The JNK signaling pathway as a potential new target for depression

Abstract

Depression is a widespread chronic medical illness that can affect thoughts, mood, and physical health. It is characterized by low mood, lack of energy, sadness, insomnia, and an inability to enjoy life. So far, however, clinical studies have shown that patients with depression do not have a satisfactory therapeutic outcome. The pathogenesis of depressive disorder is still not well understood. In recent years, c-Jun N-terminal kinase (JNK) has received more and more recognition for its signaling pathway in the regulation of depression. In this article, we review new research progress in the contribution of JNK signaling to depression and summarize the possible underlying mechanisms. JNK is an important member of the mitogen-activated protein kinases (MAPK) family, and it is also known as stress activated protein kinase because it regulates various responses to environment stresses outside and inside cells. The JNK family has three subtypes of JNK1, JNK2 and JNK3, which are different in tissue expression distribution, activity regulation and function. The pathological factors of depression such as inflammatory stress, oxidative stress and psychological stress can affect the activity of JNK and JNK downstream can regulate the neurodegeneration, neurogenesis, synaptic plasticity, neuroinflammation, glucocorticoid receptor resistance and other related signaling pathways, which are involved in the pathophysiology of depression. Examination of Jnk knockout mice has revealed JNK imposes neurogenesis-dependent control of anxiety behavior. In inflammation-induced models of depression, JNK plays important roles in depressive-like behavior through promoting the expression of proinflammatory cytokines and inflammation-related enzymes. Depressive-like behavior induced by various stress often involves alteration of JNK signaling. For example, the hippocampus in wild-type mice exposed to chronic unpredictable mild stress had higher p-JNK protein expression. Human studies also show dysregulated expression of Jnk gene in blood white cells of depressed patients. All these data indicate that there is a close relationship between JNK and depression. Furthermore, candidate drugs targeting JNK have been developed and showed certain antidepressant effects. However, there are still many problems to be solved in the understanding the regulation mechanisms of JNK in depression. These mainly include: (1) Although there are many literatures on the correlation between JNK and depression, there is not much evidence on whether there is a causal relationship. (2) Although the relationship between JNK1 and depression is relatively clear, JNK2 and JNK3 remain ambiguous. (3) The systemic mechanism of JNK regulating depression needs to be fully revealed on all aspects of the reaction and interaction, including the central nervous system, immune system, endocrine system and so on. (4) The possible side effects of treating depression with JNK as a target need to be evaluated. Future research could be carried out on the above issues. With the development of research based on JNK mechanism, the molecular pathologic nature of depression could be more elucidated. Focusing on JNK as a target may provide new ideas for depression research and bring new strategies and new drug targets for prevention and treatment of depression.