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Background: There are two generally accepted strategies for treating multiple sclerosis (MS), preventing central nervous system (CNS) damage indirectly through immunomodulatory interventions and/or repairing CNS damage by promoting remyelination. Both approaches also provide neuroprotection since they can prevent, indirectly or directly, axonal damage., Objective: Recent experimental and clinical evidence indicates that the novel immunomodulatory drug laquinimod can exert a neuroprotective role in MS. Whether laquinimod-mediated neuroprotection is exerted directly on neuronal cells or indirectly via peripheral immunomodulation is still unclear., Methods: C57Bl/6 experimental autoimmune encephalomyelitis (EAE) mice, immunised with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, were treated for 26 days with subcutaneous daily injections of laquinimod (from 1 to 25 mg/kg). Patch clamp electrophysiology was performed on acute brain striatal slices from EAE mice treated with daily (25 mg/kg) laquinimod and on acute brain striatal slices from control mice bathed with laquinimod (1-30 µM)., Results: Both preventive and therapeutic laquinimod treatment fully prevented the alterations of GABAergic synapses induced by EAE, the first limiting also glutamatergic synaptic alterations. This dual effect might, in turn, have limited glutamatergic excitotoxicity, a phenomenon previously observed early during EAE and possibly correlated with later axonal damage. Furthermore, laquinimod treatment also preserved cannabinoid CB1 receptor sensitivity, normally lost during EAE. Finally, laquinimod per se was able to regulate synaptic transmission by increasing inhibitory post-synaptic currents and, at the same time, reducing excitatory post-synaptic currents., Conclusions: Our data suggest a novel neuroprotective mechanism by which laquinimod might in vivo protect from neuronal damage occurring as a consequence of inflammatory immune-mediated demyelination.

Background Hypertrophic pachymeningitis (HP) is a rare primary or secondary inflammatory disorder that manifests with thickening of dura mater involving predominantly the tentorium and falx in the focal form. Hydrocephalus has not been reported in association with secondary HP. Case Description A 61-year-old woman presented with intracranial HP of the posterior fossa secondary to Wegener granulomatosis not responsive to corticosteroid therapy. Owing to the association of noncommunicating hydrocephalus, endoscopic third ventriculostomy was performed. There was immediate improvement of neurologic symptoms and no postoperative complications. The patient had very good clinical and radiologic outcome at 1-year follow-up. Conclusions In a case of noncommunicating hydrocephalus related to focal HP of the posterior fossa, endoscopic third ventriculostomy was effective in resolving symptoms related to increased intracranial pressure. The physiopathogenetic mechanisms and therapeutic strategies were discussed along with a review of the most relevant literature. Highlights • WG may induce hypertrophic pachymeningitis. • Posterior fossa HP can cause acute noncommunicating hydrocephalus. • Steroid therapy may be not effective in management of acute hydrocephalus. • ETV can be effective in resolving clinical deterioration and avoiding complications of ventriculoperitoneal shunt. • With ETV in HP-related hydrocephalus, immunosuppressive therapy can be postponed. [ABSTRACT FROM AUTHOR]

Background Understanding how inflammation causes neuronal damage is of paramount importance in multiple sclerosis (MS) and in other neurodegenerative diseases. Here we addressed the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) in brain tissues, and disease progression caused by inflammation in relapsing-remitting MS (RRMS) patients. Results The effect of IL-1β, but not of TNF-α, on glutamate-mediated excitatory postsynaptic currents was blocked by pifithrin-α (PFT), inhibitor of p53. The protein kinase C (PKC)/transient receptor potential vanilloid 1 (TRPV1) pathway was involved in IL-1β-p53 interaction at glutamatergic synapses, as pharmacological modulation of this inflammationrelevant molecular pathway affected PFT effects on the synaptic action of IL-1β. IL-1β-induced neuronal swelling was also blocked by PFT, and IL-1β increased the expression of p21, a canonical downstream target of activated p53. Consistent with these in vitro results, the Pro/Pro genotype of p53, associated with low efficiency of transcription of p53-regulated genes, abrogated the association between IL-1β cerebrospinal fluid (CSF) levels and disability progression in RRMS patients. The interaction between p53 and CSF IL-1β was also evaluated at the optical coherence tomography (OCT), showing that IL-1β-driven neurodegenerative damage, causing alterations of macular volume and of retinal nerve fibre layer thickness, was modulated by the p53 genotype. Conclusions Inflammatory synaptopathy and neurodegeneration caused by IL-1β in RRMS patients involve the apoptotic cascade. Targeting IL-1β-p53 interaction might result in significant neuroprotection in MS. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the synaptic mechanism of inflammatory neurodegeneration in progressive multiple sclerosis (MS). Details about the methods of the study are provided. An observation of an increased spontaneous excitatory postsynaptic currents, along with the pathogenic role of B cells in tumor necrosis factor (TNF) cerebrospinal fluid increase, is discussed. The study suggests TNF as a major neurotoxic molecule in progressive MS.

Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao’s brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Interleukin-lβ (IL-Iβ) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-lβ-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-lβ-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-lβ caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CBIRs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-lβ-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1 ) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-lβ-CBlR coupling, and TRPVl -/- mice were indeed insensitive to the synaptic and behavioral effects of both IL-lβ and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-lβ on CBIRs only in control mice, while the same treatment was ineffective in slices prepared from TRPVl-/- mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety. [ABSTRACT FROM AUTHOR]