexplored, despite that a glial neuroinflammatory response has been strongly related to the initiation and the progression of neurodegeneration in this disease (Ouchi et al., 2005). To this end, we used postmortem tissues (substantia
Discussion
There is a general consensus about the important role that CB2 receptors play endogenously against inflammatory events typical of neurodegenerative disorders, as well as about the possibilities of a pharmacological management of this function. Apparently, this may be facilitated by the frequent up-regulatory responses elicited by these receptors in the lesioned sites in most of neurodegenerative disorders (Fernández-Ruiz et al., 2007, Fernández-Ruiz et al., 2010). This also includes PD,
Conflict of interest
The authors declare that they do not have any conflict of interest.
Authors' contribution
CG supervised and conducted all immunolabeling procedures. YGG and CPG conducted the experiments with animals including the pharmacological treatments. YGG also conducted the qRT-PCR analysis. JFR designed and coordinated the whole study, and analyzed the data with CG. JFR prepared the manuscript for submission, which was approved by all authors.
Acknowledgments
This work has been supported by grants from CIBERNED (CB06/05/0089), MINECO (SAF2009/11847; SAF2012/39173) and CAM (S2011/BMD-2308). These agencies had no further role in study design, the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. Authors are indebted to the biobanks of the “Fundación CIEN”, Madrid, Spain, and of the “Banc de Teixits Neurològics, Universitat de Barcelona-Hospital Clínic”, Barcelona,
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Both authors shared the senior authorship.