semapimod and Edema

CNI-1493 is a potent anti-inflammatory agent, which deactivates macrophages and inhibits the synthesis of proinflammatory mediators. The objective of the present study was to identify the role of the central nervous system (CNS) and efferent vagus nerve signaling in CNI-1493-mediated modulation of acute inflammation in the periphery. CNI-1493 was administered either intracerebroventricularly (i.c.v., 0.1-1,000 ng/kg) or intravenously (i.v., 5 mg/kg) in anesthetized rats subjected to a standard model of acute inflammation (subcutaneous (s.c.) injection of carrageenan). I.c.v. CNI-1493 significantly suppressed carrageenan-induced paw edema, even in doses at least 6-logs lower than those required for a systemic effect. Bilateral cervical vagotomy or atropine blockade (1 mg/kg/h) abrogated the anti-inflammatory effects of CNI-1493 (1 microg/kg, i.c.v. or 5 mg/kg, i.v.), indicating that the intact vagus nerve is required for CNI-1493 activity. Recording of the efferent vagus nerve activity revealed an increase in discharge rate starting at 3-4 min after CNI-1493 administration (5 mg/kg, i.v.) and lasting for 10-14 min (control activity=87+/-5.4 impulses/s versus CNI-1493-induced activity= 229+/-6.7 impulses/s). Modulation of efferent vagus nerve activity by electrical stimulation (5 V, 2 ms, 1 Hz) of the transected peripheral vagus nerve for 20 min (10 min before carrageenan administration and 10 min after) also prevented the development of acute inflammation. Local administration of the vagus nerve neurotransmitter, acetylcholine (4 microg/kg, s.c.), or cholinergic agonists into the site of carrageenan-injection also inhibited acute inflammation. These results now identify a previously unrecognized role of efferent vagus nerve activity in mediating the central action of an anti-inflammatory agent.

Topics: Acetylcholine; Acute Disease; Animals; Atropine; Carrageenan; Dose-Response Relationship, Drug; Edema; Electric Stimulation; Ganglionic Stimulants; Hydrazones; Immunosuppressive Agents; Inflammation; Injections, Intraventricular; Male; Muscarine; Neuroimmunomodulation; Neurons, Efferent; Nicotine; Parasympathetic Nervous System; Parasympatholytics; Parasympathomimetics; Rats; Rats, Inbred Lew; Vagotomy; Vagus Nerve; Vasodilator Agents

Nitric oxide (NO), a small effector molecule produced enzymatically from L-arginine by nitric oxide synthase (NOS), is a mediator not only of important homeostatic mechanisms (e.g., blood vessel tone and tissue perfusion), but also of key aspects of local and systemic inflammatory responses. Previous efforts to develop inhibitors of NOS to protect against NO-mediated tissue damage in endotoxin shock have been unsuccessful, largely because such competitive NOS antagonists interfere with critical vasoregulatory NO production in blood vessels and decrease survival in endotoxemic animals. Accordingly, we sought to develop a pharmaceutical approach to selectively inhibit NO production in macrophages while sparing NO responses in blood vessels.. The process of cytokine-inducible L-arginine transport and NO production were studied in the murine macrophage-like cell line (RAW 264.7). A series of multivalent guanylhydrazones were synthesized to inhibit cytokine-inducible L-arginine transport. One such compound (CNI-1493) was studied further in animal models of endothelial-derived relaxing factor (EDRF) activity, carrageenan inflammation, and lethal lipopolysaccharide (LPS) challenge.. Upon activation with cytokines, macrophages increase transport of L-arginine to support the production of NO by NOS. Since endothelial cells do not require this additional arginine transport to produce NO, we reasoned that a competitive inhibitor of cytokine-inducible L-arginine transport would not inhibit EDRF activity in blood vessels, and thus might be effectively employed against endotoxic shock. CNI-1493, a tetravalent guanylhydrazone, proved to be a selective inhibitor of cytokine-inducible arginine transport and NO production, but did not inhibit EDRF activity. In mice, CNI-1493 prevented the development of carrageenan-induced footpad inflammation, and conferred protection against lethal LPS challenge.. A selective inhibitor of cytokine-inducible L-arginine transport that does not inhibit vascular EDRF responses is effective against endotoxin lethality and significantly reduces inflammatory responses.

Topics: Animals; Arginine; Biological Transport; Carrageenan; Cell Line; Dose-Response Relationship, Drug; Edema; Endotoxins; Enzyme Inhibitors; Hydrazones; Inflammation; Interferon-gamma; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Molecular Structure; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine