Depression afflicts approximately 16 percent of the world population at some point in their lives. Although antidepressant medications are available and useful, many patients remain treatment-refractory, and currently used drugs take several weeks to be effective. A recent exciting development is the finding that ketamine, which is widely used as an anesthetic in surgical settings, has efficacy as a rapidly acting antidepressant in treatment resistant patients. A single intravenous (i.v.) administration of a sub-anesthetic dose of ketamine results in prompt improvement in mood in depressed individuals, and the beneficial effect is sustained for about a week. Despite these promising results, ketamine's potential as a long-term antidepressant medication is limited due to its addictive nature, anesthetic properties, capacity to produce dissociative effects even when administered at low doses, and the invasiveness of its most common route of administration (i.v.). The proposed project takes advantage of ketamine's likely mechanism of action (inhibition of the NMDA receptor) but targets a site of the receptor (the "glycineB" receptor), which is less likely to precipitate adverse effects. Specifically, we will examine 4-chlorokynurenine (4-Cl-KYN), a brain-permeable pro-drug of the selective glycineB receptor antagonist 7-chlorokynurenic acid (7-Cl-KYNA). Notably, 4-Cl-KYN is currently under development for the treatment of neuropathic pain and, in a randomized dose escalation study in healthy human volunteers, was well tolerated and showed good oral bioavailability. Our long-term goal is to pursue the use of 4-Cl-KYN for the treatment of major depressive disorders in humans. Here, we will use mice to test the antidepressant-like properties and the side effect profile of 4-Cl-KYN. We will first, in Specific Aim #1, define the range of 4-Cl-KYN action on depression-related behaviors. These studies will evaluate dose- response relationships and include tests to predict rapid therapeutic action and to validate the glycineB receptor as a target for clinical intervention.
In Specific Aim #2, we will define biochemical and antidepressant-like effects of prolonged treatment with 4-Cl-KYN. We will measure behaviors, and the levels of both the precursor (4-Cl-KYN) and the effective compound (7-Cl-KYNA), in the brain of mice following various dosing schedules (continuous/chronic vs. intermittent, and peripheral vs. oral administration). The goal here is to address clinically relevant questions regarding prolonged efficacy, and possible tolerance or sensitization phenomena related to sustained glycineB receptor blockade. Finally, in Specific Aim #3, we will compare the side effect profiles of 4-Cl-KYN and ketamine, using treatment paradigms selected from Aim #2 and assessing behavior in tests that predict abuse and psychotomimetic potential. We anticipate that 4-Cl-KYN will prove superior to ketamine on several important experimental measures, and that successful completion of the project will allow us, to the extent possible using preclinical methods, to realistically evaluate the potential of 4-Cl-KYN as a treatment option for depression in humans.
The noncompetitive NMDA receptor antagonist ketamine has efficacy as a rapidly acting antidepressant in treatment refractory major depression patients;however, its potential as a long-term antidepressant treatment is limited due to its addictive nature, anesthetic properties, and capacity to produce dissociative effects even when administered at low doses. One alternative approach to address the urgent need for a viable alternative that safely inhibits NMDA receptor function is to target the obligatory glycine site of the receptor with 4- chlorokynurenine, which is the brain-permeable prodrug of a selective NMDA/glycine site antagonist, 7- chlorokynurenic acid. We propose to utilize validated rodent behavioral tests to determine the antidepressant- like capacity and side-effect profile of 4-chlorokynurenine, which will allow us to predict whether the drug holds potential as a future treatment option for major depressive disorder in humans.
|Zanos, Panos; Moaddel, Ruin; Morris, Patrick J et al. (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481-6|
|Zanos, Panos; Piantadosi, Sean C; Wu, Hui-Qiu et al. (2015) The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition. J Pharmacol Exp Ther 355:76-85|
|Mondrinos, Mark J; Knight, Linda C; Kennedy, Paul A et al. (2015) Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-Î´ Inhibitory Peptide: Impact on Indirect Lung Injury. J Pharmacol Exp Ther 355:86-98|