Tumour necrosis factor is linked to the pathophysiology of various neurodegenerative disorders including multiple sclerosis. Tumour necrosis factor exists in two biologically active forms, soluble and transmembrane. Here we show that selective inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis. Treatment with XPro1595, a selective soluble tumour necrosis factor blocker, improves the clinical outcome, whereas non-selective inhibition of both forms of tumour necrosis factor with etanercept does not result in protection. The therapeutic effect of XPro1595 is associated with axon preservation and improved myelin compaction, paralleled by increased expression of axon-specific molecules (e.g. neurofilament-H) and reduced expression of non-phosphorylated neurofilament-H which is associated with axon damage. XPro1595-treated mice show significant remyelination accompanied by elevated expression of myelin-specific genes and increased numbers of oligodendrocyte precursors. Immunohistochemical characterization of tumour necrosis factor receptors in the spinal cord following experimental autoimmune encephalomyelitis shows tumour necrosis factor receptor 1 expression in neurons, oligodendrocytes and astrocytes, while tumour necrosis factor receptor 2 is localized in oligodendrocytes, oligodendrocyte precursors, astrocytes and macrophages/microglia. Importantly, a similar pattern of expression is found in post-mortem spinal cord of patients affected by progressive multiple sclerosis, suggesting that pharmacological modulation of tumour necrosis factor receptor signalling may represent an important target in affecting not only the course of mouse experimental autoimmune encephalomyelitis but human multiple sclerosis as well. Collectively, our data demonstrate that selective inhibition of soluble tumour necrosis factor improves recovery following experimental autoimmune encephalomyelitis, and that signalling mediated by transmembrane tumour necrosis factor is essential for axon and myelin preservation as well as remyelination, opening the possibility of a new avenue of treatment for multiple sclerosis.

Neurogenesis proceeds throughout adulthood in the brain of most mammalian species, but the molecular mechanisms underlying the regulation of stem/progenitor cell proliferation, survival, maturation, and differentiation have not been completely unraveled. We have studied hippocampal neurogenesis in NF-B p50-deficient mice. Here we demonstrate that in absence of p50, the net rate of neural precursor proliferation does not change, but some of the steps leading to the final neuron differentiation status are hampered, resulting in ϳ50% reduction in the number of newly born neurons in the adult mutant hippocampus. Additionally, in p50 Ϫ/Ϫ mice, we observed a selective defect in short-term spatial memory performance without impairment of hippocampal-dependent spatial long-term memory and learning. Our results highlight the role of NF-B p50 in hippocampal neurogenesis and in short-term spatial memory.

Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: 1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and 2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1−/− mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive symptoms in a time dependent manner and was associated with profound hippocampal alterations such as impaired neurogenesis, reduced expression of neuroplasticity markers and myelin proteins. The onset of depressive-like behavior also coincided with increased hippocampal levels of TNF, and decreased expression of TNF receptor 2 (TNFR2), which were all fully restored after mice spontaneously recovered from pain. Notably, TNFR1−/− mice did not develop depressive-like symptoms after injury, nor were there changes in hippocampal neurogenesis and plasticity. Our data show that neuropathic pain induces a cluster of depressive-like symptoms and profound hippocampal plasticity that are dependent on TNF signaling through TNFR1.

Dysregulated hippocampal neurogenesis has been associated with neurodegenerative disorders, including Alzheimer's disease (AD), in which it may potentially represent an auto-reparatory mechanism that could counteract neuronal loss and cognitive impairment. We evaluated hippocampal neurogenesis in TgCRND8 mice and reported that, at 32 weeks of age, corresponding to an advanced AD-like neuropathology stage, increased numbers of proliferating cells, doublecortin-expressing progenitors/neuroblasts, and early postmitotic calretinin-expressing neurons were present compared with wild-type (WT) littermates. When hippocampal neural progenitor cells (NPCs) were isolated from TgCRND8 mice, we demonstrated that (1) their neurogenic potential was higher compared with WT NPCs; (2) medium conditioned by TgCRND8 NPC promoted neuronal differentiation of WT NPCs; and (3) the proneurogenic effect of TgCRND8-conditioned medium was counteracted by blockade of the receptor for advanced glycation end products (RAGE)/nuclear factor-B (NF-B) axis. Furthermore, we showed that ␤-amyloid 1-42 (A␤ 1-42 ) oligomers, but not monomers and fibrils, and the alarmin highmobility group box-1 protein (HMGB-1) could promote neuronal differentiation of NPCs via activation of the RAGE/NF-B axis. Altogether, these data suggest that, in AD brain, an endogenous proneurogenic response could be potentially triggered and involve signals (A␤ 1-42 oligomers and HMGB-1) and pathways (RAGE/NF-B activation) that also contribute to neuroinflammation/neurotoxicity. A more detailed analysis confirmed no significant increase of new mature neurons in hippocampi of TgCRND8 compared with WT mice, suggesting reduced survival and/or integration of newborn neurons. Therapeutic strategies in AD should ideally combine the ability of sustaining hippocampal neurogenesis as well as of counteracting an hostile brain microenvironment so to promote survival of vulnerable cell populations, including adult generated neurons.

Physicians treating pediatric brain tumor patients should be aware of the possible consequences associated with treatment. Psychiatric monitoring is warranted in survivors of pediatric brain tumors, but further investigation is needed to elucidate late outcomes regarding tumor type and location.