Biomedical subjects

Valentin A Pavlov

Publications and source records attributed to Valentin A Pavlov.

6 recordsLinked to original sources

PubMed2006

Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis.

The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the alpha7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an alpha7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of alpha7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.

Acetylcholine↗

PubMed2006

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia.

TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this "cholinergic antiinflammatory pathway" inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents.

Animals↗

PubMed2005

ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis.

MIF is a proinflammatory cytokine that has been implicated in the pathogenesis of sepsis, arthritis, and other inflammatory diseases. Antibodies against MIF are effective in experimental models of inflammation, and there is interest in strategies to inhibit its deleterious cytokine activities. Here we identify a mechanism of inhibiting MIF pro-inflammatory activities by targeting MIF tautomerase activity. We designed small molecules to inhibit this tautomerase activity; a lead molecule, "ISO-1 ((S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester)," significantly inhibits the cytokine activity in vitro. Moreover, ISO-1 inhibits tumor necrosis factor release from macrophages isolated from LPStreated wild type mice but has no effect on cytokine release from MIFdeficient macrophages. The therapeutic importance of the MIF inhibition by ISO-1 is demonstrated by the significant protection from sepsis, induced by cecal ligation and puncture in a clinically relevant time frame. These results identify ISO-1 as the first small molecule inhibitor of MIF proinflammatory activities with therapeutic implications and indicate the potential of the MIF active site as a novel target for therapeutic interventions in human sepsis.

Animals↗

PubMed2005

The cholinergic anti-inflammatory pathway.

The regulation of the innate immune response is critical for controlling inflammation and for the prevention and treatment of diseases. We recently demonstrated that the efferent vagus nerve inhibits pro-inflammatory cytokine release and protects against systemic inflammation, and termed this vagal function "the cholinergic anti-inflammatory pathway." The discovery that the innate immune response is regulated partially through this neural pathway provides a new understanding of the mechanisms that control inflammation. In this review, we outline the cholinergic anti-inflammatory pathway and summarize the current insights into the mechanisms of cholinergic modulation of inflammation. We also discuss possible clinical implications of vagus nerve stimulation and cholinergic modalities in the treatment of inflammatory diseases.

Animals↗

PubMed2002

Novel oxa-spermine homologues: synthesis and cytotoxic properties.

New oxa-spermine homologues 5-9 were synthesised and their anticancer properties were evaluated against a broad spectrum of cancer cells. All compounds, except 9 showed average GI(50) values in the range of 1.89-7.56 microM. SAR studies showed that the cytotoxic activity of these novel oxa-spermines depended on the length of the alkyl chain, the position of the oxa-amino functionality and also, on the type of sulphonamido group in the molecule. Although the mechanism of action of these compound remains to be elucidated, it would appear that direct drug-DNA interactions are not involved in the mode of action of these drugs.

Animals↗

PubMedDate not supplied

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.

Animals↗