Activity Dependent Mammalian Target of Rapamycin Pathway and Brain Derived Neurotrophic Factor Release is Required for the Rapid Antidepressant Effects of Puerarin

Abstract

Puerarin is a traditional Chinese medicine with beneficial effects of reduced depression-like behaviors in mice with stress. Previous studies also show that puerarin can produce neuroprotective effect via activating the Akt or increased brain-derived neurotrophic factor (BDNF) expression. Interestingly, BDNF and Akt downstream target, mammalian target of rapamycin (mTOR) mediate the fast-acting antidepressant properties of ketamine. Until now, the involvement of the mTOR signaling pathway or BDNF on puerarin-induced antidepressant effect remains unknown. We aimed to investigate whether the antidepressant-like effect induced by puerarin would associate mTOR signaling pathway and BDNF release. The antidepressant-like effects of puerarin were evaluated using the forced swim test. The activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionaic acid receptor (AMPAR)-mTOR signaling pathway and release of BDNF in the prefrontal cortex were determined. We also investigated the effect of puerarin on AMPAR trafficking through measuring the PKA phosphorylation of AMPAR subunit GluR1. Our present results show that puerarin exerted antidepressant-like responses that was mediated by AMPAR-induced mTOR signaling pathway and associated with increased BDNF release. Moreover, a significant increase in the GluR1 phosphorylation at its PKA site was noted following puerarin treatment. Our findings are the first to demonstrate that the antidepressant-like actions of puerarin require AMPAR–mTOR signaling pathway activation, are associated with an increased BDNF level and facilitate AMPAR membrane insertion. These findings provide preclinical evidence that puerarin may possess antidepressant property which is mediated by the glutamatergic system.

Chinese Herbal Medicine Interventions in Neurological Disorder Therapeutics by Regulating Glutamate Signaling

“…Recently, Puerarin has been reported to activate AMPA receptors-induced mTOR signaling pathway, increase BDNF release, as well as increase GluR1 phosphorylation at its PKA site and facilitate AMPA receptors membrane insertion. These effects seem to suggest that it may be potentially used for the treatment of depression [ 102 ]. Total saikosaponins is the major ingredient of Bupleurum yinchowense .…”

Neuroprotective Mechanisms of Puerarin in Central Nervous System Diseases: Update

“…Similarly, it has also been shown that puerarin ameliorated ovariectomy-induced depressive-like behavior possibly through enhancing neurogenesis in the dentate gyrus of the hippocampus, and upregulating BDNF and the transcription of various estrogen receptors (ERα and ERβ) [ 102 ]. Similarly, activation ofα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR)/ mTOR signaling, together with an increased release of BDNF [ 103 ], upregulation of BDNF and activation of ERK signaling in the prefrontal cortex in diabetic rats [ 104 ], contributed to the anti-depressive effects of puerarin.…”

Chinese Pharmacopoeia Revisited: A Review of Anti-Depression Herbal Sources

“…99,[102][103][104] Among them, saikosaponins a-d, quercetin, rutin, puerarin, (2Z,8Z/E,10E)-pentadecatriene-4,6-diyne-1-ol and (2Z,8Z/E,10E)-heptadecatriene-4,6-diyne-1-ol have been reported to be the active antidepressant constituents of Bupleuri Radix. 99,[104][105][106] Taken together, the antidepressant activities of Bupleuri Radix have been elucidated in several experimental models, but the underlying mechanisms of its antidepressant effects and the active metabolites are largely unknown and need future investigation.…”

“…As the consequence of this activation, a significant increase in GluR1 phosphorylation at its PKA site and BDNF released were promoted to exert antidepressant effects on experimental animals. 105…”