Roles of Akt and ERK in mTOR-Dependent Antidepressant Effects of Vanillic Acid

Abstract

Vanillic acid, an oxidized form of vanilla, is a flavoring agent with a creamy odor. Several studies have reported the neuroprotective effects of vanillic acid, which are predominantly associated with anti-inflammatory and antioxidative properties. The anti-inflammatory and antioxidative properties may result from Akt or ERK signaling activation. The activation of the mammalian target of rapamycin (mTOR), a key downstream target of Akt and ERK signaling, is a crucial therapeutic target for treating depression. However, the antidepressant effects of vanillic acid remain unknown. The present study applied the forced swim test (FST) to investigate the antidepressant effects of vanillic acid and its association with Akt, ERK, and mTOR signaling and upstream α-amino-3-hydroxy-5-methyl-4-isoxazolepropionaic acid receptor (AMPAR) in the prefrontal cortex (PFC) of mice. Vanillic acid demonstrated antidepressant effects by significantly reducing behavioral despair in the FST. None of the treatments changed locomotor activity. Additionally, vanillic acid increased AMPAR throughput, Akt, and mTOR signaling but not ERK signaling in the PFC. NBQX (an AMPAR blocker), MK 2206 (an Akt blocker), and rapamycin (an mTOR blocker) used in pretreatment attenuated the antidepressant effects of vanillic acid, but SL327 (an ERK inhibitor) did not. The immunochemical results indicated that the antidepressant effects of vanillic acid depend on the AMPAR–Akt–mTOR signaling transduction pathway. Our findings reveal an Akt-dependent, but ERK-independent, the mechanism underlying the antidepressant effects of vanillic acid, which may be beneficial for some patients with depression.

A Review of the Pharmacological Characteristics of Vanillic Acid

“…19 The intraperitoneal administration of vanillic acid resulted in dose-dependent suppression of the acetic acid-induced writhing reaction (ED50:9.3mg/kg). 20 Pretreatment with ondansetron and yohimbine inhibited the antinociceptive function, suggesting that the serotonin ergicandad renergicsy stems could be involved in the pathway underlying vanillic acid's analgesic activity. 21 In vivo, this compound was shown to interact with ASICs (Acid-sensing Ion Channels) as well as TPRV1, TRPA1, and TRPM8 receptors.…”

UHPLC-Q-TOF-MS/MS and Network Pharmacology Analysis to Reveal Quality Markers of Xinjiang Cydonia oblonga Mill. for Antiatherosclerosis

“…Vanillic acid (VA) is a phenolic compound in the oxidized form of vanillin, and VA has analgesic, antioxidant and anti-inflammatory, and neuroprotective effects on nuclear factor- κ B activation, proinflammatory cytokine production, oxidative stress, and acetylcholinesterase [ 39 , 40 ]. Studies have shown that VA acts through the regulation of adhesion processes, E-selectin, and VEGF production, thus treating AS [ 41 ].…”

Mammalian AKT, the Emerging Roles on Mitochondrial Function in Diseases

“…Moreover, many antidepressants can mediate depression-like behavior via activation of the AKT pathway, for example, by activating the AKT/ GSK3β /β-catenin signaling pathway in the hippocampus to attenuate alcohol-induced depression in mice. Nicotinamide riboside, a precursor of NAD + , can activate AKT activity to reduce depression-like behaviors [ 167 ], similar to the antidepressant vanillic acid [ 168 ]. In addition, many studies have shown that except for exogenous antidepressants, exercise therapy is an effective treatment for depression.…”