Neuroprotection from inflammation: Experimental allergic encephalomyelitis facilitates traumatic spinal cord injury recovery

Passive immunization with T cells activated against central nervous system (CNS) - associated myelin antigens has been found to provide neuroprotection following CNS trauma, leading to the concept of protective autoimmunity. However, limited research exists about whether actively induced CNS autoimmunity may offer any similar benefit. In this study, the kinetics and the effect of endogenously anti-myelin activated T cells following spinal cord injury (SCI), were investigated. Experimental allergic encephalomyelitis (EAE) was actively induced in Lewis rats following immunization with myelin basic protein (MBP). In vivo 5-Bromo-2-deoxyuridine (BrdU) incorporation from activated T cells was used as a marker of T cell- proliferation. BrdU was injected on 5th, 6th and 7th day post-induction (DPI) at all EAE-animals. On DPI 8, spinal cord compressive injury was induced by a transient extradural application of an aneurysm clip at the T8 spinal level. SCI resulted in spastic paralysis of hindlimbs, in all but sham-injured animals. Recovery from SCI was significantly better in EAE-animals. Activated mononuclear cells were selectively accumulated at the site of the injury. Axonal loss was less in the EAE group following SCI. Our findings indicate that actively induced autoimmunity against CNS myelin antigens may protect spinal cord pathways from mechanical injury

Transplantation of neural stem cells in experimetnal allergic engephalomyelitis

Neural stem cell transplantation has been proposed as a mean of cell replacement therapy for various diseases of the central nervous system (CNS). Transplanted neural precursors of various origins improved the clinical outcome in experimental models of stroke and spinal cord trauma. Although transplanted myelin-forming cells have remarkable remyelinating properties the exact mechanisms by which they react are not clear yet. In multiple sclerosis (MS), as well as in experimental allergic encephalomyelitis (EAE), a model of MS, demyelination and inflammation-related axonal pathology lead to chronic neurological disability. Here, we transplanted neural stem cells (NSCs) into the ventricles of mice at day 7 after induction of chronic EAE. Transplanted cells attenuated the clinical course of disease and migrated into the white matter. NPC transplantation down-regulated the inflammatory brain process at the acute phase of disease, as indicated by a reduction in the number of perivascular infiltrates. Demyelination and acute axonal injury in this model are considered to result mainly from the acute inflammatory process and correlate well with the chronic neurological residua. Except for the downregulation of the inflammatory process, the transplanted cells reduced the primary demyelination and axonal injury and induced the remyelination of demyelinated axons, a result though which did not derive directly from the transplanted cells. In consequence to inhibition of brain inflammation, precursor cell transplantation attenuated the primary demyelinating process and reduced the acute axonal injury. As a result, the size of demyelinated areas and extent of chronic axonal pathology were reduced in the transplanted brains. We suggest that the beneficial effect of transplanted NPCs in chronic EAE is mediated, in part, by decreasing brain inflammation and reducing tissue injury and finally to improvement in the clinical outcome.Η μεταμόσχευση των στελεχιαίων προγονικών κυττάρων του κεντρικού νευρικού συστήματος (ΚΝΣ), έχει προταθεί ως μέσο για τη θεραπεία ποικίλων νοσημάτων του ΚΝΣ. Τα μεταμοσχευμένα στελεχιαία προγονικά κύτταρα βελτίωσαν την κλινική πορεία των πειραματόζωων σε διαφορετικά πειραματικά μοντέλα όπως της εγκεφαλικής ισχαιμίας και της κάκωσης του νωτιαίου μυελού. Παρ’ όλο που τα μεταμοσχευμένα κύτταρα εμφανίζουν σημαντικές επαναμυελινωτικές ιδιότητες, δεν είναι ακόμα γνωστοί οι ακριβείς μηχανισμοί με τους οποίους δρουν. Στην πολλαπλή σκλήρυνση, όπως και στο πειραματικό μοντέλο της νόσου, την πειραματική αλλεργική εγκεφαλομυελίτιδα (ΠΑΕ), η απομυελίνωση και η παθολογία των νευραξόνων η οποία σχετίζεται με τη φλεγμονή, έχουν ως αποτέλεσμα το χρόνιο νερολογικό έλλειμμα. Στην παρούσα μελέτη μεταμοσχεύθηκαν στελεχιαία προγονικά κύτταρα του ΚΝΣ στις πλάγιες κοιλίες μυών την 7η ημέρα μετά την επαγωγή της χρόνιας ΠΑΕ. Τα μεταμοσχευμένα κύτταρα βελτίωσαν την κλινική πορεία των πειραματόζωων και μετανάστευσαν στη λευκή ουσία των εγκεφάλων τους. Η μεταμόσχευση των κυττάρων κατέστειλε τη φλεγμονώδη διαδικασία στον εγκέφαλο, όπως φάνηκε από τη μείωση των περιαγγειακών διηθήσεων. Η απομυελίνωση και η εκφύλιση των νευραξόνων σε αυτό το πειραματικό μοντέλο θεωρούνται ότι είναι αποτέλεσμα της φλεγμονής κυρίως και σχετίζονται με το χρόνιο νευρολογικό έλλειμμα. Εκτός από την ελάττωση της φλεγμονής, τα μεταμοσχευμένα κύτταρα μείωσαν την πρωτοπαθή απομυελινωτική διαδικασία και την «κάκωση» των νευραξόνων η οποία όμως, δεν προήλθε άμεσα από τα μεταμοσχευμένα κύτταρα. Ως αποτέλεσμα, η έκταση των απομυελινωμένων περιοχών καθώς και η έκταση της χρόνιας αξονικής «κάκωσης» μειώθηκαν στους εγκεφάλους των μεταμοσχευμένων πειραματόζωων. Στην παρούσα μελέτη φάνηκε ότι ο θετικός ρόλος των μεταμοσχευμένων στελεχιαίων προγονικών κυττάρων στη χρόνια ΠΑΕ οφείλεται εν μέρει, στον περιορισμό της φλεγμονής και τελικά στην περιορισμένη «κάκωση» του ιστού έχοντας ως αποτέλεσμα την καλύτερη κλινική πορεία των πειραματόζωων

Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury

Despite efforts aimed at developing novel therapeutics for traumatic brain injury (TBI), no specific pharmacological agent is currently clinically available. Here, we show that the pan-histone deacetylase (HDAC) inhibitor ITF2357, a compound shown to be safe and effective in humans, improves functional recovery and attenuates tissue damage when administered as late as 24 h postinjury. Using a well-characterized, clinically relevant mouse model of closed head injury (CHI), we demonstrate that a single dose of ITF2357 administered 24 h postinjury improves neurobehavioral recovery from d 6 up to 14 d postinjury (improved neurological score vs. vehicle; P≤0.05), and that this functional benefit is accompanied by decreased neuronal degeneration, reduced lesion volume (22% reduction vs. vehicle; P≤0.01), and is preceded by increased acetylated histone H3 levels and attenuation of injury-induced decreases in cytoprotective heat-shock protein 70 kDa and phosphorylated Akt. Moreover, reduced glial accumulation and activation were observed 3 d postinjury, and total p53 levels at the area of injury and caspase-3 immunoreactivity within microglia/macrophages at the trauma area were elevated, suggesting enhanced clearance of these cells via apoptosis following treatment. Hence, our findings underscore the relevance of HDAC inhibitors for ameliorating trauma-induced functional deficits and warrant consideration of applying ITF2357 for this indication.—Shein, N. A., Grigoriadis, N., Alexandrovich, A. G., Simeonidou, C., Lourbopoulos, A., Polyzoidou, E., Trembovler, V., Mascagni, P., Dinarello, C. A., Shohami, E. Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury