Potential of Cannabinoids in Multiple Sclerosis: Comparison
Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Anwar Abdelnaser.

Multiple sclerosis is the predominant autoimmune disorder affecting the central nervous system in adolescents and adults. Specific treatments are categorized as disease-modifying, whereas others are symptomatic treatments to alleviate painful symptoms. No singular conventional therapy is universally effective for all patients across all stages of the illness. Nevertheless, cannabinoids exhibit significant promise in their capacity for neuroprotection, anti-inflammation, and immunosuppression. 

  • multiple sclerosis
  • autoimmune disease
  • cannabinoids
  • tetrahydrocannabinol
  • cannabis
  • treatment modalities
  • immunomodulatory
  • nanomedicine

1. Introduction

Multiple sclerosis (MS) is an autoimmune disorder that affects the central nervous system (CNS) [1] and is one of the leading causes of neurological impairment in teenagers and adults [2]. Multiple sclerosis can be mainly categorized into three types: Relapsing-Remitting MS (RRMS), Secondary Progressive MS (SPMS), and Primary Progressive MS (PPMS). Most MS patients (85–90%) initially present with RRMS, with around 90% eventually transitioning to SPMS and the remaining 10% experiencing PPMS [3]. Multiple sclerosis (MS) is distinguished by the presence of muscle spasms, spasticity, neuropathic pain, bladder dysfunction, tremors, dysarthria, and cognitive impairments, such as memory disturbances [4]. There is currently a growing trend in utilizing cannabis for therapeutic purposes as a symptomatic treatment. Numerous trials and patients have reported that it may be beneficial in managing and controlling symptoms associated with multiple sclerosis (MS).

2. Cannabinoids and the Endocannabinoid System (ECS)

2.1. Cannabinoids

Cannabis sativa, Cannabis indica, and Cannabis ruderalis are the three most common species of the cannabis plant, which is in the Cannabaceae family [32][5]. The cannabis plant has a long history of practical uses, including as a food and oil source and even in producing paper and linen, two of man’s necessities [33][6]. In addition, its psychoactive qualities enabled its use in medical surgeries, even though its components and mechanism of action in the human body were unknown at the time [34][7]. Phytocannabinoids, endocannabinoids, and synthetic cannabinoids are the three primary sources of more than sixty cannabinoids with physiological effects [8]. The cannabis plant contains more than 100 phytocannabinoids, including the two most significant ones, which are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). It is believed that Δ9-THC is the primary psychoactive compound found in cannabis [9].

2.2. The Endocannabinoid System (ECS)

The primary impact of cannabinoids occurs through the endocannabinoid system (ECS), which consists of a set of signaling pathways regulated by cannabinoid receptors cannabinoid-1 (CB1) and cannabinoid-2 (CB2). The activation of these pathways is commonly triggered by the attachment of endogenous cannabinoids (endocannabinoids) like Anandamide (AEA) and 2-Arachidonoyl Glycerol (2-AG) to the CB1 and CB2 receptors [35][10]. The CB1 receptors are situated primarily in nerve terminals and function to inhibit the release of neurotransmitters. Conversely, CB2 receptors are predominantly located in immune cells. Their role encompasses regulating cytokine production and migrating immune cells within and beyond the central nervous system [36,37][11][12]. The endocannabinoid system (ECS) is essential for maintaining the body’s homeostasis by regulating the balance between the inhibitory and excitatory states of the nerves. This is accomplished by activating CB1 receptors located on inhibitory GABAergic and excitatory glutamatergic presynaptic terminals, inhibiting neurotransmitter release [38][13]. Additionally, the ECS is responsible for many physiological and pathological processes in the body. It controls biological mechanisms, such as pain, food intake, anxiety, and memory [39][14].

3. Neuroprotection Effect of Cannabinoids

The neuroprotective effect of cannabinoids in multiple sclerosis (MS) may be attributed to their role in regulating the excessive excitability of neurons in the central nervous system (CNS). The CB1 receptor is located predominantly in GABAergic neurons within the hippocampus. It is also found in neurons that use glutamate as a neurotransmitter and in astrocytes and subcellular compartments [40,41][15][16]. The release of cholinergic and dopaminergic neurotransmitters is regulated by cannabinoid signaling and the regulation of excitatory/inhibitory transmission by CB1 receptors, as shown in Figure 1 [42,43][17][18]. Studies have shown that cannabinoid-based therapy can effectively reduce symptoms of multiple sclerosis, such as spasticity, pain, gallbladder dysfunction, and tremors [44][19], which is achieved by increasing the secretion of endocannabinoids in targeted areas, activating CB1 receptors, and limiting the release of neurotransmitters from presynaptic terminals, which results in a reduction in the excessive excitatory state in the neurons and a potential neuroprotection effect of the CNS [45][20]. In addition, cannabinoids’ impact on the regulation and modulation of microglial cells within the CNS has been investigated. Inflammation has been shown to elevate CB2 receptors in glial and immune cells, even though they are less prevalent in the healthy brain, as observed in EAE models [46][21].
Figure 1. Diagram depicting the biological effects of cannabis’ active ingredients on multiple sclerosis. Abbreviations for cannabinoid receptors 1 and 2, tetrahydrocannabinol, and cannabidiol created with Biorender.
Moreover, blood samples from MS patients exhibited higher levels of pro-inflammatory cytokines and excessive expression of CB1 and CB2 receptors [47][22]. These findings, along with the observation that activating CB2 receptors reduces the secretion of TNF-α and oxidative free radicals within the brain, underscore the critical role of the ECS signaling pathway and cannabinoids in controlling CNS inflammation through immuno-regulatory functions in neurons. Furthermore, this plays a vital role in the neuroprotection of the CNS by mitigating oxidative stress. Interestingly, the part of cannabinoids in neuroprotection could also be due to their antioxidant effect. Preliminary factors in neurodegenerative diseases include oxidative stress, which occurs when reactive oxygen or nitrogen species surpass antioxidants. CBD, being a phenolic compound, exhibits reactive oxygen-scavenging properties. In experimental studies on PC12 cells, CBD demonstrated approximately 50% higher antioxidant activity than vitamins. It effectively reduced oxidative stress caused by reactive oxygen species (ROS) by limiting lipid peroxidation and inhibiting the accumulation of ROS products. Additionally, CBD reduced induced cell-apoptosis factors, such as DNA fragmentation and caspase-3 activation. These findings highlight the potential neuroprotective effects of CBD against oxidative damage in neurodegenerative conditions [48][23].

4. Immunomodulatory Effect of Cannabinoids

The presence of cannabinoid receptor 2 (CB2) in white blood cells has sparked interest in the ability of cannabinoids to regulate the immune system. THC binds to CB1 receptors in the brain, whereas CB2 receptors are found predominantly in immune cells in the peripheral nervous system. The precise role of the endocannabinoid system in immune regulation is not yet fully comprehended, despite evidence of cannabinoids affecting immune cell function [49,50][24][25]. According to a study by Nichols et al. in 2020, cannabidiol (CBD) has been recognized as an anti-inflammatory substance and has some characteristics of suppressing the immune system [51][26]. Exposure to high concentrations of cannabis can impair immune responses, according to in vitro and in vivo research. This reduces the activity and cytokine production capacity of macrophages, natural killer cells, and T lymphocytes [52][27]. However, rather than reducing immune system activity, an adequate amount of cannabis in the body increases lymphocyte metabolic activity and boosts the production of pro-inflammatory cytokines [53][28]. These dose-dependent cannabinoid activities point to the biphasic effect of cannabis constituents [52][27]. Despite this potential biphasic effect of cannabinoids, CBD has been shown in several studies to act as an immunomodulator during inflammation, regulating the inflammatory response by influencing various inflammatory cascades involving both anti-inflammatory and pro-inflammatory mediators, as discussed in the study by Furgiuele et al. [54][29]. Inflammation, axonal demyelination, and symptoms like spasticity and pain are all helped by these neuroprotective mechanisms. Using EAE murine models of multiple sclerosis, researchers found that CBD, with the help of myeloid-derived suppressor cells (MDSCs), improved EAE progression dose-dependently. According to the research conducted by Elliott et al., CBD had several effects, including a decrease in T-cell proliferation in the central nervous system (CNS) and a decrease in the pro-inflammatory cytokines IL-17 and IFNγ [55][30]. Additionally, CBD treatment decreased inflammation and axonal loss in multiple sclerosis models engineered with myelin oligodendrocyte glycoprotein (MOG) to imitate EAE. The reason for this was that CBD inhibits the infiltration of T-cells and the activation of microglial cells, as reported in the study by Kozela et al. [56][31].

5. Therapeutic Potential of Cannabinoids

Cannabidiol has demonstrated encouraging effects in treating a range of medical conditions. Within the domain of epilepsy therapy, CBD has shown efficacy as an anticonvulsant medication, particularly in the treatment of severe childhood epilepsy syndromes such as Dravet syndrome and Lennox–Gastaut syndrome. Furthermore, CBD has been studied for its potential as an antidepressant, antipsychotic, and anxiolytic agent. Moreover, CBD has demonstrated an anticancer effect. While further research is necessary to comprehend its advantages fully, CBD exhibits promise as a reliable and efficient medication, indicating therapeutic implications for inflammation, neuroprotection, epilepsy, depression, and pain [57,58][32][33]. These findings support the potential therapeutic benefits of cannabinoids in managing neuroinflammation and its impact on MS-related pathology. Research has investigated the potential of cannabinoids to inhibit the progression of multiple sclerosis (MS) and provide neuroprotection in animal models. The results have varied under different experimental conditions, as specified in Table 1, and there have yet to be any human trials conducted with appropriate doses. CBD has demonstrated effectiveness in animal MS models and human cells tested in a laboratory setting. However, its impact on the immune system of MS patients is yet to be observed [59][34]. Individual variance and genetic polymorphism may point to distinct processes or responses to cannabinoids, leading to a reasoned explanation.
Table 1.
Clinical studies on the use of cannabinoids for the management of multiple sclerosis.

References

  1. Rouleau, I.; Dagenais, E.; Tremblay, A.; Demers, M.; Roger, É.; Jobin, C.; Duquette, P. Prospective memory impairment in multiple sclerosis: A review. Prospect. Mem. Clin. Popul. 2017, 32, 922–936.
  2. Gerhard, L.; Dorstyn, D.S.; Murphy, G.; Roberts, R.M. Neurological, physical and sociodemographic correlates of employment in multiple sclerosis: A meta-analysis. J. Health Psychol. 2020, 25, 92–104.
  3. Dutta, R.; Trapp, B.D. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 2007, 68 (Suppl. 3), S22–S31.
  4. Haddad, F.; Dokmak, G.; Karaman, R. The Efficacy of Cannabis on Multiple Sclerosis-Related Symptoms. Life 2022, 12, 682.
  5. Dąbrowski, G.; Skrajda, M. Cannabinoids from Cannabis sp.: Mechanism of their activity and potential health benefits in human body. J. Educ. Health Sport 2017, 7, 936–945.
  6. Touw, M. The Religious and Medicinal Uses of Cannabis in China, India and Tibet. J. Psychoact. Drugs 2012, 13, 23–34.
  7. Li, H.L. An Archaeological and Historical Account of Cannabis in China on JSTOR. Econ. Bot. 1974, 28, 437–448.
  8. Messam, C.A.; Hou, J.; Janabi, N.; Monaco, M.C.; Gravell, M.; Major, E.O. Glial Cell Types; Academic Press: New York, NY, USA, 2002; pp. 369–387.
  9. Kumar, M.R.P.; Vijayalakshmi, C.; Ramanathan, M. Isoflavones as Nutraceuticals in Stroke: Therapeutic Targets and Signaling Pathways. In Preedy Nutraceuticals, Supplements, and Herbal Medicine in Neurological Disorders; Martin, C.R., Patel, V.B., Preedy, V.R., Eds.; Academic Press: New York, NY, USA, 2023; Chapter 50; pp. 959–978.
  10. Meyer, H.C.; Lee, F.S.; Gee, D.G. The Role of the Endocannabinoid System and Genetic Variation in Adolescent Brain Development. Neuropsychopharmacology 2017, 43, 21–33.
  11. Ashton, J.C.; Friberg, D.; Darlington, C.L.; Smith, P.F. Expression of the cannabinoid CB2 receptor in the rat cerebellum: An immunohistochemical study. Neurosci. Lett. 2006, 396, 113–116.
  12. Gong, J.P.; Onaivi, E.S.; Ishiguro, H.; Liu, Q.R.; Tagliaferro, P.A.; Brusco, A.; Uhl, G.R. Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res. 2006, 1071, 10–23.
  13. Pérez, J. Combined cannabinoid therapy via an oromucosal spray. Drugs Today 2006, 42, 495–503.
  14. Puighermanal, E.; Busquets-Garcia, A.; Maldonado, R.; Ozaita, A. Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids. Philos. Trans. R Soc. B Biol. Sci. 2012, 367, 3254–3263.
  15. Gutiérrez-Rodríguez, A.; Bonilla-Del Río, I.; Puente, N.; Gómez-Urquijo, S.M.; Fontaine, C.J.; Egaña-Huguet, J.; Elezgarai, I.; Ruehle, S.; Lutz, B.; Robin, L.M.; et al. Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus. Glia 2018, 66, 1417–1431.
  16. Jimenez-Blasco, D.; Busquets-Garcia, A.; Hebert-Chatelain, E.; Serrat, R.; Vicente-Gutierrez, C.; Ioannidou, C.; Gomez-Sotres, P.; Lopez-Fabuel, I.; Resch-Beusher, M.; Resel, E.; et al. Glucose metabolism links astroglial mitochondria to cannabinoid effects. Nature 2020, 583, 603–608.
  17. Tucci, V. (Ed.) Handbook of Neurobehavioral Genetics and Phenotyping; John Wiley & Sons: Hoboken, NJ, USA, 2017; Available online: https://books.google.com.eg/books?hl=en&lr=&id=n7RpDgAAQBAJ&oi=fnd&pg=PA25&ots=P4OtI2xJyg&sig=tfTwPhLxsI_9J7uUHVj3bwiZqvM&redir_esc=y#v=onepage&q&f=false (accessed on 3 July 2022).
  18. Marsicano, G.; Goodenough, S.; Monory, K.; Hermann, H.; Eder, M.; Cannich, A.; Azad, S.C.; Cascio, M.G.; Gutiérrez, S.O.; Van der Stelt, M.; et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 2003, 302, 84–88.
  19. Kister, I.; Bacon, T.E.; Chamot, E.; Salter, A.R.; Cutter, G.R.; Kalina, J.T.; Herbert, J. Natural History of Multiple Sclerosis Symptoms. Int. J. MS Care 2013, 15, 146–156.
  20. Wegener, N.; Koch, M. Neurobiology and systems physiology of the endocannabinoid system. Pharmacopsychiatry 2009, 42 (Suppl. S1), S79–S86.
  21. Maresz, K.; Carrier, E.J.; Ponomarev, E.D.; Hillard, C.J.; Dittel, B.N. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J. Neurochem. 2005, 95, 437–445.
  22. Jean-Gilles, L.; Braitch, M.; Latif, M.L.; Aram, J.; Fahey, A.J.; Edwards, L.J.; Robins, R.A.; Tanasescu, R.; Tighe, P.J.; Gran, B.; et al. Effects of pro-inflammatory cytokines on cannabinoid CB 1 and CB 2 receptors in immune cells. Acta Physiol. 2015, 214, 63–74.
  23. Iuvone, T.; Esposito, G.; Esposito, R.; Santamaria, R.; Di Rosa, M.; Izzo, A.A. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on β-amyloid-induced toxicity in PC12 cells. J. Neurochem. 2004, 89, 134–141.
  24. Zhu, L.X.; Sharma, S.; Stolina, M.; Gardner, B.; Roth, M.D.; Tashkin, D.P.; Dubinett, S.M. Δ-9-Tetrahydrocannabinol Inhibits Antitumor Immunity by a CB2 Receptor-Mediated, Cytokine-Dependent Pathway. J. Immunol. 2000, 165, 373–380.
  25. Klein, T.W.; Kawakami, Y.; Newton, C.; Friedman, H. Marijuana components suppress induction and cytolytic function of murine cytotoxic T cells in vitro and in vivo. J. Toxicol. Environ. Health Part A Curr. Issues 2009, 32, 465–477.
  26. Nichols, J.M.; Kaplan, B.L.F. Immune Responses Regulated by Cannabidiol. Cannabis Cannabinoid. Res. 2020, 5, 12–31.
  27. Berdyshev, E.V.; Boichot, E.; Germain, N.; Allain, N.; Anger, J.P.; Lagente, V. Influence of fatty acid ethanolamides and Δ9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. Eur. J. Pharmacol. 1997, 330, 231–240.
  28. Sánchez, C.; Velasco, G.; Guzmán, M. Metabolic stimulation of mouse spleen lymphocytes by low doses of 9-tetrahydrocannabinol. Life Sci. 1997, 60, 1709–1717.
  29. Furgiuele, A.; Cosentino, M.; Ferrari, M.; Marino, F. Immunomodulatory potential of cannabidiol in multiple sclerosis: A systematic review. J. Neuroimmune Pharmacol. 2021, 16, 251–269.
  30. Elliott, D.M.; Singh, N.; Nagarkatti, M.; Nagarkatti, P.S. Cannabidiol attenuates experimental autoimmune encephalomyelitis model of multiple sclerosis through induction of myeloid-derived suppressor cells. Front. Immunol. 2018, 9, 1782.
  31. Kozela, E.; Lev, N.; Kaushansky, N.; Eilam, R.; Rimmerman, N.; Levy, R.; Ben-Nun, A.; Juknat, A.; Vogel, Z. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br. J. Pharmacol. 2011, 163, 1507–1519.
  32. Peng, J.; Fan, M.; An, C.; Ni, F.; Huang, W.; Luo, J. A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD). Basic Clin. Pharmacol. Toxicol. 2022, 130, 439–456.
  33. Bunman, S.; Muengtaweepongsa, S.; Piyayotai, D.; Charlermroj, R.; Kanjana, K.; Kaew-Amdee, S.; Makornwattana, M.; Kim, S. Analgesic and Anti-Inflammatory Effects of 1% Topical Cannabidiol Gel in Animal Models. Cannabis Cannabinoid Res. 2023; Ahead of Print.
  34. Maayah, Z.H.; Takahara, S.; Ferdaoussi, M.; Dyck, J.R.B. The anti-inflammatory and analgesic effects of formulated full-spectrum cannabis extract in the treatment of neuropathic pain associated with multiple sclerosis. Inflamm. Res. 2020, 69, 549–558.
  35. Nichols, J.M.; Kummari, E.; Sherman, J.; Yang, E.J.; Dhital, S.; Gilfeather, C.; Yray, G.; Morgan, T.; Kaplan, B.L. CBD Suppression of EAE Is Correlated with Early Inhibition of Splenic IFN-γ + CD8+ T Cells and Modest Inhibition of Neuroinflammation. J. Neuroimmune Pharmacol. 2021, 16, 346–362.
  36. Al-Ghezi, Z.Z.; Miranda, K.; Nagarkatti, M.; Nagarkatti, P.S. Combination of cannabinoids, Δ9-tetrahydrocannabinol and cannabidiol, ameliorates experimental multiple sclerosis by suppressing neuroinflammation through regulation of miRNA-mediated signaling pathways. Front. Immunol. 2019, 10, 1921.
  37. Nahas, G.G.; Morishima, A.; Desoize, B. Effects of cannabinoids on macromolecular synthesis and replication of cultured lymphocytes. Fed. Proc. 1977, 36, 1748–1752. Available online: https://europepmc.org/article/med/844617 (accessed on 13 June 2022).
  38. Derocq, J.M.; Ségui, M.; Marchand, J.; le Fur, G.; Casellas, P. Cannabinoids enhance human B-cell growth at low nanomolar concentrations. FEBS Lett. 1995, 369, 177–182.
  39. Yang, X.; Bam, M.; Nagarkatti, S.; Nagarkatti, M. Cannabidiol Regulates Gene Expression in Encephalitogenic T cells Using Histone Methylation and noncoding RNA during Experimental Autoimmune Encephalomyelitis. Sci. Rep. 2019, 9, 15780.
  40. Kozela, E.; Juknat, A.; Kaushansky, N.; Rimmerman, N.; Ben-Nun, A.; Vogel, Z. Cannabinoids decrease the Th17 inflammatory autoimmune phenotype. J. Neuroimmune Pharmacol. 2013, 8, 1265–1276.
  41. González-García, C.; Torres, I.M.; García-Hernández, R.; Campos-Ruíz, L.; Esparragoza, L.R.; Coronado, M.J.; Grande, A.G.; García-Merino, A.; López, A.J.S. Mechanisms of action of cannabidiol in adoptively transferred experimental autoimmune encephalomyelitis. Exp. Neurol. 2017, 298, 57–67.
  42. Klein, T.W.; Newton, C.; Friedman, H. Cannabinoid receptors and immunity. Immunol. Today 1998, 19, 373–381.
  43. Ojha, S.; Kumar, B. A review on nanotechnology based innovations in diagnosis and treatment of multiple sclerosis. J. Cell Immunother. 2018, 4, 56–64.
  44. Zeng, Y.; Li, Z.; Zhu, H.; Gu, Z.; Zhang, H.; Luo, K. Recent Advances in Nanomedicines for Multiple Sclerosis Therapy. ACS Appl. Bio. Mater. 2020, 3, 6571–6597.
  45. Gunasekaran, T.; Haile, T.; Nigusse, T.; Dhanaraju, M.D. Nanotechnology: An effective tool for enhancing bioavailability and bioactivity of phytomedicine. Asian Pac. J. Trop. Biomed. 2014, 4, S1–S7.
  46. Patel, V.R.; Agrawal, Y.K. Nanosuspension: An approach to enhance solubility of drugs. J. Adv. Pharm. Technol. Res. 2011, 2, 81.
  47. Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; Rodriguez-Torres, M.D.P.; Acosta-Torres, L.S.; Diaz-Torres, L.A.; Grillo, R.; Swamy, M.K.; Sharma, S.; et al. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 2018, 16, 71.
  48. Soares, S.; Sousa, J.; Pais, A.; Vitorino, C. Nanomedicine: Principles, Properties, and Regulatory Issues. Front. Chem. 2018, 6, 360.
  49. Wu, L.; Zhang, J.; Watanabe, W. Physical and chemical stability of drug nanoparticles. Adv. Drug Deliv. Rev. 2011, 63, 456–469.
  50. Rabinow, B.E. Nanosuspensions in drug delivery. Nat. Rev. Drug Discov. 2004, 3, 785–796.
  51. Patravale, V.B.; Date, A.A.; Kulkarni, R.M. Nanosuspensions: A promising drug delivery strategy. J. Pharm. Pharmacol. 2004, 56, 827–840.
  52. Goldsmith, M.; Abramovitz, L.; Peer, D. Precision Nanomedicine in Neurodegenerative Diseases. ACS Nano 2014, 8, 1958–1965.
  53. Griffith, J.I.; Rathi, S.; Zhang, W.; Zhang, W.; Drewes, L.R.; Sarkaria, J.N.; Elmquist, W.F. Addressing BBB Heterogeneity: A New Paradigm for Drug Delivery to Brain Tumors. Pharmaceutics 2020, 12, 1205.
  54. De Rosa, G.; Salzano, G.; Caraglia, M.; Abbruzzese, A. Nanotechnologies: A strategy to overcome blood-brain barrier. Curr. Drug Metab. 2012, 13, 61–69.
  55. Ferber, S.; Tiram, G.; Sousa-Herves, A.; Eldar-Boock, A.; Krivitsky, A.; Scomparin, A.; Yeini, E.; Ofek, P.; Ben-Shushan, D.; Vossen, L.I.; et al. Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome. eLife 2017, 6, e25281.
  56. Zhang, C.; Feng, W.; Vodovozova, E.; Tretiakova, D.; Boldyrevd, I.; Li, Y.; Kürths, J.; Yu, T.; Semyachkina-Glushkovskaya, O.; Zhu, D. Photodynamic opening of the blood-brain barrier to high weight molecules and liposomes through an optical clearing skull window. Biomed. Opt. Express 2018, 9, 4850–4862.
  57. Aryal, M.; Arvanitis, C.D.; Alexander, M.; McDannold, N. Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system. Adv. Drug Deliv. Rev. 2014, 72, 94–109.
  58. Song, K.-H.; Harvey, B.K.; Borden, M.A. State-of-the-art of microbubble-assisted blood-brain barrier disruption. Theranostics 2018, 8, 4393.
  59. Hwang, D.; Dismuke, T.; Tikunov, A.; Rosen, E.P.; Kagel, J.R.; Ramsey, J.D.; Lim, C.; Zamboni, W.; Kabanov, A.V.; Gershon, T.R. Poly (2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity. Nanomedicine 2021, 32, 102345.
  60. Sindhwani, S.; Syed, A.M.; Ngai, J.; Kingston, B.R.; Maiorino, L.; Rothschild, J.; MacMillan, P.; Zhang, Y.; Rajesh, N.U.; Hoang, T.; et al. The entry of nanoparticles into solid tumours. Nat. Mater. 2020, 19, 566–575.
  61. Tylawsky, D.E.; Kiguchi, H.; Vaynshteyn, J.; Gerwin, J.; Shah, J.; Islam, T.; Boyer, J.A.; Boué, D.R.; Snuderl, M.; Greenblatt, M.B.; et al. P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis. Nat. Mater. 2023, 22, 391–399.
  62. Calapai, F.; Cardia, L.; Sorbara, E.E.; Navarra, M.; Gangemi, S.; Calapai, G.; Mannucci, C. Cannabinoids, blood–brain barrier, and brain disposition. Pharmaceutics 2020, 12, 265.
  63. Adusumilli, N.C.; Hazuka, E.L.; Friedman, A.J. Nanotechnology to deliver cannabinoids in dermatology. Precis. Nanomed. 2021, 4, 787–794.
  64. Gajofatto, A.; Benedetti, M.D. Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? World J. Clin. Cases WJCC 2015, 3, 545.
  65. Lucas, C.J.; Galettis; Schneider, J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br. J. Clin. Pharmacol. 2018, 84, 2477.
  66. Millar, S.A.; Maguire, R.F.; Yates, A.S.; O’sullivan, S.E. Towards Better Delivery of Cannabidiol (CBD). Pharmaceuticals 2020, 13, 219.
  67. Grotenhermen, F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin. Pharmacokinet. 2003, 42, 327–360.
  68. Fraguas-Sánchez, A.I.; Fernández-Carballido, A.; Martin-Sabroso, C.; Torres-Suárez, A.I. Stability characteristics of cannabidiol for the design of pharmacological, biochemical and pharmaceutical studies. J. Chromatogr. B 2020, 1150, 122188.
  69. Onaivi, E.S.; Chauhan, B.P.S.; Sharma, V. Challenges of cannabinoid delivery: How can nanomedicine help? Nanomedicine 2020, 15, 2023–2028.
  70. Rebelatto, E.R.L.; Rauber, G.S.; Caon, T. An update of nano-based drug delivery systems for cannabinoids: Biopharmaceutical aspects & therapeutic applications. Int. J. Pharm. 2023, 635, 122727.
  71. Aparicio-Blanco, J.; Sebastián, V.; Benoit, J.P.; Torres-Suárez, A.I. Lipid nanocapsules decorated and loaded with cannabidiol as targeted prolonged release carriers for glioma therapy: In vitro screening of critical parameters. Eur. J. Pharm. Biopharm. 2019, 134, 126–137.
  72. Durán-Lobato, M.; Álvarez-Fuentes, J.; Fernández-Arévalo, M.; Martín-Banderas, L. Receptor-targeted nanoparticles modulate cannabinoid anticancer activity through delayed cell internalization. Sci. Rep. 2022, 12, 1–17.
  73. Bruni, N.; della Pepa, C.; Oliaro-Bosso, S.; Pessione, E.; Gastaldi, D.; Dosio, F. Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules 2018, 23, 2478.
  74. Stella, B.; Baratta, F.; della Pepa, C.; Arpicco, S.; Gastaldi, D.; Dosio, F. Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain. Drugs 2021, 81, 1513.
More
Video Production Service