Methods and compositions for treatment of central nervous system disorders

A method of screening for substance that increases or decreases an effect of a substance that stimulates a nicotine receptor, comprising

• a) contacting a cell having a nicotine receptor with the substance that stimulates a nicotine receptor;
• b) contacting the cell with a test substance;
• and
• c) determining any increase or decrease in phosphorylation of JAK2 in the presence of the test substance relative to a level of JAK2 phosphorylation measured when the cell is in contact with a substance that stimulates a nicotine receptor in the absence of the test substance,
• wherein an increase in JAK2 phosphorylation indicates that the test substance increases the effect of the substance that stimulates a nicotine receptor on the nicotine receptor;
• and wherein a decrease in JAK2 phosphorylation indicates that the test substance decreases the effect of the substance that stimulates a nicotine receptor on the nicotine receptor.

A method of screening for substance that inhibits or stimulates an AT2 receptor, comprising,

• a) contacting a cell having a nicotine receptor and an AT2 receptor with a substance that stimulates the nicotine receptor;
• b) contacting the cell with a test substance;
• and
• c) determining any increase or decrease in phosphorylation of JAK2 in the presence of the test substance relative to a level of JAK2 phosphorylation measured when the cell is in contact with the substance that stimulates the nicotine receptor in the absence of the test substance,
• wherein an increase in JAK2 phosphorylation indicates that the test substance inhibits the AT2 receptor;
• wherein a decrease in JAK2 phosphorylation indicates that the test substance stimulates the AT2 receptor;
• and
• wherein any effect of the test substance on the nicotine receptor in the absence of the AT2 receptor is predetermined and any increase or decrease in JAK2 phosphorylation is determined relative to any JAK2 phosphorylation related to such effects.

A method of screening for a substance that impairs or enhances the effect of a substance that stimulates the AT2 receptor, comprising,

• a) contacting a cell having a nicotine receptor and an AT2 receptor with a substance that stimulates the nicotine receptor and a substance that stimulates the AT2 receptor;
• b) contacting the cell with a test substance;
• and
• c) determining any increase or decrease in phosphorylation of JAK2 in the presence of the test substance relative to a level of JAK2 phosphorylation measured when the cell is in contact with the substance that stimulates the nicotine receptor and the substance that stimulates the AT2 receptor in the absence of the test substance, wherein an increase in JAK2 phosphorylation indicates that the test substance impairs the effect of the substance that stimulates the AT2 receptor, or enhances the effect of the substance that inhibits the AT2 receptor;
• and
• wherein a decrease in JAK2 phosphorylation indicates that the test substance enhances the effect of the substance that stimulates the AT2 receptor, or impairs the effect of the substance that inhibits the AT2 receptor.

A method of screening for substances that have an effect on β amyloid-associated neurotoxicity mediated by a nicotinic receptor, comprising

• a) contacting a cell having a nicotine receptor with β amyloid peptide and determining a level of Janus-Activated Kinase 2 (JAK2) phosphorylation;
• and
• b) contacting the cell with a test substance and determining any increase or decrease in phosphorylation of JAK2,
• wherein an increase in JAK2 phosphorylation indicates that the test substance is a candidate substance for further evaluation as a substance capable of decreasing P amyloid-associated neurotoxicity.

A method of screening for substances that decrease the neurotoxicity of β amyloid peptides mediated by a nicotinic receptor, comprising,

• a) contacting a cell having a nicotine receptor with a β amyloid peptide and determining a level of Janus-Activated Kinase 2 (JAK2) phosphorylation;
• and
• b) contacting the cell with a test substance and determining any increase or decrease in phosphorylation of JAK2,
• wherein any increase in JAK2 phosphorylation indicates that the test substance decreases the neurotoxicity of β amyloid peptides.

A pharmaceutical composition for treatment or prophylaxis of a central nervous disorder for administration to a subject suffering from the disorder, comprising,

• a) a substance that stimulates a nicotine receptor;
• and
• b) either or both of at least one inhibitor of the AT2 receptor or at least one inhibitor of a substance that stimulates the AT2 receptor;
• and
• c) a pharmaceutically acceptable carrier.

A pharmaceutical composition for treatment or prophylaxis of a neurodegenerative disorder for administration to a subject suffering from the disorder, comprising,

• a) a substance that stimulates a nicotine receptor;
• and
• b) either or both of at least one inhibitor of the AT2 receptor or at least one inhibitor of a substance that stimulates the AT2 receptor;
• and
• c) a pharmaceutically acceptable carrier.