Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis.

Background: Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite treatments advances, a reliable tool able to capture the transition from RRMS to SPMS is lacking. A T cell chimeric MS model demonstrated that T cells derived from relapsing patients exacerbate excitatory transmission of central neurons, a synaptotoxic event absent during remitting stages. We hypothesized the re-emergence of T cell synaptotoxicity during SPMS and investigated the synaptoprotective effects of siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, known to reduce grey matter damage in SPMS patients. Methods: Data from healthy controls (HC), SPMS patients, and siponimod-treated SPMS patients were collected. Chimeric experiments were performed incubating human T cells on murine cortico-striatal slices, and recording spontaneous glutamatergic activity from striatal neurons. Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery. Results: SPMS patient-derived T cells significantly increased the striatal excitatory synaptic transmission (n=40 synapses) compared to HC T cells (n=55 synapses), mimicking the glutamatergic alterations observed in active RRMS-T cells. Siponimod treatment rescued SPMS T cells synaptotoxicity (n=51 synapses). Homologous chimeric experiments highlighted S1P5R involvement in the siponimod's protective effects. Conclusion: Transition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target.

Interaction between miR-142-3p and BDNF Val/Met Polymorphism Regulates Multiple Sclerosis Severity.

MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1ß), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1ß in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1ß levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1ß-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.

Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a progressive neurodegenerative disease of the central nervous system characterized by inflammation-driven synaptic abnormalities. Interleukin-9 (IL-9) is emerging as a pleiotropic cytokine involved in MS pathophysiology. METHODS: Through biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. RESULTS: We demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects. CONCLUSIONS: The data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system.

Pharmacological blockade of 2-AG degradation ameliorates clinical, neuroinflammatory and synaptic alterations in experimental autoimmune encephalomyelitis.

The endocannabinoid system (ECS) is critically involved in the pathophysiology of Multiple Sclerosis (MS), a neuroinflammatory and neurodegenerative disease of the central nervous system (CNS). Over the past decade, researchers have extensively studied the neuroprotective and anti-inflammatory effects of the ECS. Inhibiting the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) has emerged as a promising strategy to mitigate brain damage in MS. In this study, we investigated the effects of a novel reversible MAGL inhibitor (MAGLi 432) on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. We assessed its implications on motor disability, neuroinflammation, and synaptic dysfunction. Systemic in vivo treatment with MAGLi 432 resulted in a less severe EAE disease, accompanied by increased 2-AG levels and decreased levels of arachidonic acid (AA) and prostaglandins (PGs) in the brain. Additionally, MAGLi 432 reduced both astrogliosis and microgliosis, as evidenced by decreased microglia/macrophage density and a less reactive morphology. Flow cytometry analysis further revealed fewer infiltrating CD45+ and CD3+ cells in the brains of MAGLi 432-treated EAE mice. Finally, MAGLi treatment counteracted the striatal synaptic hyperexcitability promoted by EAE neuroinflammation. In conclusion, MAGL inhibition significantly ameliorated EAE clinical disability and striatal inflammatory synaptopathy through potent anti-inflammatory effects. These findings provide new mechanistic insights into the neuroprotective role of the ECS during neuroinflammation and highlight the therapeutic potential of MAGLi-based drugs in mitigating MS-related inflammatory and neurodegenerative brain damage.

Effects of elastic stockings on peripheral and central nervous system.

BACKGROUND: Prospective study to investigate the effects of elastic stockings (GCS) 23-32 mmHg at ankle on Hoffmann reflex (H-reflex) from soleus muscle under rest and after a walking program. METHODS: Fourteen subjects wore two types of GCS, at different times. Electrophysiological examinations were carried out at rest without and with GCS, immediately after walking with GCS and 20 minutes later after removing GCS. RESULTS: Peripheral nerve conduction remained unchanged after using the GCS. Conversely, walking with GCS led to changes in a spinal cord pathway expressed as a decrease of H-threshold and an increase of H-size as a function of stimulus intensity, which lasted for at least 20 minutes. CONCLUSIONS: GCS has no effect on the peripheral nervous system. The GCS intolerance and the discomfort sometimes reported by patients do not derive from a dysfunction of the lower limb peripheral nervous system. A positive action on spinal reflex excitability is detected after walking while wearing GCS. We suggest that nervous descending activity due to voluntary contractions, and afferent cutaneous discharge, enhanced by movement under compression, converge on inhibitory interneurons, thus impinging on presynaptic pathways. All this can lead to an enhancement of the monosynaptic responses. Higher limb oxygenation detected during walking with GCS, found by other Authors, could increase the sensitivity of the muscle spindle afferents and/or motor neuron excitability resulting in an increase in H-reflex excitability, with potential positive effects on neuromuscular activities improving proprioception and postural control of the lower limbs.

Multicenter randomized trial comparing compression with elastic stocking versus bandage after surgery for varicose veins.

OBJECTIVES: Postoperative limb compression is widely used after venous surgery to prevent thromboembolism and to reduce hemorrhage, edema, hematoma, and pain. Only limited studies have been published regarding the most adequate postoperative compression therapy after varicose vein surgery. This study evaluated the effectiveness of a new stocking kit used for postoperative limb compression. METHODS: The study compared the clinical practicability, ease to use, effectiveness, and safety of a postoperative stocking system (23 to 32 mmHg at the ankle) with compression bandages (control group). This prospective, randomized, open-label clinical trial, was performed in three Italian centers specializing in venous surgery. Sixty consecutive patients (classification CEAP C2,(S)) underwent unilateral varicose vein surgery at one of the three centers. After surgery, patients were randomized for postoperative compression therapy with a new stocking system (Sigvaris Postoperative Kit; Ganzoni Sigvaris Corp, Winterthur, Switzerland) or standard stretch bandages (30 patients per group). Primary end points were incidence of venous thromboembolism, hemorrhage, limb hematoma, or edema. RESULTS: No episodes of venous thromboembolism were observed. The mean area of thigh hematoma on postoperative days 7 and 14 was 75.70 cm² and 2.93 cm², respectively, for the stocking group, and 92.97 cm² and 5.42 cm² for the bandage group (not significant). On postoperative day 7, edema was found in 50% of the patients wearing bandages and in 20% of the patients wearing the stocking kit, which was a significant reduction. No statistical difference was recorded for postoperative pain; however, better patient acceptance and quality of life after the operation were recorded in the stocking group. CONCLUSION: Patients can be effectively treated with the Sigvaris Postoperative Kit. Patients treated with stockings have less edema compared with standard bandaging, and the application of the stocking kit improves patient quality of life and compliance with postoperative compression therapy.