The ELR+ CXC chemokines CXCL1 and CXCL2 are up-regulated in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, their functional significance and the pathways regulating their expression are largely unknown. We show that transfer of encephalitogenic CD4+ Th17 cells is sufficient to induce CXCL1 and CXCL2 transcription in the spinal cords of naive, syngeneic recipients. Blockade or genetic silencing of CXCR2, a major receptor for these chemokines in mice, abrogates blood–brain barrier (BBB) breakdown, CNS infiltration by leukocytes, and the development of clinical deficits during the presentation as well as relapses of EAE. Depletion of circulating polymorphonuclear leukocytes (PMN) had a similar therapeutic effect. Furthermore, injection of CXCR2+ PMN into CXCR2−/− mice was sufficient to restore susceptibility to EAE. Our findings reveal that a Th17–ELR+ CXC chemokine pathway is critical for granulocyte mobilization, BBB compromise, and the clinical manifestation of autoimmune demyelination in myelin peptide–sensitized mice, and suggest new therapeutic targets for diseases such as MS.

No abstract

Experimental autoimmune encephalomyelitis (EAE) is a Tcell-mediated autoimmune disease of the CNS that is widely used as an animal model of multiple sclerosis. In this study, we investigate the role of CXCL13, a chemokine involved in the development and organization of secondary lymphoid tissues, in the pathogenesis of EAE. We detected CXCL13 mRNA and protein in spinal cords of mice with EAE. CXCL13-deficient mice exhibited a mild, self-limited form of disease. CXCL13 appeared to be important for the establishment of chronic white matter lesions. Furthermore, adoptive transfer experiments with CXCL13-deficient hosts indicate that the chemokine plays a distinct role during the effector phase. Our findings raise the possibility that reagents that antagonize or inhibit CXCL13 might be useful for the treatment of neuroinflammatory diseases such as multiple sclerosis.

Curcumin, a chemical constituent present in the spice turmeric, is known to prevent the aggregation of amyloid peptide implicated in the pathophysiology of Alzheimer's disease. While curcumin is known to bind directly to various amyloid aggregates, no systematic investigations have been carried out to understand its ability to bind to the amyloid aggregates including oligomers and fibrils. In this study, we constructed computational models of (i) Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper β-sheet assembly and (ii) full-length Aβ fibril β-sheet assembly. Curcumin binding in these models was evaluated by molecular docking and molecular dynamics (MD) simulation studies. In both the models, curcumin was oriented in a linear extended conformation parallel to fiber axis and exhibited better stability in the Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper model (Ebinding  = -10.05 kcal/mol) compared to full-length Aβ fibril model (Ebinding  = -3.47 kcal/mol). Analysis of MD trajectories of curcumin bound to full-length Aβ fibril shows good stability with minimum Cα-atom RMSD shifts. Interestingly, curcumin binding led to marked fluctuations in the (14) HQKLVFFA(21) region that constitute the fibril spine with RMSF values ranging from 1.4 to 3.6 Å. These results show that curcumin binding to Aβ shifts the equilibrium in the aggregation pathway by promoting the formation of non-toxic aggregates.

Ever since the discovery of aspirin, small molecule therapeutics have been widely prescribed to treat inflammation and pain. Aspirin and several small molecule NSAIDs are known to inhibit the enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2). Despite the success of NSAIDs to treat inflammatory disorders, the development of a clinically useful small molecule NSAIDs with decreased side effect profiles is an ongoing effort. The recent discovery and development of selective COX-2 inhibitors was a step toward this direction. Emerging trends are represented by the progress in the development of hybrid agents such as nitric oxide donor-NSAIDs (NO-NSAIDs) and dual COX/lipoxygenase (LOX) inhibitors. This review focuses on the recent advances in the rational design of small molecule NSAIDs in therapy.