HINT1 Is Involved in the Chronic Mild Stress Elicited Oxidative Stress and Apoptosis Through the PKC ε/ALDH-2/4HNE Pathway in Prefrontal Cortex of Rats

Abstract

Major depressive disorder (MDD) is a severe, highly heterogeneous, and life-threatening psychiatric disease which affects up to 21% of the population worldwide. A new hypothesis suggests that the mitochondrial dysfunction causing oxidative stress (OS) and dysregulation of apoptosis in brain might be one of the key pathophysiological factors in MDD. Histidine triad nucleotide binding protein 1 (HINT1), which was first supposed to be protein kinase C (PKC) inhibitor, has been gradually demonstrated to be involved in diverse neuropsychiatric diseases. It still remains elusive that how HINT1 involves in depression. The present study utilized a rat model exposed to chronic mild stress (CMS) to explore the involvement of HINT1 in depression. Face validity, construct validity and predictive validity of CMS model were comprehensive evaluated in this study. Behavioral tests including sucrose preference test, open field test, and elevated plus maze and forced swimming test revealed that stressed rats displayed elevated level of anxiety and depression compared with the controls. CMS rats showed a significant decrease of superoxide dismutase, and a marked increase malondialdehyde levels in prefrontal cortex (PFC). We also found the CMS rats had elevated expression of HINT1, decreased levels of phosphorylated-PKC ε and aldehyde dehydrogenase-two (ALDH-2), and accumulated 4-hydroxynonenal (4HNE) in PFC. Moreover, CMS increased the levels of cleaved caspase-3 and Bax, and decreased the level of Bcl-2 in PFC. The alterations in behavior and molecule were prevented by antidepressant venlafaxine. These results demonstrated that HINT1 was involved in the CMS elicited OS and apoptosis in PFC, probably through the PKC ε/ALDH-2/4HNE pathway. The results suggest that the suppression of HINT1 might have potential as a novel therapeutic strategy for depression.

Identification of Genetic Variations in the NAD-Related Pathways for Patients with Major Depressive Disorder: A Case-Control Study in Taiwan

“…SIRTs are NAD-dependent deacetylases and ALDHs are responsible for the removal of toxic intermediate aldehyde products. It has been shown that both genetic markers play essential roles in the NAD-related pathways and may be associated with the pathology of MDD [27,30]. Therefore, all SIRTs and ALDHs genes were also included in our search.…”

Electrolytic lesions of the bilateral ventrolateral orbital cortex not only directly reduce depression-like behavior but also decreased desperate behavior induced by chronic unpredicted mild stress in rats

“…The SPT is used to test for anhedonia which is one of the core symptoms of depression and a sign of the success of the CUMS model [ 25 ]. This experiment was divided into training and testing stages.…”

Histidine Triad Nucleotide-Binding Protein 1 Improves Critical Limb Ischemia by Regulating Mitochondrial Homeostasis

“…As Hint1 has been shown to participate in the regulation of the apoptotic pathway [12], it is likely to be involved in the process of angiogenesis and skeletal muscle regeneration in areas of hindlimb ischemia with ischemic necrosis, where monocytes and macrophages are known to play a critical role [23]. To investigate whether Hint1 deficiency affects the inflammatory condition of ischemic muscle, we performed flow cytometry to measure muscular inflammation.…”

“…Hint1 is involved in mitochondrial-related oxidative stress and apoptosis [23]. Hint2, an isomer of Hint1, is an important mitochondrial enzyme with similar substrate specificities with Hint1 [24].…”