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Cannabidiol in Neurological and Neoplastic Diseases: Latest Developments on the Molecular Mechanism of Action

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Cannabidiol in Neurological and Neoplastic Diseases: Latest Developments on the Molecular Mechanism of Action International Journal of Molecular Sciences Review Cannabidiol in Neurological and Neoplastic Diseases: Latest Developments on the Molecular Mechanism of Action Marcin Ozarowski˙ 1 , Tomasz M. Karpi ´nski 2,* , Aleksandra Zieli ´nska 3,4 , Eliana B. Souto 4,5 and Karolina Wielgus 1 1 Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants—State Research Institute, Wojska Polskiego 71B, 60-630 Pozna´n,Poland; [email protected] (M.O.); [email protected] (K.W.) 2 Chair and Department of Medical Microbiology, Pozna´nUniversity of Medical Sciences, Wieniawskiego 3, 61-712 Pozna´n,Poland 3 Institute of Human Genetics, Polish Academy of Sciences, Strzeszy´nska32, 60-479 Pozna´n,Poland; [email protected] 4 Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; [email protected] 5 CEB—Center of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal * Correspondence: [email protected]; Tel.: +48-61-854-61-38 Abstract: As the major nonpsychotropic constituent of Cannabis sativa, cannabidiol (CBD) is regarded as one of the most promising therapeutic agents due to its proven effectiveness in clinical trials for many human diseases. Due to the urgent need for more efficient pharmacological treatments for several chronic diseases, in this review, we discuss the potential beneficial effects of CBD for Alzheimer’s disease, epilepsy, multiple sclerosis, and neurological cancers. Due to its wide range Citation: Ozarowski,˙ M.; Karpi´nski, of pharmacological activities (e.g., antioxidant, anti-inflammatory, and neuroprotective properties), T.M.; Zieli´nska,A.; Souto, E.B.; Wielgus, K. Cannabidiol in CBD is considered a multimodal drug for the treatment of a range of neurodegenerative disorders, Neurological and Neoplastic and various cancer types, including neoplasms of the neural system. The different mechanisms of Diseases: Latest Developments on the action of CBD are here disclosed, together with recent progress in the use of this cannabis-derived Molecular Mechanism of Action. Int. constituent as a new therapeutic approach. J. Mol. Sci. 2021, 22, 4294. https:// doi.org/10.3390/ijms22094294 Keywords: Cannabis sativa; cannabidiol; CBD; mechanism of action; Alzheimer’s disease; epilepsy; multiple sclerosis; cancer; pharmacological activity Academic Editor: Philippe De Deurwaerdère Received: 24 March 2021 1. Introduction Accepted: 19 April 2021 Published: 21 April 2021 It has been long recognized that Cannabis sativa L. has a great potential for medical application for different human diseases [1,2]. Its first medical use was marked in Central C. sativa Publisher’s Note: MDPI stays neutral Asia, including China and India, where was used to treat several conditions nearly with regard to jurisdictional claims in five millennia ago [3]. Nowadays, the therapeutic potential of phytocannabinoids and published maps and institutional affil- unique extracts from C. sativa have been the focus of interest of multiple research groups iations. worldwide. The latest scientific reports have opened the potential therapeutic use of the main C. sativa compounds, such as delta-9-tetrahydrocannabinol (D9-THC) and cannabidiol (CBD). The American Food and Drug Agency (FDA) approved dronabinol and nabilone to treat chemotherapy side-effects (nausea and vomiting) and for appetite stimulation in wasting diseases. In 2018, CBD was approved for the treatment of two types of pediatric Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. epilepsy, namely, Dravet syndrome and Lennox–Gastaut syndrome. This article is an open access article Cannabidiol is one of the major nonpsychotropic constituents of C. sativa and it is distributed under the terms and considered a promising therapeutic agent due to its already proven effectiveness against conditions of the Creative Commons neurological diseases [1,2,4,5]. CBD belongs to the group of terpenophenols. This bioactive Attribution (CC BY) license (https:// compound consists of 21 carbon atoms and, according to International Union of Pure and creativecommons.org/licenses/by/ Applied Chemistry (IUPAC) terminology, is described as 2-[(1R,6R)-3-methyl-6-prop-1- 4.0/). en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol [6]. The structural formula for CBD Int. J. Mol. Sci. 2021, 22, 4294. https://doi.org/10.3390/ijms22094294 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 19 Int. J. Mol. Sci. 2021, 22, 4294 2 of 18 for CBD is shown in Figure 1. The chemical activity of this Cannabis sativa-derived iscompound shown in Figureis based1. The on chemicalthe locati activityon of hydroxyl of this Cannabis groups sativa either-derived in the compound phenolic ring (at the 0 isC-1 based′ and on C-5 the′ positions) location of hydroxyland the methyl groups either group in at the the phenolic C-1 position ring (at of the the C-1 cyclohexeneand ring 0 C-5andpositions) the pentyl and chain the methyl at the groupC-3′ of at the C-1phenolic position ring. of the On cyclohexene the other ringhand, and the the ring of CBD pentyl chain at the C-30 of the phenolic ring. On the other hand, the ring of CBD is inactive inis theinactive C-4 position in the C-4 [6]. position Thanks to [6]. hydrogen Thanks bonds, to hydrogen CBD has bonds, an affinity CBD to has amino an acidsaffinity to amino (includingacids (including threonine, threonine, tyrosine, glutamic tyrosine, acid, glutamic glutamine). acid, Besides glutamine). its activity Besides in the central its activity in the nervouscentral systemnervous (CNS), system other (CNS), properties other (e.g., proper anti-inflammatory,ties (e.g., antinausea,anti-inflammatory, antitumor, antinausea, anticonvulsantantitumor, anticonvulsant and anxiolytic), and have anxiolytic), also been reported have [also7]. been reported [7]. 21 30 2 FigureFigure 1. 1.The The structural structural formula formula of cannabidiol of cannabidiol (CBD, C (CBD,21H30O C2). H O ). InIn this this review, review, the the current current state ofstate the of art the knowledge art knowledge is discussed is discussed with respect with to the respect to the molecularmolecular mechanisms mechanisms of action of action of CBD of inCBD Alzheimer’s in Alzheimer’s disease (AD), disease epilepsy, (AD), multiple epilepsy, multiple sclerosis, and the role of CBD in compromising the pathological process of these diseases. Thesclerosis, impact and of CBD the on role many of CBD types in of cancer,compromising including neoplasmsthe pathological of the neural process system, of these is diseases. alsoThe addressed. impact of CBD on many types of cancer, including neoplasms of the neural system, is also addressed. 2. Materials and Methods 2. MaterialsIn this review, and publicationsMethods available in PubMed and Scopus databases and available through the Google search engine were taken into account. The following keywords and their combinationsIn this review, were publications used: “cannabidiol”, available “CBD”, in PubMed “Alzheimer’s and Scopus disease”, databases “epilepsy”, and available “multiplethrough sclerosis”,the Google “cancer”, search “neural engine system”. were take Additionaln into account. searches includedThe following references keywords and fromtheir identifiedcombinations publications. were used: In the “cannabidiol”, screening process, “CBD”, articles “Alzheimer’s published in predatorydisease”, “epilepsy”, journals“multiple and sclerosis”, research before “cancer”, 1980 were “neural excluded. system”. Additional searches included references 3.from Recent identified Developments publications. on the Molecular In the screening Mechanism process, of Action articles of CBD forpublished in predatory Alzheimer’sjournals and Disease research before 1980 were excluded. CBD is a potential bioactive for the treatment of neuroinflammatory-derived diseases, epilepsy,3. Recent anxiety, Developments and schizophrenia on the [Molecular8]. Due to its Mechanism antioxidant, of anti-inflammatory, Action of CBD and for neuroprotectiveAlzheimer’s Disease properties, cannabidiol was proposed as a promising innovative strategy for Alzheimer’s disease [9,10]. Moreover, CBD reduces the hyperphosphorylation of tau proteinCBD [9], inhibits is a acetylcholinesterasepotential bioactive activity for [11the], and treatment deposition of and neuroinflammatory-derived expression of beta- amyloiddiseases, [10 ,epilepsy,12,13]. These anxiety, pharmacological and schizophrenia points of action [8]. are involvedDue to in theits complexantioxidant, anti- pathogenesisinflammatory, of Alzheimer’s and neuroprotective disease. However, properties the molecular, cannabidiol mechanisms was proposed of CBD in thisas a promising fieldinnovative are still tostrategy be fully described. for Alzheimer’s A study by Hugesdisease et al. [[9,10].14] described Moreover, that CBD CBD (10 µM) reduces the rescuedhyperphosphorylation the deficit in long-term of tau hippocampal protein [9], potentiation inhibits inacetylcholinesterase c57/black six mice induced activity [11], and β bydepositionamyloid and (Ab 1–42)expression by a receptor-independent of beta-amyloid mechanism, [10,12,13]. such These as 5HT1A, pharmacological adenosine points of A2A, and the receptor CB1. CBD pharmacological activities were also reported to be related toaction diverse are non-CB1/non-CB2 involved in the mechanisms complex pathogenes [15,16]. is of Alzheimer’s
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