Treatment of inflammation using α7 receptor-binding cholinergic agonists
View Patent ↗A method of treating a patient suffering from pancreatitis comprising treating said patient with a therapeutically effective amount of a cholinergic agonist selective for an α7 nicotinic receptor in an amount sufficient to decrease the amount of the proinflammatory cytokine that is released from a macrophage wherein said condition is acute pancreatitis. The compounds of the present invention include a quaternary analog of cocaine; (1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethyl ester; a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IV), and an oligonucleotide or mimetic capable of attenuating the symptoms of acute pancreatitis wherein the oligonucleotide or mimetic consists essentially of a sequence greater than 5 nucleotides long that is complementary to an mRNA of an α7 cholinergic receptor. The variables of formulae (I), (II), (III) and (IV) are described herein.
1. A method for identifying an antibody that is an agonist selective for an α7 nicotinic receptor, wherein the method comprises obtaining an antibody that binds an α7 receptor or fragment thereof, and determining whether the antibody is an agonist selective for the α7 nicotinic receptor by (i) determining whether the antibody inhibits release of a proinflammatory cytokine from a mammalian cell, and (ii) determining whether the antibody is reactive with at least one nicotinic receptor that is not an α7 receptor, wherein an antibody that inhibits release of a proinflammatory cytokine from a mammalian cell and is not reactive with at least one nicotinic receptor that is not an α7 receptor, is an agonist selective for an α7 nicotinic receptor.
2. The method of claim 1 , wherein the proinflammatory cytokine is selected from the group consisting of tumor necrosis factor (TNF), interleukin (IL)-1β, IL-6, IL18 and HMG-1.
3. The method of claim 2 , wherein the proinflammatory cytokine is TNF.
4. The method of claim 1 , wherein the mammalian cell is an immune cell.
5. The method of claim 1 , wherein the mammalian cell is a macrophage.
6. The method of claim 1 , further comprising treating the mammalian cell with an agent that stimulates a proinflammatory cytokine cascade.
7. The method of claim 6 , wherein the agent is LPS.
8. The method of claim 1 , wherein determining inhibition of proinflammatory cytokine release comprises measuring mRNA of the proinflammatory cytokine.
9. The method of claim 1 , wherein determining proinflammatory cytokine release comprises measuring the proinflammatory cytokine protein.
10. The method of claim 1 , wherein determining proinflammatory cytokine release comprises measuring the proinflammatory cytokine activity.