Further characterization of high mobility group box 1 (HMGB1) as a proinflammatory cytokine: central nervous system effects

High mobility group box 1 (HMGB1), an abundant, highly conserved cellular protein, is widely known as a nuclear DNA-binding protein. HMGB1 has been recently implicated as a proinflammatory cytokine because of its role as a late mediator of endotoxin lethality and ability to stimulate release of proinflammatory cytokines from monocytes. Production of central cytokines is a critical step in the pathway by which endotoxin and peripheral proinflammatory cytokines, including interleukin-1beta (IL-1) and tumor necrosis factor-alpha (TNF), produce sickness behaviors and fever. Intracerebroventricular (ICV) administration of HMGB1 has been shown to increase TNF expression in mouse brain and induce aphagia and taste aversion. Here we show that ICV injections of HMGB1 induce fever and hypothalamic IL-1 in rats. Furthermore, we show that intrathecal administration of HMGB1 produces mechanical allodynia (lowering of the response threshold to calibrated stimuli). Finally, while endotoxin (lipopolysaccharide, LPS) administration elevates IL-1 and TNF mRNA in various brain regions, HMGB1 mRNA is unchanged. It remains possible that HMGB1 protein is released in brain in response to LPS. Nonetheless, these data suggest that HMGB1 may play a role as an endogenous pyrogen and support the concept that HMGB1 has proinflammatory characteristics within the central nervous system.     

The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation

This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral a7 subunit-containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed.     

Piperazinyl-linked fluoroquinolone dimers possessing potent antibacterial activity against drug-resistant strains of Staphylococcus aureus

The synthesis of symmetric and asymmetric piperazinyl-linked dimers of the fluoroquinolone class of antibiotics is described. Specific dimers are shown to possess potent antibacterial activity against drug-resistant strains of Staphylococcus aureus, including strains possessing resistance due to the NorA multidrug efflux pump and a mutation in the quinolone resistance-determining region of topoisomerase IV.     

Hydroxamido vanadates: aqueous chemistry and function in protein tyrosine phosphatases and cell cultures

The protein tyrosine phosphatases (PTPases) are a group of regulatory enzymes that are critically important to a wide variety of cellular functions. A number of these PTPases have significant potential as targets for therapeutic intervention, for instance, in diabetes and autoimmune disease treatment. The hydroxylamine complex, bis(N,N-dimethylhydroxamido)hydroxooxovanadate (DMHAV), is an excellent inhibitor of the two PTPases, protein tyrosine phosphatase 1B (PTP1B) and leucocyte common antigen related phosphatase (LAR). However, because of the similarity of the active site architecture within the group of known PTPases, DMHAV is probably an effective inhibitor of most PTPases. Information gleaned from studies of the mechanism of inhibition of PTPases by peptide-derived inhibitors, together with information from comparative protein modelling and studies of the aqueous chemistry of DMHAV, has provided insights for the development of selective PTPase inhibitors. In cell cultures, DMHAV is effective in increasing phosphotyrosine levels on the insulin receptor and greatly facilitates glucose transport and glycogen synthesis. Selective PTPase inhibitors that are developed from the basis of the hydroxylamine motif may lead to effective vanadate-based complexes that have potential as therapeutic agents.     

Tarsier brain component composition and its implications for systematics

The taxonomic position ofTarsius has been a topic of some debate. Recent molecular and anatomical studies have shoen that tarsiers share a number of derived traits with Anthropoids. These include aspects of their reporductive biology and aspects of their olfactory and visual systems. It has, therefore, been suggested that, despite a number of convergences with strepsirhine primates, tarsiers should be classified with the Anthropoid primates. We use comparative analyses of relative primate brain part volumes to determine whetherTarsius should be classified as a Haplorhine. We show that, for each of seven brain components whose relative size discriminates unequivocally between Strepsirhines and Haplorhines, the tarsiers fall in the Haplorhine distribution. These results confirm their classification with the Haplorhines.     

Genomic structure and chromosome location of the murine PDE1B phosphodiesterase gene

Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby participating in regulation of the intracellular concentrations of these second messengers. The PDE1 family is defined by regulation of activity by calcium and calmodulin. We have cloned and characterized the mouse PDE1B gene, which encodes the 63-kDa calcium/calmodulin-dependent PDE (CaM-PDE), an isozyme that is expressed in the CNS in the olfactory tract, dentate gyrus, and striatum and may participate in learning, memory, and regulation of phosphorylation of DARPP-32 in dopaminergic neurons. We screened an I-129/SvJ mouse genomic library and identified exons 2–13 of the PDE1B gene that span 8.4 kb of genomic DNA. Exons range from 67 to 205 nucleotides and introns from 91 to 2250 nucleotides in length. Exon 1 was not present in the 3 kb of genomic DNA 5′ to exon 2 in our clones. The mouse PDE1B gene shares many similar or identical exon boundaries as well as considerable sequence identity with the rat PDE4B and PDE4D genes and the Drosophila dunce cAMP-specific PDE gene dnc, suggesting that these genes all arose from a common ancestor. Using fluorescence in situ hybridization, we localized the PDE1B gene to the distal tip of mouse Chromosome (Chr) 15. Received: 10 November 1997 / Accepted: 12 March 1998     

Design,synthesis and evaluation of constrained tetrahydroimidazopyrimidine derivatives as antagonists of corticotropin-releasing factor type 1 receptor (CRF1R)

Several tetrahydroimidazopyrimidines were prepared using silver assisted cyclization as the key step. The binding affinities of compounds thus prepared were evaluated in vitro toward hCRF₁R. Initial lead compound 16 (K_i = 32 nM) demonstrated modest putative anxiolytic effects in the mouse canopy test. Further optimization using parallel synthesis provided compounds with K_i’s <50 nM.