Method for identifying JNK and MLK inhibitors for treatment of neurological conditions

A method for assessing a compound's ability to prevent neuronal cell death occurring in a mammal susceptible to or having a neurological condition, comprising:

• a) contacting a compound with neuronal cells transfected with a mutated protein or treated with a neurotoxin that induces neuronal cell death;
• and
• b) determining the number of neuronal cells that die;
• wherein a decreased number of dead neuronal cells in the presence of the compound compared to the number of dead neuronal cells in the absence of the compound is indicative of the compound's ability to prevent neuronal cell death occurring in a mammal susceptible to or having a neurological condition.

A method for assessing the ability of a JNK and/or MLK inhibitor to prevent neuronal cell death occurring in a mammal susceptible to or having a neurological condition, comprising:

• a) contacting a JNK and/or MLK inhibitor with neuronal cells having activated MLK and/or JNK activity;
• b) contacting, in the presence of the compound, surviving cells from step (a) with an agent that induces apoptosis;
• and
• c) comparing the level of apoptosis in the cell in the presence of the JNK and/or MLK inhibitor with the level of apoptosis in the cell in the absence of the JNK and/or MLK inhibitor;
• wherein the JNK and/or MLK inhibitor is a potentially useful drug for treating the mammal when the level of apoptosis in the cell in the presence of the JNK and/or MLK inhibitor is less than the level of apoptosis in the cell in the absence of the JNK and/or MLK inhibitor.

A method for screening a compound's ability to inhibit JNK and/or MLK activity and thereby prevent neuronal cell death occurring in a mammal susceptible to or having a neurological condition, comprising:

• a) contacting a compound with a JNK and/or MLK protein and substrate therefor;
• b) measuring the level of JNK and/or MLK activity;
• c) comparing the level of JNK and/or MLK activity in the presence of the compound with the level of JNK and/or MLK activity in the absence of the compound, wherein a decrease in JNK and/or MLK activity in the presence of the compound is indicative that the compound is a JNK and/or MLK inhibitor;
• d) contacting the compound with neuronal cells having activated MLK and/or JNK activity;
• e) comparing the occurrence of apoptosis in the cell in the presence of the compound with the occurrence of apoptosis in the cell in the absence of the JNK and/or MLK inhibitor;
• wherein the JNK and/or MLK inhibitor is a potentially useful drug for treating the mammal when the occurrence of apoptosis in the cell in the presence of the JNK and/or MLK inhibitor is less than the occurrence of apoptosis in the cell in the absence of the JNK and/or MLK inhibitor.

A method for assessing a compound's ability to inhibit JNK and/or MLK activity and thereby prevent neuronal cell death occurring in a mammal susceptible to or having a neurological condition, comprising:

• a) incubating a compound in the presence of JNK and/or MLK and appropriate JNK and/or MLK substrate therefor, under conditions sufficient for enzymatic activity;
• and
• b) determining the presence or amount of phosphorylated product;
• wherein a change in amount of phosphorylated product, when compared to incubating JNK and/or MLK with appropriate substrates absent the compound, is indicative of the compound's ability to inhibit the enzymatic activity of JNK and/or MLK and thereby prevent neuronal cell death in a mammal susceptible to or having a neurological condition.

A method for assessing a compound's ability to inhibit JNK and/or MLK kinase activity and thereby prevent neuronal cell death occurring in a mammal susceptible to or having a neurological condition, comprising:

• (a) contacting a neuronal cell with a compound under conditions sufficient for JNK and/or MLK enzymatic activity;
• and
• (b) determining the presence or amount of phosphorylated JNK and/or MLK product;
• wherein a change in amount of phosphorylated product, when compared to incubating a cell absent the compound, is indicative of the compound's ability to inhibit JNK and/or MLK kinase activity and thereby prevent neuronal cell death occurring in a mammal susceptible to or having a neurological condition.

A method for assessing a compound's ability to inhibit MLK and/or JNK kinase activity and thereby prevent neuronal cell death occurring in a mammal susceptible to or having a neurological condition, comprising:

• (a) administering to an animal an amount of compound under conditions sufficient to allow for proper pharmacodynamic absorption and distribution thereof in the animal;
• and
• (b) determining the physiological status of the animal;
• wherein a change in physiological status, when compared to an animal not administered the compound, is indicative of the compound's ability to inhibit MLK and/or JNK kinase activity and thereby prevent neuronal cell death occurring in a mammal susceptible to or having a neurological condition.