7

Abstract: Multiple sclerosis is characterized by inflammatory processes occurring within the central nervous system. In multiple sclerosis, inflammation could be either a physiological response secondary to the immune system activation or a phenomenon triggered by primary cytodegeneration of neurons and/or oligodendrocytes without the involvement of immune cells. The arachidonic acid metabolism is activated via cyclooxygenases (COXs) and lipoxygenases (LOXs) in postmortem brain samples and in the cerebrospinal fluid of multiple sclerosis patients. It has been hypothesized that the arachidonic acid–mediated neuroinflammation could play a role in the pathogenic mechanisms triggering demyelination, oligodendrocyte loss, axonal pathology and, ultimately, motor dysfunctions, which are hallmarks of multiple sclerosis. COX-2 and 5-LOX selective inhibitors efficiently inhibit each of the hallmarks mentioned above in different animal models of multiple sclerosis. Thus, it is suggested that the arachidonic acid pathway represents a potential pharmacological target to ameliorate multiple sclerosis pathology and symptoms.

Keywords: Arachidonic acid; Cyclooxygenases; Inflammation; Lipoxygenases; Multiple sclerosis

Introduction

Multiple sclerosis is a multifactorial degenerative disease of the central nervous system characterized by immune system activation, inflammation, and demyelination. The genesis of the inflammatory process and its role in the onset and progression of the disease is still under debate, although advances have been made over the past decades of scientific research. For instance, it has been hypothesized that the central inflammation observed in multiple sclerosis is a physiological response secondary to the immune system activation. Different subtypes of CD4⁺ T helper lymphocytes—Th1 and Th17—and cytotoxic CD8⁺ lymphocytes have been shown to trigger neuroinflammation in multiple sclerosis (1). These activated lymphocytes migrate to the brain, recall peripheral monocytes/macrophages, and ultimately lead to myelin loss and apoptosis and/or necrosis of mature oligodendrocytes. Resident astrocytes and microglia are activated after lymphocytes infiltration. As a consequence, several inflammatory mediators like cytokines (chemokines, IL2, IL3, TNFα, IFNγ, and many others) are released by these cells in the extracellular compartment where they exert cytotoxic activity against oligodendrocytes (2–5).

In some types of multiple sclerosis, the disease seems to develop independently of the autoimmune mechanisms, particularity in those disease types—histological patterns III and IV—that show no evidence of immune activation at demyelinated lesions (6, 7). In these cases, inflammation maybe triggered by primary cytodegeneration of neurons and/or oligodendrocytes without the involvement of immune cells (8). Regardless of the biological process underlying inflammation, it has been consistently shown that inflammation is directly involved in the progression of multiple sclerosis (9). In recent years, there has been a growing interest in understanding the role of inflammatory mediators derived from the activation of arachidonic acid metabolism (e.g., prostaglandins and leukotrienes) in the disease (10). Prostaglandins and leukotrienes are abundantly produced in the central nervous system of multiple sclerosis patients, contributing to the severity of the disease. Therefore, it has been suggested that anti-inflammatory treatments targeting the arachidonic acid pathway, by using nonsteroidal anti-inflammatory drugs (NSAIDs), might be beneficial for treating multiple sclerosis.

Activation of the Arachidonic Acid Cascade in Multiple Sclerosis

Scientific evidences show that arachidonic acid metabolism is excessively activated in the central nervous system of multiple sclerosis patients as well as in the brain of animals from experimental models of multiple sclerosis. It has been hypothesized that arachidonic acid products could play a role in the pathogenic mechanisms underlying demyelination, oligodendrocytes loss, and axonal pathology that represent common hallmarks of multiple sclerosis. Arachidonic acid is a membrane omega-6 fatty acid molecule released in the cytoplasm by the hydrolytic activity of the cytosolic phospholipase A₂ (cPLA₂) (Figure 1). It has been shown that the concentration of several molecules that activate cPLA₂, such as reactive oxygen species and cytokines, is increased in multiple sclerosis (11–14). After being released into the cytoplasm, arachidonic acid is metabolized by the activity of cyclooxygenases (COXs) 1 and 2 into prostacyclins, prostaglandins (PGs), and thromboxanes (TXs), and by the lipoxygenases (LOXs), 5-LOX, 12-LOX and/or 15-LOX into leukotrienes (LTs) and lipoxins (LXs). As far as COXs are concerned, both isoforms lead to the production of PGE₂. COX-1 is constitutively expressed, whereas COX-2 is induced during inflammation and seems to be the major source of PGE₂ production. Particularly, COX-2 expression appears to be induced in oligodendrocytes and immune cells during the processes of demyelination (15–17). The proinflammatory PGs and LTs that are upregulated in multiple sclerosis represent promising therapeutic targets as suggested by animal models of multiple sclerosis.

Figure 1 Schematic representation of the arachidonic acid metabolic pathway. COX= cyclooxygenase, LOX= lipoxygenase, HPETE= hydroperoxyeicosatetraenoic acid.

ARACHIDONIC ACID PATHWAY ACTIVATION IN PATIENTS AFFECTED BY MULTIPLE SCLEROSIS

Arachidonic acid activation has been found in the cerebrospinal fluid and in postmortem brain of multiple sclerosis patients (see Table 1 for details of primary data). It has been shown that COX-2 is expressed in active demyelinating lesions (15), and also in dying oligodendrocytes (16) suggesting a potential role for COX-2 in the biological mechanisms underlying the death of oligodendrocytes. Moreover, COX-2 is also expressed by inflammatory cells like macrophages and microglia that are located at active lesions (17). These data are in line with previous findings showing that COX-derived prostaglandins are excessively produced in the central nervous system of multiple sclerosis patients. The levels of prostaglandins PGD₂, PGE₂, and PGF₂, and prostacyclin PGI₂, were upregulated in the cerebrospinal fluid of patients during relapsing and remitting phases (18–20). PGE₂ levels were also elevated in lymphocytes extracted from the peripheral blood of patients; the highest levels were reached at the onset of the disease or just before symptoms, suggesting that PGE₂ could be involved in disease initiation (21).

TABLE 1 Primary data concerning arachidonic acid pathway alterations in the CSF, brain tissue, and peripheral blood of multiple sclerosis patients and in the brain of EAE, TMEV, and cuprizone mice

		Multiple Sclerosis Patients	Animal Models of Multiple Sclerosis
			EAE model	TMEV model	Cuprizone model
Cyclooxygenase (COX) pathway	COX-1	NT	4-fold increase of mRNA (27); expressed in microglia/macrophages (29)	NT	Up to 30% increase in protein, 70% increase in mRNA (34); expressed in microglia and/or macrophages and astrocytes
	COX-2	Expressed in brain tissue within apoptotic oligodendrocytes and microglia and/or macrophages (15–17)	Up to 5-fold increase of mRNA (27,31); expressed in microglia and/or macrophages and in endothelial cells (28–29)	Expressed in apoptotic oligodendrocytes and in astrocytes (15–16)	No change in protein, 50% increase in mRNA (34); expressed in apoptotic oligodendrocytes (34, 35)
	PGD2	Expressed in the CSF of patients only (18)	No change—50% decreased levels (27,31)	NT	Up to 1-fold increased levels (34, 35)
	PGE2	Increased levels in the CSF (18–20) and in peripheral lymphocytes (21)	1-fold increased levels (27,31)	NT	Up to 5-fold increased levels (34, 35)
	PGF2α	Increased levels in the CSF (18–20)	No change (27)	NT	NT
	PGI2	Increased levels in the CSF (18)	2-fold increased levels (27)	NT	50% increased levels (34)
	TXA2	NT	NT	NT	NT
	TXB2	NT	50% decreased levels (27)	NT	Up to 1-fold increased levels (34, 35)
Lipoxygenase (LOX) pathway	5-LOX	NT	8-fold increase of mRNA (27)	NT	30% increase of protein, 3.5-fold increase of mRNA (39)
	12-LOX	NT	10-fold increase of mRNA (27)	NT	NT
	15-LOX	NT	10-fold increase of mRNA (27)	NT	NT
	LTB4	40–100% increase in the CSF (22, 23)	50% decrease (27)	NT	NT
	LTC4	0–30% increase in the CSF (18, 22, 23)	80% decrease (27)	NT	NT
	LTD4	No change in the CSF (23)	60% decrease (27)	NT	NT
	LTE4	No change in the CSF (23)	NT	NT	NT
	LXA4	NT	NT	NT	NT
	LXB4	NT	NT	NT	NT

NT= not tested, CSF= cerebrospinal fluid, PG= prostaglandin, TX= tromoxane, LT= leukotriene, LX=lipoxin, EAE= experimental autoimmune encephalomyelitis, TMEV= Theiler’s murine encephalomyelitis virus.

As far as the metabolism of arachidonic acid by LOX enzymes is concerned, the levels of LTB₄ and LTC₄ in the cerebrospinal fluid of multiple sclerosis patients were elevated (18, 22). The same authors, in their second publication on the same topic, were able to replicate the results for LTB₄, but not for LTC₄, LTD₄, and LTE₄ levels (23). Overall, these data have suggested that, in multiple sclerosis, the metabolism of arachidonic acid through 5-LOX enzymatic activity was augmented. In 2010, a study, conducted in postmortem white matter specimens of multiple sclerosis patients, identified the 5-LOX gene as a top risk gene for multiple sclerosis (24).

ARACHIDONIC ACID PATHWAY ACTIVATION IN ANIMAL MODELS OF MULTIPLE SCLEROSIS

The arachidonic acid metabolic pathway is activated in three different animal models of multiple sclerosis: the experimental autoimmune encephalomyelitis (EAE), the Theiler’s murine encephalomyelitis virus (TMEV), and the cuprizone model (see Table 1 for details of primary data). In the EAE model, the upstream enzyme cPLA₂ has been shown to play a key role in the pathogenesis of the disease as cPLA₂ knockout mice and naïve mice treated with a cPLA₂ specific inhibitor were both resistant to EAE induction (25, 26). Downstream cPLA₂, COX-2, inducible PGE₂ synthase, and PGE₂ levels were all increased in the brain of EAE mice (27). COX-2 was expressed in the resident microglia, infiltrating macrophages, and endothelial cells of the brain of EAE mice (28–29). Concerning the four receptors of PGE₂, EP1, EP2, and EP4 were upregulated by one-, two-, and threefold, respectively (30). EP2 and EP4 have been implicated in the stimulation of lymphocytes CD4+ release and their activation in EAE model (30). Moreover, COX-1 expression and PGI₂ levels were upregulated in the brain of EAE mice, whereas the concentration of PGD₂ was downregulated, and the concentration of PGF_2α was unchanged (27). However, one study conducted in a chronic relapsing type of EAE showed conflicting findings. While the increase of COX-1, COX-2, and PGE₂ was confirmed, the PGD₂ levels remained unchanged in all the analyzed brain tissues (cerebral cortex, cerebellum, and spinal cord) (31). Interestingly, the increase of COX-2 expression and PGE₂ levels was observed in early stages of the disease (31), suggesting a pathogenic role.

In the TMEV model, COX-2 expression was observed in the spinal cord (15). Specifically, COX-2 was expressed in oligodendrocytes undergoing apoptosis as indicated by immunohistochemistry experiments that found colocalization of the COX-2 protein and the apoptotic mediator caspase-3. These data were confirmed in a further study published in 2010 (16). The latter also showed that COX-2 mediates mechanisms of excitotoxicity against cultured oligodendrocytes (16). COX-2 and PGE₂ gene expression were also found in primary cultures of astrocytes from TMEV-infected mice (32). The inhibition of PGE₂ signaling at a downstream level using AH23848, which is a mixed EP1 and EP4 inhibitor, resulted in decreased pathogenesis of demyelinating disease (about 20% decrease) and severity of viral load (about 85% decrease) in the central nervous system (33).

Similar results were obtained in the cuprizone model of demyelination. Cuprizone takes about 5 to 6 weeks to induce a maximum demyelination in the brain, but oligodendrocytes express apoptotic markers earlier, starting from the first week of intoxication (34). In the brain of cuprizone-treated mice, both COX-1 and COX-2 were significantly upregulated, but the change in the expression showed different courses (34). COX-2 gene expression was found to be upregulated in the early phases of the cuprizone treatment when demyelination was not yet detectable, whereas COX-1 was upregulated later on at the peak of astrogliosis and microglia and/or macrophages activation concomitantly with severe demyelination (34). Interestingly, this observation led to the hypothesis that COX-2 precedes oligodendrocytes loss and is involved in the apoptotic processes. COX-2 was expressed in apoptotic caspase-3-expressing oligodendrocytes as early as after 1 week of cuprizone treatment (35). Further investigation in the COX-2 pathway showed that the cortical levels of several prostaglandins (PGE₂, PGD₂, PGI₂, and TXB₂), were upregulated (34, 35). The increase in PGE₂ concentration was more than the other prostaglandins, and the expression of its receptors, EP1, EP2, and EP4, was upregulated at the peak of demyelination (35). Interestingly, only EP2 protein expression was increased in the early stage, after 1 week of cuprizone treatment, and has been implicated in the initiation of demyelination and oligodendrocytes loss (35).

Regarding LOXs, there is an increasing consent supporting the role of 5-LOX and its downstream products in the mechanisms of immune cell recall in the brain, and in the development of axonal damage and of motor disabilities. The 5-LOX gene was found to be a top risk gene in EAE (24). The brain concentrations of 5-LOX products, LTB₄ and LTD₄, were upregulated (18, 22–23), and favored the migration of inflammatory cells and lymphocytes in the brain of EAE mice (36–38). In the cuprizone model, the brain expression of 5-LOX was highly increased (39). In addition, 5-LOX has been implicated in cuprizone-mediated axonal damage and motor dysfunction development (39). Overall, the data generated from the animal research indicate that the arachidonic acid pathway contributes to the development of multiple sclerosis–like pathology, especially via COX-2 and 5-LOX metabolism.

Anti-inflammatory Therapy in Multiple Sclerosis

Arachidonic acid–mediated inflammation is typically inhibited with nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs have variable specificity against the two isoforms of COX. While some NSAIDs (e.g., ibuprofen, indomethacin, and naproxen), have mixed inhibitory effect on both COX-1 and COX-2 others, like the coxibs (e.g., celecoxib, rofecoxib, and valdecoxib) and nimesulide, specifically inhibit COX-2 (40). NSAIDs have been administered to patients affected by multiple sclerosis to counteract symptoms related to flu, but no clinical trials have ever evaluated whether NSAIDs could reduce multiple sclerosis pathology as well. Animal models of multiple sclerosis have demonstrated the beneficial effects of NSAIDs. Furthermore, the pharmacological inhibition of LOX-mediated metabolism of arachidonic acid exerts some beneficial effects. The following paragraphs describe the available evidence on the potential of COX and LOX inhibitors as therapeutics for multiple sclerosis.

NSAIDs TREATMENT IN PATIENTS AFFECTED BY MULTIPLE SCLEROSIS

It is not known whether NSAIDs have an inhibitory effect on the pathology of multiple sclerosis. To date, NSAIDs have been administered to patients to treat flu-like symptoms without taking into consideration of their potential role in oligodendrocytes survival and myelin protection (41–46). Nevertheless, some NSAIDs were shown to ameliorate fatigue (approximate percentage of improvement: 10–20% with aspirin, 30% with naproxen, and 20% with ibuprofen) and improve cognitive abilities (approximate fold change of improvement: 1-fold with naproxen, 0.5-fold with ibuprofen, and 2-fold with acetaminophen) (46, 47). It could be hypothesized that these effects may be secondary to the attenuation of brain pathology due to NSAIDs treatment, as suggested by the following data from experimental models of multiple sclerosis.

EFFECT OF NSAIDs IN ANIMAL MODELS OF MULTIPLE SCLEROSIS

Non-selective COX inhibitors and COX-2 selective drugs have shown protective effects in EAE, cuprizone and TMEV murine models of multiple sclerosis. In the EAE model, mixed COX-1/2 inhibitors (indometacin and naproxen) delayed the onset (about 8 days delay with naproxen) and the severity of the disease (about 30% improvement with indometacin and 70% with naproxen) (26, 48, 49). In the cuprizone model, COX-1 knockout mice normally develop demyelination in the same extent as matched wild type mice, indicating that COX-1 is not involved in the demyelination process. Conversely, knocking out the COX-2 gene inhibited demyelination (about 40% inhibition in the corpus callosum and complete recovery in the cortex) and restored motor functions (35).

Selective targeting of COX-2 has provided a large number of evidence, supporting the prominent role of this isoform in disease initiation and severity. The administration of selective COX-2 inhibitors (LM01, LM08, LM11, and NS398), or coxibs (rofecoxib, celecoxib, and lumiracoxib) interfered with EAE induction by decreasing physical dysfunctions, inflammation, and demyelination; the protective effects of these compounds were mediated through the inhibition of adhesion and chemoattractant molecules, and the reduction of monocyte infiltration (48–51). Specifically, LM01, LM08, LM11, and NS398 inhibited the paralysis period (percentage inhibition: 48, 95, 76, and 43, respectively), inflammation (percentage inhibition: 85, 84, 78, and 81, respectively), and demyelination (percentage inhibition: 74, 67, 53, and 61, respectively) (50). Celecoxib prevented EAE induction, reduced the expression of adhesion and chemoattractant molecules (histological nonquantitative data), and inhibited the number of infiltrating monocytes (49). Rofecoxib and lumiracoxib reduced inflammation by 90% and 85%, respectively (51).

In the TMEV model, the COX-2 selective inhibitor CAY10542, reduced demyelination by 25%, and prevented the death of oligodendrocytes (16). The efficacy of COX-2 targeting has been confirmed in the cuprizone model as well, as celecoxib greatly reduced demyelination (about 30% reduction in the corpus callosum and complete recovery in the cortex) along with a full recovery of motor abilities (35). In this model, COX-2 expression exerts deleterious effects on the oligodendrocytes through the production of PGE₂, with in turn contributes to loss of oligodendrocytes by interacting with the EP2 receptor: the administration of an EP2 antagonist to cuprizone mice showed similar protective effects as the ones induced by celecoxib (35).EAE mice treated with an inhibitor of cPLA₂ showed marked beneficial activity (about 85% inhibition of disease severity) (26). Because of this observation, the question arises whether, the protective effect is mediated merely through the inhibition of the COX pathway or the inhibition of LOX activity is also involed. It has been shown that 5-LOX selective inhibition delayed the onset of EAE by about 5 days (26). Similarly, in the cuprizone model, 5-LOX inhibition resulted in reduced axonal pathology and ameliorated motor disabilities without any improvement in the demyelination severity (39). Overall, these data suggest that COX-2 and 5-LOX inhibition have some nonoverlapping activities (52).

NSAIDs Administration: Future Perspectives

Most of the currently available pharmacological medications for multiple sclerosis counteract the activity of the autoimmune system. Lymphocytes are the leading factors in the autoimmune-mediated mechanisms implicated in the disruption of myelin proteins and the death of oligodendrocytes. First-generation drugs (interferons and glatiramer acetate) and second-generation drugs (fingolimod, mitoxantrone, rituximab, ocrelizumab, ofatumumab, and others) reduce disease severity, progression, and relapses; their main mechanism of action include sequestration of lymphocytes in the lymph node, and reduction of their access to the brain (53–56). However, these drugs do not directly target the arachidonic acid metabolism. Based on the literature, NSAIDs are currently administered to patients if flu-like symptoms occur. However, growing evidence supports the hypothesis that COX-2 and 5-LOX enzymes promote downstream mechanisms that ultimately lead to oligodendrocyte degeneration and axon pathology, respectively, and that both contribute to the development of motor disabilities. The combination of COX-2 and 5-LOX selective inhibitors has the potential to improve multiple sclerosis pathology. Moreover, multiple sclerosis has been associated with platelet activation and augmented cardiovascular risk, which are considered as causal factors in the pathogenesis of the disease (57, 58). Interestingly, it has been recently observed that peripheral blood platelets of patients highly express COX-2 (58). In the light of these evidence, the administration of COX-2 selective NSAIDs could reduce both cardiovascular risk and the progression of multiple sclerosis.

Conclusion

Several pharmacological studies, conducted in experimental animal models of multiple sclerosis, suggest that NSAIDs that selectively inhibit the COX-2 isoform represent promising medications for reducing oligodendrocytes apoptosis, demyelination, and motor dysfunction. In addition, it is suggested that 5-LOX inhibitors could be beneficial to counteract axonal pathology and to inhibit motor disabilities as well. The coadministration of COX-2 and 5-LOX inhibitor is a promising way forward for multiple sclerosis treatment.

Conflict of interest: The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

Copyright and permission statement: To the best of my knowledge, the materials included in this chapter do not violate copyright laws. All original sources have been appropriately acknowledged and/or referenced. Where relevant, appropriate permissions have been obtained from the original copyright holder(s).

REFERENCES

1. McFarland HF, Martin R. Multiple sclerosis: A complicated picture of autoimmunity. Nat Immunol. 2007Sep;8(9):913–19. http://dx.doi.org/10.1038/ni1507
2. Benveniste EN, Merrill JE. Stimulation of oligodendroglial proliferation and maturation by interleukin-2. Nature. 1986 Jun;321(6070):610–13. http://dx.doi.org/10.1038/321610a0
3. Renner K, Hellerbrand S, Hermann F, Riedhammer C, Talke Y, Schiechl G., et al. IL-3 promotes the development of experimental autoimmune encephalitis. JCI Insight. 2016 Oct;1(16):e87157. http://dx.doi.org/10.1172/jci.insight.87157
4. Zajicek JP, Wing NJ, Scolding DA. Compston, interactions between oligodendrocytes and microglia. A major role for complement and tumour necrosis factor in oligodendrocyte adherence and killing. Brain. 1992 Dec:115(Pt 6):1611–31. http://dx.doi.org/10.1093/brain/115.6.1611-a
5. Vartanian T, Li M, Zhao M, Stefansson K. Interferon-gamma-induced oligodendrocyte cell death: Implications for the pathogenesis of multiple sclerosis. Mol Med. 1995 Nov;1(7):732–43
6. Lucchinetti CF, Bruck W, Rodriguez M, Lassmann H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol. 1996 Jul;6(3):259–74. http://dx.doi.org/10.1111/j.1750-3639.1996.tb00854.x
7. Lassmann H. Cortical lesions in multiple sclerosis: Inflammation versus neurodegeneration. Brain. 2012 Oct;135(Pt 10):2904–5. http://dx.doi.org/10.1093/brain/aws260
8. Stys PK. Multiple sclerosis: Autoimmune disease or autoimmune reaction? Can J Neurol Sci. 2010 Sep;37(Suppl 2):16–23. http://dx.doi.org/10.1017/S0317167100022393
9. Pérez-Cerdá F, Sánchez-Gómez MV and Matute C. The link of inflammation and neurodegeneration in progressive multiple sclerosis. Multiple Sclerosis and Demyelinating Disorders. Cross Mark. 2016 July;1:9. https://doi.org/10.1186/s40893-016-0012-0
10. Palumbo S, Bosetti F. Alterations of brain eicosanoid synthetic pathway in multiple sclerosis and in animal models of demyelination: Role of cyclooxygenase-2. Prostaglandins Leukot Essent Fatty Acids. 2013 Sep;89(5):273–8. http://dx.doi.org/10.1016/j.plefa.2013.08.008
11. Rajda C, Pukoli D, Bende Z, Majláth Z, Vécsei L. Excitotoxins, mitochondrial and redox disturbances in multiple sclerosis. Int J Mol Sci. 2017 Feb;18(2):353. http://dx.doi.org/10.3390/ijms18020353
12. Kiekkas P, Aretha D, Karga M, Karanikolas M. Self report may lead to underestimation of ‘wrong dose’ medication errors. Br J Clin Pharmacol. 2009 Dec;68(6):963–4. http://dx.doi.org/10.1111/j.1365-2125.2009.03530.x
13. Burman J, Svensson E, Fransson M, Loskog ASI, Zetterberg H, Raininko R, et al. The cerebrospinal fluid cytokine signature of multiple sclerosis: A homogenous response that does not conform to the Th1/Th2/Th17 convention. J Neuroimmunol. 2014;277:153–9. http://dx.doi.org/10.1016/j.jneuroim.2014.10.005
14. Khaibullin T, Ivanova V, Martynova E, Cherepnev G, Khabirov F, Granatov E, et al. Elevated levels of proinflammatory cytokines in cerebrospinal fluid of multiple sclerosis patients. Front Immunol. 2017 Oct;8(1/2):531. http://dx.doi.org/10.3389/fimmu.2017.00531
15. Carlson NG, Hill KE, Tsunoda I, Fujinami RS, Rose JW. The pathologic role for COX-2 in apoptotic oligodendrocytes in virus induced demyelinating disease: Implications for multiple sclerosis. J Neuroimmunol. 2006 Mar;174(1/2):21–31. http://dx.doi.org/10.1016/j.jneuroim.2006.01.008
16. Carlson NG, Rojas MA, Redd JW, Tang P, Wood B, Hill KE, et al. Cyclooxygenase-2 expression in oligodendrocytes increases sensitivity to excitotoxic death. J Neuroinflammation. 2010 Apr; 7:25. http://dx.doi.org/10.1186/1742-2094-7-25
17. Rose JW, Hill KE, Watt HE, Carlson NG. Inflammatory cell expression of cyclooxygenase-2 in the multiple sclerosis lesion. J Neuroimmunol. 2004 Mar;149(1/2):40–9. http://dx.doi.org/10.1016/j.jneuroim.2003.12.021
18. Dore-Duffy P, Ho SY, Donovan C. Cerebrospinal fluid eicosanoid levels: Endogenous PGD2 and LTC4 synthesis by antigen-presenting cells that migrate to the central nervous system. Neurology. 1991 Feb;41(2 Pt 1):322–4. http://dx.doi.org/10.1212/WNL.41.2_Part_1.322
19. Rosnowska M, Cendrowski W, Sobocinnska Z, Wieczorkiewicz A. Prostaglandins E2 and F2 alpha in the cerebrospinal fluid in patients with multiple sclerosis. Acta Med Pol. 1981 Jan;22(1):97–103.
20. Bolton C, Turner AM, Turk JL. Prostaglandin levels in cerebrospinal fluid from multiple sclerosis patients in remission and relapse. J Neuroimmunol. 1984; Jun;6(3):151–9. http://dx.doi.org/10.1016/0165-5728(84)90002-X
21. Dore-Duffy P, Donaldson JO, Koff T, Longo M, Perry W. Prostaglandin release in multiple sclerosis: Correlation with disease activity. Neurology 1986 Dec;36(12):1587–90. http://dx.doi.org/10.1212/WNL.36.12.1587
22. Neu I, Mallinger J, Wildfeuer A, Mehlber L. Leukotrienes in the cerebrospinal fluid of multiple sclerosis patients. Acta Neurol Scand. 1992 Dec;86(6):586–7. http://dx.doi.org/10.1111/j.1600-0404.1992.tb05491.x
23. Neu IS, Metzger G, Zschocke J, Zelezny R, Mayatepek E. Leukotrienes in patients with clinically active multiple sclerosis. Acta Neurol Scand. 2001 Mar; 105(1):63–6. http://dx.doi.org/10.1034/j.1600-0404.2002.00070.x
24. Whitney LW, Ludwin SK, McFarland HF, Biddison WE. Microarray analysis of gene expression in multiple sclerosis and EAE identifies 5-lipoxygenase as a component of inflammatory lesions. J Neuroimmunol. 2001 Dec;12(1/2):40–8. http://dx.doi.org/10.1016/S0165-5728(01)00438-6
25. Marusic S, Leach MW, Pelker JW, Azoitei ML, Uozumi N, Cui J, et al. Cytosolic phospholipase A2 alpha-deficient mice are resistant to experimental autoimmune encephalomyelitis. J Exp Med. 2005 Sep;202(6):841–51. http://dx.doi.org/10.1084/jem.20050665
26. Marusic S, Thakker P, Pelker JW, Stedman NL, Lee KL, McKew JC, et al. Blockade of cytosolic phospholipase A2 alpha prevents experimental autoimmune encephalomyelitis and diminishes development of Th1 and Th17 responses. J Neuroimmunol. 2008 Oct;204(1/2):29–37. http://dx.doi.org/10.1016/j.jneuroim.2008.08.012
27. Kihara Y, Matsushita T, Kita Y, Uematsu S, Akira S, Kira J, et al. Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. Proc Natl Acad Sci U S A. 2009 Dec 10;106(51):21807–12. http://dx.doi.org/10.1073/pnas.0906891106
28. Aloisi F, Serafini B, Adorini L. Glia-T cell dialogue. J Neuroimmunol. 2000 Jul 24;107(2):111. http://dx.doi.org/10.1016/S0165-5728(00)00231-9
29. Deininger MH, Schluesener HJ. Cyclooxygenases-1 and -2 are differentially localized to microglia and endothelium in rat EAE and glioma. J Neuroimmunol. 1999 Mar;95(1/2):202–8. http://dx.doi.org/10.1016/S0165-5728(98)00257-4
30. Esaki Y, Li Y, Sakata D, Yao C, Segi-Nishida E, Matsuoka T, et al. Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2010 Jun 23;107(27):12233–8. http://dx.doi.org/10.1073/pnas.0915112107
31. Ayoub SS, Wood EG, Hassan SU, Bolton C. Cyclooxygenase expression and prostaglandin levels in central nervous system tissues during the course of chronic relapsing experimental autoimmune encephalomyelitis (EAE). Inflamm Res. 2011 Jun;60(10):919–28. http://dx.doi.org/10.1007/s00011-011-0352-3
32. Molina-Holgado E, Arévalo-Martín A, Ortiz S, Vela JM, Guaza C. Theiler’s virus infection induces the expression of cyclooxygenase-2 in murine astrocytes: Inhibition by the anti-inflammatory cytokines interleukin-4 and interleukin-10. Neurosci Lett. 2002 May;324(3):237–41. http://dx.doi.org/10.1016/S0304-3940(02)00209-4
33. Kim SJ, Jin YH, Kim BS. Prostaglandin E2 produced following infection with Theiler’s virus promotes the pathogenesis of demyelinating disease. PLoS One. 2017 Apr;12(4):e0176406. http://dx.doi.org/10.1371/journal.pone.0176406
34. Palumbo S, Toscano CD, Parente L, Weigert R, Bosetti F. Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination. Prostaglandins Leukot Essent Fatty Acids. 2011 Jul;85(1):29–35. http://dx.doi.org/10.1016/j.plefa.2011.04.001
35. Palumbo S, Toscano CD, Parente L, Weigert R, Bosetti F. The cyclooxygenase-2 pathway via the PGE(2) EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination. J Neurochem. 2011 May;121(3):418–27. http://dx.doi.org/10.1111/j.1471-4159.2011.07363.x
36. Kihara Y, Yokomizo T, Kunita A, Morishita Y, Fukayama M, Ishii S, et al. The leukotriene B4 receptor, BLT1, is required for the induction of experimental autoimmune encephalomyelitis. Biochem Biophys Res Commun. 2010;Apr 9;394(3):673–8. http://dx.doi.org/10.1016/j.bbrc.2010.03.049
37. Lee W, Su Kim H, Lee GR. Leukotrienes induce the migration of Th17 cells. Immunol Cell Biol. 2015 May–Jun;93(5):472–9. http://dx.doi.org/10.1038/icb.2014.104
38. Wang L, Du C, Lv J, Wei W, Cui Y, Xie X. Antiasthmatic drugs targeting the cysteinyl leukotriene receptor 1 alleviate central nervous system inflammatory cell infiltration and pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 2011 Sep;187(5):2336–45. http://dx.doi.org/10.4049/jimmunol.1100333
39. Yoshikawa K, Palumbo S, Toscano CD, Bosetti F. Inhibition of 5-lipoxygenase activity in mice during cuprizone-induced demyelination attenuates neuroinflammation, motor dysfunction and axonal damage. Prostaglandins Leukot Essent Fatty Acids. 2011 Jul;85(1):43–52. http://dx.doi.org/10.1016/j.plefa.2011.04.022
40. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001 Aug;345(6):433–42. http://dx.doi.org/10.1056/NEJM200108093450607
41. Munschauer FE, Kinkel RP. Managing side effects of interferon-beta in patients with relapsing-remitting multiple sclerosis. Clin Ther. 1997 Jan;19(5):883–93. http://dx.doi.org/10.1016/S0149-2918(97)80042-2
42. Reess J, Haas J, Gabriel K, Fuhlrott A, Fiola M. Both paracetamol and ibuprofen are equally effective in managing flu-like symptoms in relapsing-remitting multiple sclerosis patients during interferon beta-1a (AVONEX) therapy. Mult Scler. 2002 Apr;8(1):15–18. http://dx.doi.org/10.1191/1352458502ms771sr
43. Mora JS, Kao KP, Munsat TL. Indomethacin reduces the side effects of intrathecal interferon. N Engl J Med. 1984 Jan;310(2):126–7. http://dx.doi.org/10.1056/NEJM198401123100219
44. Río J, Nos C, Bonaventura I, Arroyo R, Genis D, Sureda B, et al. Corticosteroids, ibuprofen, and acetaminophen for IFNbeta-1a flu symptoms in MS: A randomized trial. Neurology. 2004 Aug;63(3):525–8. http://dx.doi.org/10.1212/01.WNL.0000133206.44931.25
45. Brandes DW, Bigley K, Hornstein W, Cohen H, Au W, Shubin R. Alleviating flu-like symptoms with dose titration and analgesics in MS patients on intramuscular interferon beta-1a therapy: A pilot study. Curr Med Res Opin. 2007 Jul;23(7):1667–2. http://dx.doi.org/10.1185/030079907X210741
46. Leuschen MP, Filipi M, Healey K. A randomized open label study of pain medications (naproxen, acetaminophen and ibuprofen) for controlling side effects during initiation of IFN beta-1a therapy and during its ongoing use for relapsing-remitting multiple sclerosis. Mult Scler. 2004 Dec;10(6):636–42. http://dx.doi.org/10.1191/1352458504ms1114oa
47. Wingerchuk DM, Benarroch EE, O’Brien PC, Keegan BM, Lucchinetti CF, Noseworthy JH, et al. A randomized controlled crossover trial of aspirin for fatigue in multiple sclerosis. Neurology. 2005 Apr;64(7):1267–9. http://dx.doi.org/10.1212/01.WNL.0000156803.23698.9A
48. Reder AT, Thapar M, Sapugay AM, Jensen MA. Eicosenoids modify experimental allergic encephalomyelitis. Am J Ther. 1995 Sep;2(9):711–20. http://dx.doi.org/10.1097/00045391-199509000-00020
49. Miyamoto K, Miyake S, Mizuno M, Oka N, Kusunoki S, Yamamura T. Selective COX-2 inhibitor celecoxib prevents experimental autoimmune encephalomyelitis through COX-2-independent pathway. Brain. 2006 Aug;129(Pt 8):1984–92. http://dx.doi.org/10.1093/brain/awl170
50. Muthian G, Raikwar HP, Johnson C, Rajasingh J, Kalgutkar A, Marnett LJ, et al. COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis. J Clin Immunol. 2006 Jan;26(1):73–85. http://dx.doi.org/10.1007/s10875-006-8787-y
51. Ni J1, Shu YY, Zhu YN, Fu YF, Tang W, Zhong XG, et al. COX-2 inhibitors ameliorate experimental autoimmune encephalomyelitis through modulating IFN-gamma and IL-10 production by inhibiting T-bet expression. J Neuroimmunol. 2007;May;186(1/2):94–103. http://dx.doi.org/10.1016/j.jneuroim.2007.03.012
52. Kong W, Hooper KM, Ganea D. The natural dual cyclooxygenase and 5-lipoxygenase inhibitor flavocoxid is protective in EAE through effects on Th1/Th17 differentiation and macrophage/microglia activation. Brain Behav Immun. 2016 Mar;53:59–71. http://dx.doi.org/10.1016/j.bbi.2015.11.002
53. Bar-Or A, Calabresi PA, Arnold D, Markowitz C, Shafer S, Kasper LH, et al. Rituximab in relapsing-remitting multiple sclerosis: A 72-week, open-label, phase I trial. Ann Neurol. 2008 Mar;63(3):395–400. http://dx.doi.org/10.1002/ana.21363
54. Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A, Barkhof F, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: A phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011 Nov;378(9805):1779–87. http://dx.doi.org/10.1016/S0140-6736(11)61649-8
55. Menge T, Weber MS, Hemmer B, Kieseier BC, von Büdingen HC, Warnke C, et al. Disease-modifying agents for multiple sclerosis: Recent advances and future prospects. Drugs. 2008 Nov;68(17):2445–68. http://dx.doi.org/10.2165/0003495-200868170-00004
56. Rice GP. Treatment of secondary progressive multiple sclerosis: Current recommendations and future prospects. BioDrugs. 1999 Nov;12(4):267–77. http://dx.doi.org/10.2165/00063030-199912040-00004
57. Jadidi D, Mohammadi M, Moradi T. High risk of cardiovascular diseases after diagnosis of multiple sclerosis. Mult Scler. 2013 Jan;19(10):1336–40. http://dx.doi.org/10.1177/1352458513475833
58. Morel A, Miller E, Bijak M, Saluk J. The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients. Mol Cell Biochem. 2016 Aug;420(1/2):85–94. http://dx.doi.org/10.1007/s11010-016-2770-6