3:43 PM
Feb 14, 2018
 |  BC Extra  |  Preclinical News

Three targets in the same brain region could alleviate depression

A Zhejiang University team published a pair of papers in Nature suggesting ketamine works by modulating the firing of neurons in the lateral habenula, a brain region that controls reward signaling. The studies point to three different targets in the brain structure that could be used to create a more selective therapy.

Ketamine, an NMDA receptor antagonist, has been shown to alleviate depression symptoms more quickly than marketed therapies, and Johnson & Johnson (NYSE:JNJ) has a version of the drug, esketamine, in Phase III for the indication. However, ketamine binds to multiple receptors in the brain and has undesirable psychological side effects.

The first study asked whether ketamine’s antidepressant action might be due to effects on the spiking of lateral habenula neurons, which previous studies had shown is aberrantly high in mouse models of the condition.

In mouse and rat models of depression, local infusion of ketamine into the lateral habenula decreased burst firing of the structure’s neurons and was sufficient to alleviate the animals’ depression-like symptoms. The researchers found the effects depended on the NMDA receptor and calcium channel T-type, suggesting either could be a target for the disease.

The second study identified a third target in the same brain region -- potassium channel Kir4.1 (KCNJ10) expressed in astrocytes. A proteomic screen showed KCNJ10 was more highly expressed in the lateral habenula of depressed rats than healthy rats. In a rat model of depression, shRNA knockdown of KCNJ10 or expression of a dominant-negative KCNJ10 construct decreased lateral habenula burst firing and depression-like behaviors.

According to BioCentury's BCIQ database, no companies are developing compounds against KCNJ10 or calcium channel T-type for depression.

Ketamine has long been known to bind NMDA receptors, regarded by many as the drug’s primary target for depression. However, the role of NMDA receptors in depression has been called into question as a ketamine metabolite was found to alleviate depression without inhibiting NMDA receptors (see BioCentury Innovations May 26, 2016).

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