Sub-Acute Treatment of Curcumin Derivative J147 Ameliorates Depression-Like Behavior Through 5-HT1A-Mediated cAMP Signaling

Abstract

Background Major depressive disorder (MDD) is a severe mental disorder related to the deficiency of monoamine neurotransmitters, particularly to abnormalities of 5-HT (5-hydroxytryptamine, serotonin) and its receptors. Our previous study suggested that acute treatment with a novel curcumin derivative J147 exhibited antidepressant-like effects by increasing brain derived neurotrophic factor (BDNF) level in the hippocampus of mice. The present study expanded upon our previous findings and investigated the antidepressant-like effects of sub-acute treatment of J147 for 3 days in male ICR mice and its possible relevancy to 5-HT 1A and 5-HT 1B receptors and downstream cAMP-BDNF signaling. Methods J147 at doses of 1, 3, and 9 mg/kg (via gavage) was administered for 3 days, and the anti-immobility time in the forced swimming and tail suspension tests (FST and TST) was recorded. The radioligand binding assay was used to determine the affinity of J147 to 5-HT 1A and 5-HT 1B receptor. Moreover, 5-HT 1A or 5-HT 1B agonist or its antagonist was used to determine which 5-HT receptor subtype is involved in the antidepressant-like effects of J147. The downstream signaling molecules such as cAMP, PKA, pCREB, and BDNF were also measured to determine the mechanism of action. Results The results demonstrated that sub-acute treatment of J147 remarkably decreased the immobility time in both the FST and TST in a dose-dependent manner. J147 displayed high affinity in vitro to 5-HT 1A receptor prepared from mice cortical tissue and was less potent at 5-HT 1B receptor. These effects of J147 were blocked by pretreatment with a 5-HT 1A antagonist NAD-299 and enhanced by a 5-HT 1A agonist 8-OH-DPAT. However, 5-HT 1B receptor antagonist NAS-181 did not appreciably alter the effects of J147 on depression-like behaviors. Moreover, pretreatment with NAD-299 blocked J147-induced increases in cAMP, PKA, pCREB, and BDNF expression in the hippocampus, while 8-OH-DPAT enhanced the effects of J147 on these proteins’ expression. Conclusion The results suggest that J147 induces rapid antidepressant-like effects during a 3-day treatment period without inducing drug tolerance. These effects might be mediated by 5-HT 1A -dependent cAMP/PKA/pCREB/BDNF signaling.

An Update on the Exploratory Use of Curcumin in Neuropsychiatric Disorders

“…The administration of curcumin has been shown to regulate serotonin (5-HT), dopamine (DA), and noradrenaline (NA) levels. Twenty studies reported an increment of 5-HT levels in the hippocampus, striatum or frontal cortex, which may be due to the interaction found between curcumin and 5-HT/cAMP/PKA/CREB/BDNF-signaling pathway or 5-HT 1A/1B and 5-HT 2C receptors [ 35 , 40 , 80 , 83 , 85 , 90 ]. Besides, fifteen studies reported an increased level of DA [ 38 , 41 , 42 , 44 , 45 , 46 , 48 , 49 , 55 , 72 , 77 , 81 , 87 , 91 ].…”

The Inhibitory Effect of Curcumin Derivative J147 on Melanogenesis and Melanosome Transport by Facilitating ERK-Mediated MITF Degradation

“…However, the poor bioavailability of curcumin and chemically modified curcumin (CMC) limits its application ( Karthikeyan et al, 2020 ). To solve this problem, J147 is developed as a potent compound of curcumin derivative with greater stability and bioavailability ( Li et al, 2020 ). In this work, we explored the inhibitory influences of J147 on pigment and underlying mechanisms in vitro and in vivo .…”

“…But, the poor bioavailability of curcumin limits its application ( Karthikeyan et al, 2020 ). To solve this problem, J147 is developed as a potent compound of curcumin derivative with greater stability and bioavailability ( Li et al, 2020 ). J147 has a neuroprotective effect and is currently in phase I clinical trials for Alzheimer’s disease.…”

Potential Role of Curcumin for the Treatment of Major Depressive Disorder

“…Findings from animal trials have demonstrated curcumin can alter the concentrations and activity of many of these neurotransmitters. For example, the acute administration of curcumin ameliorated depression-like behaviour in mice through its stimulatory influence on the 5-HT 1A receptor [ 30 ]. In ovariectomised mice, curcumin modulated depression-like behaviours and improved the serotonin content in several brain regions by upregulating tryptophan hydroxylase-2 and 5-HT 1A/2A receptor messenger RNA (mRNA) and downregulating monoamine oxidase A mRNA in the limbic system [ 13 ].…”