2008/03/18
Biochem Biophys Res Commun. 2008 Mar 10
A new EAE model of brain demyelination induced by intracerebroventricular pertussis toxin.
Zhao CB, Coons SW, Cui M, Shi FD, Vollmer TL, Ma CY, Kuniyoshi SM, Shi J.
Experimental autoimmune encephalomyelitis (EAE) is a primary animal model of multiple sclerosis (MS). MS predominantly presents with evidence of lesions in the subcortical periventricular white matter regions of the brain. Research into the pathogenesis of the demyelinating lesions in the brain has been hampered by the fact that conventional models of EAE present with progressive ascending paralysis which recapitulates mainly the spinal cord lesions of multiple sclerosis. There is little evidence of brain involvement. Systemic administration of pertussis toxin (PTx) has been shown to induce the proinflammatory cascade of TGF-beta, IL-6, and Th17 in the central nervous system, which recently has been identified as essential in the development of EAE. To determine whether intracerebroventricular (icv) administration of PTx would result in subcortical periventricular demyelinating lesions in the brain, we examined the effect in a MOG induced EAE model. We found that icv PTx induced subcortical periventricular brain lesions that resemble the pathologic demyelinating lesions of MS. Moreover, icv PTx induced Th17 infiltration and increased expression of cytokines IL-6 and TGF-beta. We thus generated a highly reproducible model with remarkable histological similarities to the predominant demyelinating brain lesions seen in MS.
Nat Clin Pract Neurol. 2008 Mar 11
Mechanisms of Disease: aquaporin-4 antibodies in neuromyelitis optica.
Jarius S, Paul F, Franciotta D, Waters P, Zipp F, Hohlfeld R, Vincent A, Wildemann B; Vanderbilt.
Neuromyelitis optica (NMO) is a rare CNS inflammatory disorder that predominantly affects the optic nerves and spinal cord. Recent serological findings strongly suggest that NMO is a distinct disease rather than a subtype of multiple sclerosis. In NMO, serum antibodies, collectively known as NMO-IgG, characteristically bind to cerebral microvessels, pia mater and Virchow-Robin spaces. The main target antigen for this immunoreactivity has been identified as aquaporin-4 (AQP4). The antibodies are highly specific for NMO, and they are also found in patients with longitudinally extensive transverse myelitis without optic neuritis, which is thought to be a precursor to NMO in some cases. An antibody-mediated pathogenesis for NMO is supported by several observations, including the characteristics of the AQP4 antibodies, the distinct NMO pathology-which includes IgG and complement deposition and loss of AQP4 from spinal cord lesions-and emerging evidence of the beneficial effects of B-cell depletion and plasma exchange. Many aspects of the pathogenesis, however, remain unclear.
J Biol Chem. 2008 Mar 11
The CB2 cannabinoid receptor controls myeloid progenitor trafficking. Involvement in the pathogenesis of an animal model of multiple sclerosis.
Palazuelos J, Davoust N, Julien B, Hatterer E, Aguado T, Mechoulam R, Benito C, Romero J, Silva A, Guzman M, Nataf S, Galve-Roperh I.
Cannabinoids are potential agents for the development of therapeutic strategies against multiple sclerosis. Here we analyzed the role of the peripheral CB2 cannabinoid receptor in the control of myeloid progenitor cell trafficking towards the inflamed spinal cord and their contribution to microglial activation in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE). CB2 receptor knock-out mice showed an exacerbated clinical score of the disease when compared to their wild-type littermates, and this occurred in concert with extended axonal loss, T-lymphocyte (CD4+) infiltration and microglial (CD11b+) activation. Immature bone marrow-derived CD34+ myeloid progenitor cells, which play a role in neuroinflammatory pathologies, were shown to express CB2 receptors and to be abundantly recruited towards the spinal cords of CB2 knock-out EAE mice. Bone marrow-derived cell transfer experiments further evidenced the increased contribution of these cells to microglial replenishment in the spinal cords of CB2-deficient animals. In line with these observations, selective pharmacological CB2 activation markedly reduced EAE symptoms, axonal loss and microglial activation. CB2 receptor manipulation altered the expression pattern of different chemokines (CCL2, 3, 5) and their receptors CCR1, 2), thus providing a mechanistic explanation for its role in myeloid progenitor recruitment during neuroinflamation. These findings demonstrate the protective role of CB2 receptors in EAE pathology; provide evidence for a new site of CB2 receptor action, namely the targeting of myeloid progenitor trafficking and its contribution to microglial activation; and support the potential use of non-psychoactive CB2 agonists in therapeutic strategies for multiple sclerosis and other neuroinflammatory disorders.
J Clin Invest. 2008 Mar 13
Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis.
Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, Monsonego A, Shir AB, Engel Y, Gozin M, Weiner HL.
Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS). Thus, therapeutic approaches promoting neuroprotection could aid the treatment of progressive MS. Here, we used what we believe is a novel water-soluble fullerene derivative (ABS-75) attached to an NMDA receptor antagonist, which combines antioxidant and anti-excitotoxic properties, to block axonal damage and reduce disease progression in a chronic progressive EAE model. Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with myelin-oligodendrocyte glycoprotein (MOG). Reduced disease progression in ABS-75-treated mice was associated with reduced axonal loss and demyelination in the spinal cord. Fullerene ABS-75 halted oxidative injury, CD11b(+) infiltration, and CCL2 expression in the spinal cord of mice without interfering with antigen-specific T cell responses. In vitro, fullerene ABS-75 protected neurons from oxidative and glutamate-induced injury and restored glutamine synthetase and glutamate transporter expression in astrocytes under inflammatory insult. Glutamine synthetase expression was also increased in the white matter of fullerene ABS-75-treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases.
Acta Biochim Biophys Sin (Shanghai). 2008 Mar;40(3):217-25.
Identification and characterization of a novel peptide ligand of Tie2 for targeting gene therapy.
Wu X, Li Z, Yao M, Wang H, Qu S, Chen X, Li J, Sun Y, Xu Y, Gu J.
Tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2 (Tie2) has been considered as a rational target for gene therapy in solid tumors. In order to identify a novel peptide ligand of Tie2 for targeted gene therapy, we screened a phage display peptide library and identified a candidate peptide ligand NSLSNASEFRAPY (designated GA5). Binding assays and Scatchard analysis revealed that GA5 could specifically bind to Tie2 with a dissociation constant of 2.1×10(-8)M. In addition, we showed that GA5 was internalized into tumor cells highly expressing Tie2. In the biodistribution assay, (125)I-GA5 was mainly accumulated in SPC-A1 xenograft tumors that express Tie2. In gene delivery studies, GA5-conjugated polyethylenimine vector could achieve greater transgene transduction than non-targeted vectors both in vitro and in vivo. Tumor growth inhibition was observed in SPC-A1 xenograft-bearing mice that received eight intratumoral injections of GA5-polyethylenimine/p53 complexes in 3 weeks. The difference in tumor volume between the experiment and control groups was significant (P<0.05). Our results showed that GA5 is a potentially efficient targeting element for cancer gene or molecular therapy.
J Immunol. 2008 Jan 15;180(2):1258-67.
Recognition and degradation of myelin basic protein peptides by serum autoantibodies: novel biomarker for multiple sclerosis.
Belogurov AA Jr, Kurkova IN, Friboulet A, Thomas D, Misikov VK, Zakharova MY, Suchkov SV, Kotov SV, Alehin AI, Avalle B, Souslova EA, Morse HC 3rd, Gabibov AG, Ponomarenko NA.
The pathologic role of autoantibodies in autoimmune disease is widely accepted. Recently, we reported that anti-myelin basic protein (MBP) serum Abs from multiple sclerosis (MS) patients exhibit proteolytic activity toward the autoantigen. The aim of this study is to determine MBP epitopes specific for the autoantibodies in MS and compare these data with those from other neuronal disorders (OND), leading to the generation of new diagnostic and prognostic criteria. We constructed a MBP-derived recombinant “epitope library” covering the entire molecule. We used ELISA and PAGE/surface-enhanced laser desorption/ionization mass spectroscopy assays to define the epitope binding/cleaving activities of autoantibodies isolated from the sera of 26 MS patients, 22 OND patients, and 11 healthy individuals. The levels of autoantibodies to MBP fragments 48-70 and 85-170 as well as to whole MBP and myelin oligodendrocyte glycoprotein molecules were significantly higher in the sera of MS patients than in those of healthy donors. In contrast, selective reactivity to the two MBP fragments 43-68 and 146-170 distinguished the OND and MS patients. Patients with MS (77% of progressive and 85% of relapsing-remitting) but only 9% of patients with OND and no healthy donors were positive for catalysis, showing pronounced epitope specificity to the encephalitogenic MBP peptide 81-103. This peptide retained its substrate properties when flanked with two fluorescent proteins, providing a novel fluorescent resonance energy transfer approach for MS studies. Thus, anti-MBP autoantibody-mediated, epitope-specific binding and cleavage may be regarded as a specific characteristic of MS compared with OND and healthy donors and may serve as an additional biomarker of disease progression.
