INTRODUCTION:

Multiple Sclerosis (MS) is an autoimmune disorder accompanied by long-lasting inflammation, facilitated with autoreactive T-cells in the white matter of the central nervous system (CNS)¹, Besides, it is characterized by degeneration of oligodendrocytes which leads to the destruction of myelin sheath in the motor neurons, and it is one of the significant genesis for non-traumatic dysfunction in the younger population. Recent findings implicate that dysregulation of G protein-coupled receptors (GPCRs) contribute in the pathogenesis of MS through trigging T-cell invasion, antigen presentation, T-cell differentiation, cytokine production and T-cell proliferation².

In addition, demyelination and edema are the prevailing signs of neurological lesions of MS, caused by inflammatory cells crossing the blood-brain barrier (BBB) during disease progression.

MS is generally categorized into 4 types, i) Relapsing-remitting MS (RRMS), ii) Secondary progressive MS (SPMS), iii) Primary progressive MS (PPMS) and iv) Progressive relapsing MS (PRMS)³. Approximately, 65% of the people are affected with RRMS and further develops to SPMS. Around 10-15% of the people are diagnosed with PPMS, where it majorly affects the brain and spinal neurons in an excessive manner⁴ and the possibility of recovery rate is reported to be lower than the other types.

Histopathological studies using Luxol fast blue staining (LFB) in MS patients has showed more demyelinated lesions with abundant reduction in oligodendrocyte and microglial population^5–9. In chronic conditions, few myelin sheaths have also been observed with less stained area which reflects the possibility of remyelination of the neurons in MS^10,11.

Even though the exact reason causing oligodendrocyte death and myelin damage is yet to be discovered. It is widely accepted that pre-phagocytic phase occurs before full-sized myelin damage. Early lesions in MS patients who died immediately, were said to have a large proportion of oligodendrocytes with shrieked nuclei, but they didn't always exhibit the normal apoptotic features^12–15. Activated caspase-3 immunoreactivity was recurrently deficient in MS, which represents the alternative neuronal apoptotic pathways^16,17. In the early stage, the pre-phagocytic areas seem to be significant in LFB histopathological study and it denotes the importance of inflammatory responses mediated through pre-phagocytic mechanism in MS and it has been considered as one of the causative event of MS pathogenesis.^12,13,15,18.

Interestingly, in the recent years, the researchers are mainly focusing on adenosinergic system for MS through activation of adenosine A1 receptors. It has been found to exhibit the predominant anti-inflammatory and immunosuppressive activity in MS progression. Reports indicate that dysfunction of adenosinergic system promotes the neuroinflammatory cascades, and increases the stimulation of microglia/macrophage deteriorates, oligodendrocyte toxicity, demyelination and followed by axonal damage^19,20. Furthermore, the alteration in the function of the adenosinergic system and reduction of adenosine level is noticed in MS patients. Among the adenosinergic receptors, A1 receptors expression level was remarkably decreased in MS patients which is majorly required to prevent the demyelination of neurons through its anti-inflammatory and immunosuppressive mechanism. Also, the activation of A1 receptors could increase the adenosine level which could prevent the demyelination of motor neurons by suppressing the T-cell invasion, antigen presentation, T-cell differentiation, cytokine production and T-cell proliferation^2,20,21. Therefore, in this review, we have summarized the importance of adenosinergic A1 system in the prevention of MS disease progression and explored the beneficials of targeting adenosinergic A1 receptors by its agonists in MS.

Adenosinergic System:

Adenosine, a purine nucleoside which is present in each cell, acts through stimulating 4 types of G-proteins receptors; A1, A2A, A2B and A3. It also comprises of all characteristics of cell function, not only by activating G-proteins²² but also through P1 and P2Y (P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁R_S, P2Y₁₂, P2Y₁₃, P2Y₁₄R_S) receptors. Interestingly, A1 receptor actively participates in CNS functions through regulating the inflammatory responses and pro-inflammatory cytokines levels²³.

Adenosine modulates the inflammatory response by restricting macrophage activation is considered to be one of the protective mechanisms in the MS. Also, the endogenous adenosine acts along with bacterial components to enhance the PFKFB3 isozyme production, resulting in further fructose 2,6- bisphosphate accumulation. Overall, these processes increase glycolytic flux and favor ATP generation, it aids to compensate the energy failure in MS like neuro-degenerated conditions¹⁹.

Adenosine receptors performs various cell signaling functions by coupling with G proteins. Signaling occurs due to either activation or suppression of adenylyl cyclase and followed by reduction or rise in intracellular cyclic AMP (cAMP) concentrations. Moreover, A1 receptor stimulation has been associated with Gi protein facilitated suppression of adenyl cyclase along with regulation of different kinase pathways like protein kinase C (PKC), phosphoinositide kinase (PI3) and mitogen activated protein kinase (MAPK)²⁴. Hence, the regulation of various protein kinase pathways by adenosinergic system especially through A1 receptors can exert significant anti-neuroinflammatory and immunosuppressive activity in MS like conditions, where the autoimmune and inflammatory responses plays an imperative role that determines the disease severity.

Role of Adenosinergic System in Pathophysiology of Multiple Sclerosis:

The major cause for the neuronal damage in the MS is demyelination, yet it remains unclear. Few factors that might influence the MS pathology are ecological, hereditary factors or communicable mediators. Majorly, the pathogenesis of MS based on immune response can be classified into natural and adaptable responses in which the natural responses are due to the microbial endotoxin products that triggers the toll-like receptors (TLR) in neurons followed by inflammatory reactions. The specific endotoxin binding to TLR leads to the formation of cytokines which is further carried out as an adaptable response. Thus, naturally occurring responses involved in initiation as well as in the development of pathogenesis of adaptable responses by activation of T and B immune cells^25,26. In ordinary and wounded brain, the extracellular nucleotides either purines or pyrimidines are the most essential components in the protection of brain. It has been shown that not only ATP (adenosine triphosphate) but also adenosine is involved in neuroprotective mechanism in MS like conditions especially through preventing demyelination and neuroinflammation which is the major component resulting in MS.

Adenosine is reported to exhibit immunosuppressive and anti-inflammatory effects, thereby decreasing or altering in the functions of adenosine that leads to enhanced macrophage activation and inflammation in the CNS^19,27,28. Macrophage activation could be done when, binding of particular antigen to T lymphocytes and then initiates the adaptable responses by antigen presenting cells (APC) which contains the complexes of B cells, dendritic cells, microglia and macrophages. The communication between the APC and T cells phenotype (CD4+ and CD8+) are the major key factors to inducing the adaptable responses^25,29 which further activates the CD4+ (cluster differentiation 4+) cells through MHC proteins (major histocompatibility complex)³⁰. CD4+ cells have effector cells that are differentiated into definite cytokines such as Th1, Th2 and Th17. Furthermore, Th1 secretes interferon gamma, Th2 secretes IL-4 and IL-13 respectively. Importantly, Th17, recently identified phenotypes of CD4+ cell is found to secrete IL-17, IL-21, IL-22 and IL-26 (Il-interleukin), which majorly results in neuroinflammation and demyelination in MS patients²⁵. This CD4+ cells also increase the concentration of GM-CSF (granulocyte-macrophage colony-stimulating factor) level in the CSF (cerebral spinal fluid) of MS patients which promotes the immune mediated disease progression³¹. This GM-CSF contains MS associated polymorphism in the IL-2 receptor alpha gene^32,33. CD4+ mediated IL-17 release is specific because it leads to formation of MS plaques followed by demyelination and axonal loss, which is considered to be the major cause of MS. Along with CD4+ immune cells, the CD8+ cells also play a major role in MS abrasions and have a direct effect in the development of MS. The CD8+ also stimulates the CD4+ cell explosion due to perforin, which may execute the breakdown of axons and enables vascular permeability leading to the destruction of oligodendrocytes and followed by demylination²⁵ (Fig. 1). These CD4+ immune cells also interrupt the BBB directly and enters into brain parenchyma which initiates the loss of oligodendrocytes along with axonal damage leading to neuronal cell death³⁴. The above detrimental events are predominantly occurring in adenosinergic declined conditions.

Fig 1: Adenosinergic system in MS pathogenesis and possible role of A1 receptors agonist in prevention of disease progression.

In the pathology of MS, the activation of Antigen presenting cells (APC) by autoimmune reactions due to various factors, the major histocompatibility complex is activated and by which CD4+ T cells are stimulated. It further increases the concentration of granulocyte-macrophage colony-stimulating factor (GM-CSF). Further, GM-CSF, CD4+ T-cells along with their effector cells cross the BBB where the integrity of the BBB is disturbed because of adenosinergic system dysfunction. The crossed components activate the microglia and macrophages leads to pro-inflammatory cytokines storm. These neuroinflammatory responses mediate oligodendrocytes toxicity followed by drastic demyelination of motor neurons. The activation of A1AR receptors expressed in the surface of macrophages by its agonist could blocks the macrophage activation and neuroinflammatory responses thereby prevents the oligodendrocytes toxicity and demyelination.

A1AR (A1 Adenosine Receptor) Agonists as A Major Target for MS:

The development of MS in humans and experimental animals has been linked to A1 adenosine receptors dysfunction in the CNS. The A1 receptor is primarily expressed on monocyte/macrophage lineage cells in both brain and blood cells, which has been reported to be reduced in MS patients, lead to macrophage stimulation and CNS inflammation. This finding indicates that A1 receptors expression is required to suppress the neuro-inflammatory cascades and neurodegeneration. Reports implicate that lack of A1 receptors may exhibit suppression of anti-inflammatory genes and microglia/macrophages activation, which promotes the oligodendrocyte cytotoxicity, demyelination, and axonal injury. Experimental data indicates that adenosine A1 receptor agonist, N6-cyclohexyladenosine has protected the myelin sheath and reversed the demyelination in lysolecithin (LPC) induced demyelination rat model³⁵. It evidences that agonism of A1 receptors may represses the pro-inflammatory reactions, reduces oligodendrocyte cytotoxicity, and control the MS symptoms and demyelination¹⁹. ADORA2, an another specific A1AR agonist ameliorated the MS symptoms by its anti-inflammatory effects on T cells and exhibited protection at early stages of MS³⁵. A1AR agonists are also in the clinical trials for neuropathic pain because of its anti-neuroinflmmatory potential ³⁶. Adenosine A1 receptor agonist also protects against cisplatin indued ototoxicity by suppressing the inflammatory responses initiated by ROS generation via NOX3 and NADPH oxidase which evidences the anti-oxidant and anti-inflammatory ability in neuroinflammatory conditions³⁷.

CONCLUSION:

It can be concluded that the activation of A1AR exerts the anti-neuroinflammatory, antioxidant and immunosuppressive activity. Therefore, the A1AR agonists are the promising therapeutic agents for the management of MS like neurodegenerative and demyelinated conditions. As various factors are responsible for the progression of MS, it has become a big challenge to overcome the disease. Hence, planning a novel strategy to alter adenosinergic events could be a great tool to relieve the MS symptoms and prevent the disease progression.

ACKNOWLEDGEMENT:

The authors acknowledge the research infrastructure and generous support by JSS Academy of Higher Education and Research, Mysuru, India.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Hafler, D. A. Multiple Sclerosis. J. Clin. Invest. 2004, 113 (6), 788–794. https://doi.org/10.1172/JCI21357.

2. Du, C.; Xie, X. G Protein-Coupled Receptors as Therapeutic Targets for Multiple Sclerosis. Cell Res. 2012, 22 (7), 1108–1128. https://doi.org/10.1038/cr.2012.87.

3. Nylander, A.; Hafler, D. A. Multiple Sclerosis. J. Clin. Invest. 2012, 122 (4), 1180–1188. https://doi.org/10.1172/JCI58649.

4. Ghasemi, N.; Razavi, S.; Nikzad, E. Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. Yakhteh 2017, 19 (1), 1–10.

5. Boyd, A.; Zhang, H.; Williams, A. Insufficient OPC Migration into Demyelinated Lesions Is a Cause of Poor Remyelination in MS and Mouse Models. Acta Neuropathol. (Berl.) 2013, 125 (6), 841–859. https://doi.org/10.1007/s00401-013-1112-y.

6. Hametner, S.; Wimmer, I.; Haider, L.; Pfeifenbring, S.; Brück, W.; Lassmann, H. Iron and Neurodegeneration in the Multiple Sclerosis Brain. Ann. Neurol. 2013, 74 (6), 848–861. https://doi.org/10.1002/ana.23974.

7. Kuhlmann, T.; Miron, V.; Cui, Q.; Cuo, Q.; Wegner, C.; Antel, J.; Brück, W. Differentiation Block of Oligodendroglial Progenitor Cells as a Cause for Remyelination Failure in Chronic Multiple Sclerosis. Brain J. Neurol. 2008, 131 (Pt 7), 1749–1758. https://doi.org/10.1093/brain/awn096.

8. Wolswijk, G. Oligodendrocyte Survival, Loss and Birth in Lesions of Chronic-Stage Multiple Sclerosis. Brain J. Neurol. 2000, 123 ( Pt 1), 105–115. https://doi.org/10.1093/brain/123.1.105.

9. Zrzavy, T.; Hametner, S.; Wimmer, I.; Butovsky, O.; Weiner, H. L.; Lassmann, H. Loss of “homeostatic” Microglia and Patterns of Their Activation in Active Multiple Sclerosis. Brain J. Neurol. 2017, 140 (7), 1900–1913. https://doi.org/10.1093/brain/awx113.

10. Périer, O.; Grégoire, A. Electron Microscopic Features of Multiple Sclerosis Lesions. Brain J. Neurol. 1965, 88 (5), 937–952. https://doi.org/10.1093/brain/88.5.937.

11. Prineas, J. W.; Connell, F. Remyelination in Multiple Sclerosis. Ann. Neurol. 1979, 5 (1), 22–31. https://doi.org/10.1002/ana.410050105.

12. Barnett, M. H.; Prineas, J. W. Relapsing and Remitting Multiple Sclerosis: Pathology of the Newly Forming Lesion. Ann. Neurol. 2004, 55 (4), 458–468. https://doi.org/10.1002/ana.20016.

13. Henderson, A. P. D.; Barnett, M. H.; Parratt, J. D. E.; Prineas, J. W. Multiple Sclerosis: Distribution of Inflammatory Cells in Newly Forming Lesions. Ann. Neurol. 2009, 66 (6), 739–753. https://doi.org/10.1002/ana.21800.

14. Prineas, J. W.; Parratt, J. D. E. Oligodendrocytes and the Early Multiple Sclerosis Lesion. Ann. Neurol. 2012, 72 (1), 18–31. https://doi.org/10.1002/ana.23634.

15. Stadelmann, C.; Timmler, S.; Barrantes-Freer, A.; Simons, M. Myelin in the Central Nervous System: Structure, Function, and Pathology. Physiol. Rev. 2019, 99 (3), 1381–1431. https://doi.org/10.1152/physrev.00031.2018.

16. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination - PubMed https://pubmed.ncbi.nlm.nih.gov/10852536/ (accessed Apr 20, 2021).

17. Veto, S.; Acs, P.; Bauer, J.; Lassmann, H.; Berente, Z.; Setalo, G.; Borgulya, G.; Sumegi, B.; Komoly, S.; Gallyas, F.; Illes, Z. Inhibiting Poly (ADP-Ribose) Polymerase: A Potential Therapy against Oligodendrocyte Death. Brain J. Neurol. 2010, 133 (Pt 3), 822–834. https://doi.org/10.1093/brain/awp337.

18. Marik, C.; Felts, P. A.; Bauer, J.; Lassmann, H.; Smith, K. J. Lesion Genesis in a Subset of Patients with Multiple Sclerosis: A Role for Innate Immunity? Brain J. Neurol. 2007, 130 (Pt 11), 2800–2815. https://doi.org/10.1093/brain/awm236.

19. Sánchez-Gómez; Gonzalez Fernandez; Matute, C. Adenosine and Multiple Sclerosis. Adenosine Key Link Metab. Brain Act. 2013, 435–457. https://doi.org/10.1007/978-1-4614-3903-5_21.

20. Johnston, J. B.; Silva, C.; Gonzalez, G.; Holden, J.; Warren, K. G.; Metz, L. M.; Power, C. Diminished Adenosine A1 Receptor Expression on Macrophages in Brain and Blood of Patients with Multiple Sclerosis. Ann. Neurol. 2001, 49 (5), 650–658.

21. Mayne, M.; Shepel, P. N.; Jiang, Y.; Geiger, J. D.; Power, C. Dysregulation of Adenosine A1 Receptor-Mediated Cytokine Expression in Peripheral Blood Mononuclear Cells from Multiple Sclerosis Patients. Ann. Neurol. 1999, 45 (5), 633–639. https://doi.org/10.1002/1531-8249(199905)45:5<633:aid-ana12>3.0.co;2-x.

22. Jacobson, K. A.; Gao, Z.-G. Adenosine Receptors as Therapeutic Targets. Nat. Rev. Drug Discov. 2006, 5 (3), 247–264. https://doi.org/10.1038/nrd1983.

23. Adenosine-Associated Delivery Systems https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863639/ (accessed Feb 16, 2021).

24. Haskó, G.; Linden, J.; Cronstein, B.; Pacher, P. Adenosine Receptors: Therapeutic Aspects for Inflammatory and Immune Diseases. Nat. Rev. Drug Discov. 2008, 7 (9), 759–770. https://doi.org/10.1038/nrd2638.

25. Loma, I.; Heyman, R. Multiple Sclerosis: Pathogenesis and Treatment. Curr. Neuropharmacol. 2011, 9 (3), 409–416. https://doi.org/10.2174/157015911796557911.

26. Gandhi, R.; Laroni, A.; Weiner, H. L. Role of the Innate Immune System in the Pathogenesis of Multiple Sclerosis. J. Neuroimmunol. 2010, 221 (1–2), 7–14. https://doi.org/10.1016/j.jneuroim.2009.10.015.

27. Inoue, K.; Koizumi, S.; Tsuda, M. The Role of Nucleotides in the Neuron--Glia Communication Responsible for the Brain Functions. J. Neurochem. 2007, 102 (5), 1447–1458. https://doi.org/10.1111/j.1471-4159.2007.04824.x.

28. Apolloni, S.; Montilli, C.; Finocchi, P.; Amadio, S. Membrane Compartments and Purinergic Signalling: P2X Receptors in Neurodegenerative and Neuroinflammatory Events. FEBS J. 2009, 276 (2), 354–364. https://doi.org/10.1111/j.1742-4658.2008.06796.x.

29. Komiyama, Y.; Nakae, S.; Matsuki, T.; Nambu, A.; Ishigame, H.; Kakuta, S.; Sudo, K.; Iwakura, Y. IL-17 Plays an Important Role in the Development of Experimental Autoimmune Encephalomyelitis. J. Immunol. Baltim. Md 1950 2006, 177 (1), 566–573. https://doi.org/10.4049/jimmunol.177.1.566.

30. Alberts, B.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. T Cells and MHC Proteins. Mol. Biol. Cell 4th Ed. 2002.

31. Carrieri, P. B.; Provitera, V.; De Rosa, T.; Tartaglia, G.; Gorga, F.; Perrella, O. Profile of Cerebrospinal Fluid and Serum Cytokines in Patients with Relapsing-Remitting Multiple Sclerosis: A Correlation with Clinical Activity. Immunopharmacol. Immunotoxicol. 1998, 20 (3), 373–382. https://doi.org/10.3109/08923979809034820.

32. Monaghan, K. L.; Wan, E. C. K. The Role of Granulocyte-Macrophage Colony-Stimulating Factor in Murine Models of Multiple Sclerosis. Cells 2020, 9 (3), 611. https://doi.org/10.3390/cells9030611.

33. Dy, V.; G, K.; Pd, H.; M, B.; La, P.; P, van der V.; He, de V.; S, A.; Cd, D. GM-CSF Promotes Migration of Human Monocytes across the Blood Brain Barrier. Eur. J. Immunol. 2015, 45 (6), 1808–1819. https://doi.org/10.1002/eji.201444960.

34. Kaskow, B. J.; Baecher-Allan, C. Effector T Cells in Multiple Sclerosis. Cold Spring Harb. Perspect. Med. 2018, 8 (4). https://doi.org/10.1101/cshperspect.a029025.

35. Morandi, F.; Horenstein, A. L.; Rizzo, R.; Malavasi, F. The Role of Extracellular Adenosine Generation in the Development of Autoimmune Diseases https://www.hindawi.com/journals/mi/2018/7019398/ (accessed Jan 22, 2021). https://doi.org/10.1155/2018/7019398.

36. Gao, Z.-G.; Jacobson, K. A. Emerging Adenosine Receptor Agonists. Expert Opin. Emerg. Drugs 2007, 12 (3), 479–492. https://doi.org/10.1517/14728214.12.3.479.

37. Kaur, T.; Borse, V.; Sheth, S.; Sheehan, K.; Ghosh, S.; Tupal, S.; Jajoo, S.; Mukherjea, D.; Rybak, L. P.; Ramkumar, V. Adenosine A1 Receptor Protects Against Cisplatin Ototoxicity by Suppressing the NOX3/STAT1 Inflammatory Pathway in the Cochlea. J. Neurosci. 2016, 36 (14), 3962–3977. https://doi.org/10.1523/JNEUROSCI.3111-15.2016.

Received on 24.04.2021 Modified on 10.09.2021

Research J. Pharm. and Tech. 2022; 15(7):3025-3028.

DOI: 10.52711/0974-360X.2022.00505