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Biomedicines
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Targeting CB2 Receptors: Potential Investigational Treatments for Neurodegenerative Diseases
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Targeting CB2 Receptors: Potential Investigational Treatments for Neurodegenerative Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 14678

Special Issue Editor

Dr. Nicoletta Galeotti

E-Mail Website
Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy
Interests: neurodegenerative diseases; neuroinflammation; microglia; neuropathic pain
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The prevalence of neurodegenerative diseases, such as multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease, is continuously growing worldwide, which leads to great social–economic burdens. Despite the therapeutic improvement achieved in recent decades, novel effective treatments remain an urgent need. Growing evidence indicates that neuroinflammation is associated with neurodegenerative diseases. Hence, resolving chronic inflammation bears great promise as a novel treatment strategy to reduce neuronal damage and to foster a permissive environment for further regeneration effort. The interest in Cannabis sativa L. phytocomplex as a medicinal tool is a recently emerging topic, and inflammatory diseases represent a promising field of application for cannabis and its preparations. It is known that activation of the endocannabinoid system, and especially the cannabinoid type 2 receptor (CB2R), decreases inflammation. Alongside its non-psychoactive effect, it makes the CB2R receptor a perfect target for treating diseases accompanied by neuroinflammation, including neurodegenerative diseases.

In this Special Issue, we will summarize the role of CB2R in neurodegenerative disorders and will focus on investigations on the potential efficacy, pharmacokinetics, and underlying mechanisms of bioactive natural products and synthetic small molecules acting with CB2R to be exploited as innovative treatments.

We encourage scientists to submit results with potential for application in neurological disease, and research that might shed light on the underlying causes of neurodegenerative disorders. The topics of this Special Issue should be of interest for neurologists, neuroscientists, and physicians in different areas of medicine.

Dr. Nicoletta Galeotti
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegenerative diseases
  • CB2 receptors
  • endocannabinoid system
  • neuroinflammation
  • microglia
  • multiple sclerosis
  • Parkinson’s disease
  • Alzheimer’s disease
  • cannabinoid
  • cannabinoid receptor
  • CB2R

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Published Papers (5 papers)

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Research

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14 pages, 4717 KiB  
Article
The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition
by Vittoria Borgonetti, Claudia Mugnaini, Federico Corelli and Nicoletta Galeotti
Biomedicines 2023, 11(6), 1546; https://doi.org/10.3390/biomedicines11061546 - 26 May 2023
Cited by 6 | Viewed by 1806
Abstract
Neuropathic pain is a chronic disabling condition with a 7–10% of prevalence in the general population that is largely undertreated. Available analgesic therapies are poorly effective and are often accompanied by numerous side effects. Growing evidence indicates cannabinoids are a valuable treatment opportunity [...] Read more.
Neuropathic pain is a chronic disabling condition with a 7–10% of prevalence in the general population that is largely undertreated. Available analgesic therapies are poorly effective and are often accompanied by numerous side effects. Growing evidence indicates cannabinoids are a valuable treatment opportunity for neuropathic pain. The endocannabinoid system is an important regulator of pain perception through the CB1 receptors, but CB1 agonists, while largely effective, are not always satisfactory pain-relieving agents in clinics because of their serious adverse effects. Recently, several CB2 agonists have shown analgesic, anti-hyperalgesic, and anti-allodynic activity in the absence of CB1-induced psychostimulant effects, offering promise in neuropathic pain management. The aim of this study was to evaluate the anti-neuropathic activity of a novel selective CB2 agonist, COR167, in a preclinical model of peripheral neuropathy, the spared nerve injury (SNI). Oral COR167, in a dose-dependent manner, attenuated mechanical allodynia and thermal hyperalgesia after acute and repeated administration, showing the absence of tolerance induction. At anti-neuropathic doses, COR167 did not show any alteration in the locomotor behavior. SNI mice showed increased microglial levels of HDAC1 protein in the ipsilateral side of the spinal cord, along with NF-kB activation. COR167 treatment prevented the HDAC1 overexpression and the NF-kB activation and increased the levels of the anti-inflammatory cytokine IL-10 through a CB2-mediated mechanism. Oral administration of COR167 shows promising therapeutic potential in the management of neuropathic pain conditions. Full article
(This article belongs to the Special Issue Targeting CB2 Receptors: Potential Investigational Treatments for Neurodegenerative Diseases)
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18 pages, 3434 KiB  
Article
CB2 Agonist GW842166x Protected against 6-OHDA-Induced Anxiogenic- and Depressive-Related Behaviors in Mice
by Xiaojie Liu, Hao Yu, Bixuan Chen, Vladislav Friedman, Lianwei Mu, Thomas J. Kelly, Gonzalo Ruiz-Pérez, Li Zhao, Xiaowen Bai, Cecilia J. Hillard and Qing-song Liu
Biomedicines 2022, 10(8), 1776; https://doi.org/10.3390/biomedicines10081776 - 22 Jul 2022
Cited by 10 | Viewed by 2917
Abstract
In addition to motor dysfunction, patients with Parkinson’s disease (PD) are often affected by neuropsychiatric disorders, such as anxiety and depression. In animal models, activation of the endocannabinoid (eCB) system produces anxiolytic and antidepressant-like behavioral effects. CB2 agonists have demonstrated neuroprotective effects against [...] Read more.
In addition to motor dysfunction, patients with Parkinson’s disease (PD) are often affected by neuropsychiatric disorders, such as anxiety and depression. In animal models, activation of the endocannabinoid (eCB) system produces anxiolytic and antidepressant-like behavioral effects. CB2 agonists have demonstrated neuroprotective effects against neurotoxin-induced dopamine neuron loss and deficits in motor function. However, it remains unknown whether CB2 agonism ameliorates anxiogenic- and depressive-like behaviors in PD models. Here, we report that the selective CB2 agonist GW842166x exerted neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced loss of dopaminergic terminals and dopamine release in the striatum, which were blocked by the CB2 antagonist AM630. We found that 6-OHDA-treated mice exhibited anxiogenic- and depressive-like behaviors in the open-field, sucrose preference, novelty-suppressed feeding, marble burying, and forced swim tests but did not show significant changes in the elevated plus-maze and light–dark box test. GW842166x treatments ameliorated 6-OHDA-induced anxiogenic- and depressive-like behaviors, but the effects were blocked by CB2 antagonism, suggesting a CB2-dependent mechanism. These results suggest that the CB2 agonist GW842166x not only reduces 6-OHDA-induced motor function deficits but also anxiogenic- and depressive-like behaviors in 6-OHDA mouse models of PD. Full article
(This article belongs to the Special Issue Targeting CB2 Receptors: Potential Investigational Treatments for Neurodegenerative Diseases)
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Review

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31 pages, 1426 KiB  
Review
Cannabinoid CB2 Receptors in Neurodegenerative Proteinopathies: New Insights and Therapeutic Potential
by Barbara Vuic, Tina Milos, Lucija Tudor, Marcela Konjevod, Matea Nikolac Perkovic, Maja Jazvinscak Jembrek, Gordana Nedic Erjavec and Dubravka Svob Strac
Biomedicines 2022, 10(12), 3000; https://doi.org/10.3390/biomedicines10123000 - 22 Nov 2022
Cited by 8 | Viewed by 3585
Abstract
Some of the most prevalent neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease, are proteinopathies characterized by the accumulation of specific protein aggregates in the brain. Such misfolded protein aggregates can trigger modulation of the innate and adaptive immune systems and subsequently lead to [...] Read more.
Some of the most prevalent neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease, are proteinopathies characterized by the accumulation of specific protein aggregates in the brain. Such misfolded protein aggregates can trigger modulation of the innate and adaptive immune systems and subsequently lead to chronic neuroinflammation that drives the onset and progression of neurodegenerative diseases. Since there is still no effective disease-modifying treatment, new therapeutic targets for neurodegenerative proteinopathies have been sought. The endocannabinoid system, and in particular the cannabinoid CB2 receptors, have been extensively studied, due to their important role in neuroinflammation, especially in microglial cells. Several studies have shown promising effects of CB2 receptor activation on reducing protein aggregation-based pathology as well as on attenuating inflammation and several dementia-related symptoms. In this review, we discuss the available data on the role of CB2 receptors in neuroinflammation and the potential benefits and limitations of specific agonists of these receptors in the therapy of neurodegenerative proteinopathies. Full article
(This article belongs to the Special Issue Targeting CB2 Receptors: Potential Investigational Treatments for Neurodegenerative Diseases)
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19 pages, 1008 KiB  
Review
The Role of Cannabinoid Type 2 Receptors in Parkinson’s Disease
by Maria Sofia Basile and Emanuela Mazzon
Biomedicines 2022, 10(11), 2986; https://doi.org/10.3390/biomedicines10112986 - 20 Nov 2022
Cited by 6 | Viewed by 2324
Abstract
Parkinson’s disease (PD) is the second most frequent neurodegenerative disease and currently represents a clear unmet medical need. Therefore, novel preventive and therapeutic strategies are needed. Cannabinoid type 2 (CB2) receptors, one of the components of the endocannabinoid system, can regulate neuroinflammation in [...] Read more.
Parkinson’s disease (PD) is the second most frequent neurodegenerative disease and currently represents a clear unmet medical need. Therefore, novel preventive and therapeutic strategies are needed. Cannabinoid type 2 (CB2) receptors, one of the components of the endocannabinoid system, can regulate neuroinflammation in PD. Here, we review the current preclinical and clinical studies investigating the CB2 receptors in PD with the aim to clarify if these receptors could have a role in PD. Preclinical data show that CB2 receptors could have a neuroprotective action in PD and that the therapeutic targeting of CB2 receptors could be promising. Indeed, it has been shown that different CB2 receptor-selective agonists exert protective effects in different PD models. Moreover, the alterations in the expression of CB2 receptors observed in brain tissues from PD animal models and PD patients suggest the potential value of CB2 receptors as possible novel biomarkers for PD. However, to date, there is no direct evidence of the role of CB2 receptors in PD. Further studies are strongly needed in order to fully clarify the role of CB2 receptors in PD and thus pave the way to novel possible diagnostic and therapeutic opportunities for PD. Full article
(This article belongs to the Special Issue Targeting CB2 Receptors: Potential Investigational Treatments for Neurodegenerative Diseases)
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20 pages, 1432 KiB  
Review
The Antimicrobial Properties of Cannabis and Cannabis-Derived Compounds and Relevance to CB2-Targeted Neurodegenerative Therapeutics
by HeeJue Hong, Lucy Sloan, Deepak Saxena and David A. Scott
Biomedicines 2022, 10(8), 1959; https://doi.org/10.3390/biomedicines10081959 - 12 Aug 2022
Cited by 12 | Viewed by 3125
Abstract
Cannabinoid receptor 2 (CB2) is of interest as a much-needed target for the treatment or prevention of several neurogenerative diseases. However, CB2 agonists, particularly phytocannabinoids, have been ascribed antimicrobial properties and are associated with the induction of microbiome compositional fluxes. When developing novel [...] Read more.
Cannabinoid receptor 2 (CB2) is of interest as a much-needed target for the treatment or prevention of several neurogenerative diseases. However, CB2 agonists, particularly phytocannabinoids, have been ascribed antimicrobial properties and are associated with the induction of microbiome compositional fluxes. When developing novel CB2 therapeutics, CB2 engagement and antimicrobial functions should both be considered. This review summarizes those cannabinoids and cannabis-informed molecules and preparations (CIMPs) that show promise as microbicidal agents, with a particular focus on the most recent developments. CIMP–microbe interactions and anti-microbial mechanisms are discussed, while the major knowledge gaps and barriers to translation are presented. Further research into CIMPs may proffer novel direct or adjunctive strategies to augment the currently available antimicrobial armory. The clinical promise of CIMPs as antimicrobials, however, remains unrealized. Nevertheless, the microbicidal effects ascribed to several CB2 receptor-agonists should be considered when designing therapeutic approaches for neurocognitive and other disorders, particularly in cases where such regimens are to be long-term. To this end, the potential development of CB2 agonists lacking antimicrobial properties is also discussed. Full article
(This article belongs to the Special Issue Targeting CB2 Receptors: Potential Investigational Treatments for Neurodegenerative Diseases)
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