The central nervous system (CNS) is one of the most complex physiological systems, and treatment of CNS disorders represents an area of major medical need. One critical aspect of the CNS is its lack of regeneration, such that damage is often permanent. The damage often leads to neurodegeneration, and so strategies for neuroprotection could lead to major medical advances. The G protein-coupled receptor (GPCR) family is one of the major receptor classes, and they have been successfully targeted clinically. One class of GPCRs is those activated by bioactive lysophospholipids as ligands, especially sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Research has been increasingly demonstrating the important roles that S1P and LPA, and their receptors, play in physiology and disease. In this review, I describe the role of S1P and LPA receptors in neurodegeneration and potential roles in neuroprotection. Much of our understanding of the role of S1P receptors has been through pharmacological tools. One such tool, fingolimod (also known as FTY720), which is a S1P receptor agonist but a functional antagonist in the immune system, is clinically efficacious in multiple sclerosis by producing a lymphopenia to reduce autoimmune attacks; however, there is evidence that fingolimod is also neuroprotective. Furthermore, fingolimod is neuroprotective in many other neuropathologies, including stroke, Parkinson\'s disease, Huntington\'s disease, Rett syndrome, Alzheimer\'s disease, and others that are discussed here. LPA receptors also appear to be involved, being upregulated in a variety of neuropathologies. Antagonists or mutations of LPA receptors, especially LPA1, are neuroprotective in a variety of conditions, including cortical development, traumatic brain injury, spinal cord injury, stroke and others discussed here. Finally, LPA receptors may interact with other receptors, including a functional interaction with plasticity related genes.

BACKGROUND: Clinically, ischemic reperfusion injury is the main cause of stroke injury. This study aimed to assess the effectiveness of fingolimod in suppressing inflammation caused by ischemic brain injury and explore its pharmacological mechanisms.
METHODS: In total, 75 male Sprague-Dawley rats were randomly and equally assigned to five distinct groups: sham, middle cerebral artery occlusion/reperfusion (MCAO/R) surgery, fingolimod low-dose (F-L), fingolimod medium-dose (F-M), and fingolimod high-dose (F-H). Neurobehavioral tests, 2,3,5-triphenyltetrazolium chloride staining, and the brain tissue drying-wet method were conducted to evaluate neurological impairment, cerebral infarction size, and brain water content. Enzyme-linked immunosorbent assay was employed to quantify pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) protein levels. Western blotting and immunohistochemical staining were performed to assess high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and nuclear factor kappa-B p65 (NF-κBp65) levels.
RESULTS: Rats in the F-L, F-M, and F-H groups exhibited lower Longa scores, reduced infarction volumes, and decreased brain edema than those in the MCAO/R group. Additionally, the F-L, F-M, and F-H groups exhibited lower serum levels of IL-1β, IL-6, and TNF-α than those of the MCAO/R group. Additionally, F-L, F-M, and F-H treatments resulted in decreased HMGB1, TLR4, and NF-κBp65 protein expression levels in the hippocampus of MCAO/R rats.
CONCLUSIONS: Fingolimod was found to reduce ischemic brain injury in a dose-dependent manner. Moreover, it was also found to alleviate inflammation following ischemic brain injury via the HMGB1/TLR4/NF‑κB signaling pathway.

BACKGROUND: Pediatric-onset Multiple Sclerosis (POMS) patients show more inflammatory disease compared with adult-onset MS. However, highly effective treatments are limited with only fingolimod being approved in Italy and natalizumab prescribed as off-label treatment.
OBJECTIVE: to compare the efficacy of natalizumab versus fingolimod in POMS.
METHODS: This is an observational longitudinal multicentre study including natalizumab- and fingolimod-treated POMS patients (N-POMS and F-POMS, respectively). We collected Annual Relapse Rate (ARR), Expanded Disability Status Scale (EDSS), Symbol Digit Modality Test (SDMT), and MRI activity at baseline (T0), 12-18 months (T1), and last available observation (T2).
RESULTS: We enrolled 57 N-POMS and 27 F-POMS patients from six Italian MS Centres. At T0, N-POMS patients showed higher ARR (p = 0.03), higher EDSS (p = 0.003) and lower SDMT (p = 0.04) at baseline compared with F-POMS. Between T0 and T1 ARR improved for both N-POMS and F-POMS (p < 0.001), while EDSS (p < 0.001) and SDMT (p = 0.03) improved only for N-POMS. At T2 (66.1 ± 55.4 months) we collected data from 42 out of 57 N-POMS patients showing no further ARR decrease.
CONCLUSIONS: Both natalizumab and fingolimod showed high and sustained efficacy in controlling relapses and natalizumab also associated to a disability decrease in POMS. This latter effect might be partly mediated by the high inflammatory activity at baseline in N-POMS.

OBJECTIVE: To evaluate the effect of discontinuation or prolongation of DMT on the activity of the disease during pregnancy and in the postpartum period in patients with aggressive MS from the Moscow region.
METHODS: The study included female patients with an aggressive course of MS receiving DMT at the time of pregnancy. The patients were followed-up for the period 2016 to February 2024.
RESULTS: There were 17 cases of pregnancy during natalizumab (NZ) therapy; discontinuation of therapy in the first trimester of pregnancy provoked a resumption of disease activity in half of the patients. There were no exacerbations in patients whose therapy was prolonged until the 34th week of pregnancy. In 5 patients receiving fingolimod (FGL), therapy was discontinued upon the establishment of pregnancy, which caused the resumption of disease activity in three out of 5 cases. In 3 patients receiving anti-B-cell therapy, pregnancy occurred within a few months after the next infusion, there were no exacerbations during pregnancy.
CONCLUSIONS: The cancellation of NS therapy in the early stages of pregnancy in most cases leads to the resumption of disease activity during pregnancy. Exacerbations in the postpartum period also correlated with early discontinuation of therapy and with a long period before the restart of infusions. Prolongation of infusions to 30-34 weeks of pregnancy contributed to stabilization of the condition throughout the perinatal period. Discontinuation of FGL therapy at the onset of pregnancy increased the risk of repeated relapses of the disease, up to the development of inflammatory immune restoration syndrome during pregnancy and contributed to the increase in disability in the postpartum period.
UNASSIGNED: Оценить влияние отмены или пролонгирования терапии препаратами, изменяющими течение рассеянного склероза (ПИТРС) 2-ой линии на активность заболевания во время беременности и в послеродовом периоде у пациенток с агрессивным РС.
UNASSIGNED: В наблюдение были включены пациентки с агрессивным течением РС, получающие ПИТРС 2-й линии терапии к моменту наступления беременности, наблюдавшиеся в Московской области в период с 2016 по 2024 г.
UNASSIGNED: Наблюдалось 17 случаев беременности на фоне терапии натализумабом (НЗ), отмена терапии в первом триместре беременности спровоцировала возобновление активности заболевания у половины больных. У пациенток, которым терапия была пролонгирована до 34 нед беременности, обострений не отмечалось. У 5 пациенток, получающих терапию финголимодом (ФГЛ), отмена терапии проводилась по факту установления беременности, что вызвало возобновление активности заболевания в 3 из 5 случаев. У 3 пациенток, получающих анти-B-клеточную терапию, беременность наступила в течение нескольких месяцев после очередной инфузии, обострений во время беременности не отмечалось.
UNASSIGNED: Отмена НЗ на ранних сроках беременности в большинстве случаев приводила к возобновлению активности заболевания во время беременности. Обострения в послеродовом периоде также сочетались с ранним прекращением терапии и с длительным периодом до дальнейшего продолжения инфузий. Пролонгирование инфузий НЗ до 30—34 нед беременности способствовало стабилизации состояния в течение всего перинатального периода. Прекращение терапии ФГЛ при наступлении беременности увеличило риск повторных рецидивов заболевания вплоть до развития синдрома воспалительного восстановления иммунитета во время беременности и способствовало нарастанию инвалидизации в послеродовом периоде.

BACKGROUND: The transition from fingolimod (FIN) to siponimod (SIP) for Multiple Sclerosis (MS) treatment in the occurrence of Secondary Progressive Multiple Sclerosis (SPMS) diagnosis has increasingly attracted considerable interest in the recent literature.
METHODS: We evaluated the efficacy and safety of a direct switch from FIN to SIP in nine MS patients who had switched directly from FIN to SIP due to SPMS diagnosis at the Multiple Sclerosis Center of the University Hospital Policlinico of Bari.
CONCLUSIONS: Real-world results from our cohort demonstrated that the direct switch from FIN to SIP in patients transitioning in SP course is associated with clinical and disability progression stability, with a favorable safety profile.

UNASSIGNED: This case report highlights the importance of monitoring ocular health for patients starting on siponimod treatment, a sphingosine-1-phosphate receptor modulator, for relapsing-remitting multiple sclerosis. By showing how medication adverse events present in patients, we can revisit the current guidelines on ophthalmic evaluation recommendations.
UNASSIGNED: We report a 60-year-old patient who presented with unilateral blurry vision upon initiating siponimod therapy for the treatment of relapsing-remitting multiple sclerosis. Her exam findings did not show visual field defects but were significant for cystoid macular edema distorting the foveal contour. Upon stopping siponimod therapy, the patient\'s macular edema and symptoms resolved significantly within 7 days and completely resolved 1 month later.
UNASSIGNED: This case showcases siponimod-associated cystoid macular edema in a patient without known risk factors, such as diabetes mellitus and uveitis. The patient also had the earliest reported symptom onset to date following the initiation of siponimod therapy. Current recommendations from the American Academy of Ophthalmology and FDA stress the importance of ophthalmic evaluation three to four months after treatment initiation for patients with a history of risk factors. Given our current case and its comparison with four previously reported cases, we recommend that physicians inform patients of possible ocular adverse events with siponimod therapy regardless of their past medical history and duration of treatment.

We describe the case of a gentleman with relapsing-remitting multiple sclerosis and chronic lymphocytopenia secondary to treatment with fingolimod who presented with disseminated histoplasmosis after receiving the third dose of the Moderna coronavirus disease 2019 (mRNA-1273) vaccine. Following the vaccination the patient noted fatigue which worsened over time along with gradual weight loss. A few months later he noted low-grade fever and finally shortness of breath. A diagnosis of disseminated histoplasmosis was performed based on urine, blood, and imaging data. He responded well to prolonged antifungal treatment. Fingolimod was discontinued and replaced with glatiramer acetate. He has been clinically stable until the time of this report, 33 months following symptom onset.

A report of Balo\'s concentric sclerosis developed alongside with fingolimod use in a patient with previously diagnosed multiple sclerosis.

OBJECTIVE: In multiple sclerosis (MS), MRI markers can measure the potential neuroprotective effects of fingolimod beyond its anti-inflammatory activity. In this study we aimed to comprehensively explore, in the real-word setting, whether fingolimod not only reduces clinical/MRI inflammatory activity, but also influences the progression of irreversible focal and whole brain damage in relapsing-remitting [RR] MS patients.
METHODS: The \"EVOLUTION\" study, a 24-month observational, prospective, single-arm, multicenter study, enrolled 261 RRMS patients who started fingolimod at 32 Italian MS centers and underwent biannual neurological assessments and annual MRI evaluations. Study outcomes included the proportions of evaluable RRMS patients achieving at 24 months: (1) no new/enlarging T2-hyperintense white matter (WM) lesions and/or clinical relapses; (2) a modified classification of \"No Evidence of Disease Activity 4\" (\"modified NEDA-4\") defined as no new/enlarging T2-hyperintense WM lesions, clinical relapses, and 6-month confirmed disability progression, and a yearly percentage lateral ventricular volume change on T2-FLAIR images < 2%; (3) less than 40% of active lesions at baseline and month 12 evolving to permanent black holes (PBHs).
RESULTS: At month 24, 76/160 (47.5%; 95% confidence interval [CI] = 39.8%;55.2%) RRMS patients had no clinical/MRI activity. Thirty-nine of 170 RRMS patients (22.9%; 95% CI = 16.6%;29.3%) achieved \"modified NEDA-4\" status. Forty-four of 72 RRMS patients (61.1%; 95% CI = 49.8%;72.4%) had less than 40% of active WM lesions evolving to PBHs. The study confirmed the established safety and tolerability profile of fingolimod.
CONCLUSIONS: By comparing our results with those from the literature, the EVOLUTION study seems to indicate a neuroprotective effect of fingolimod, limiting inflammatory activity, brain atrophy and PBH development.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder. With the method of indirect immunofluorescence assay (IIF), more anti-NMDAR encephalitis patients have been discovered when its first onset. But it was rare that anti-NMDAR encephalitis overlapped with multiple sclerosis (MS) documented in literatures. Here, we present a case who initially developed anti-NMDAR encephalitis and MS. Furthermore, we concluded the characteristics of patients who were diagnosed as anti-NMDAR encephalitis overlapping with MS. Additionally, due to the relapsing process, mycophenolate mofetil and sequentially fingolimod for the treatment were taken, which subsequently led to the development of a lymphoproliferative disease in his brain and other organs. This case illustrates the complex role of immunosuppressive agents.