3,3′-Diindolylmethane Promotes BDNF and Antioxidant Enzyme Formation via TrkB/Akt Pathway Activation for Neuroprotection against Oxidative Stress-Induced Apoptosis in Hippocampal Neuronal Cells

Abstract

3,3′-Diindolylmethane (DIM), a metabolite of indole-3-carbinol present in Brassicaceae vegetables, possesses various health-promoting effects. Nonetheless, the effect of DIM on neurodegenerative diseases has not been elucidated clearly. In this study, we hypothesized DIM may protect neuronal cells against oxidative stress-induced apoptosis by promoting the formation of brain-derived neurotrophic factor (BDNF) and antioxidant enzymes through stabilizing the activation of the tropomyosin-related kinase receptor B (TrkB) cascade and we investigated the effect of DIM on oxidative stress-mediated neurodegenerative models. DIM protected neuronal cells against oxidative stress-induced apoptosis by regulating the expression of apoptosis-related proteins in glutamate-treated HT-22 cells. Additionally, DIM improved the expression of BDNF and antioxidant enzymes, such as heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, and NAD(P)H quinine oxidoreductase-1, by promoting the activation of the TrkB/protein kinase B (Akt) pathway in the cells. Consistent with in vitro studies, DIM attenuated memory impairment by protecting hippocampal neuronal cells against oxidative damage in scopolamine-treated mice. Conclusionally, DIM exerted neuroprotective and antioxidant actions through the activation of both BDNF production and antioxidant enzyme formation in accordance with the TrkB/Akt pathway in neuronal cells. Such an effect of DIM may provide information for the application of DIM in the prevention of and therapy for neurodegenerative diseases.

Enteromorpha prolifera Extract Improves Memory in Scopolamine-Treated Mice via Downregulating Amyloid-β Expression and Upregulating BDNF/TrkB Pathway

“…The expression of BDNF increases protein synthesis by enhancing translation initiation via multiple signaling pathways, such as Akt [61]. In previous studies, the BDNF/TrkB/Akt-signaling pathway was activated by memory behavioral training for spatial reference and working memory [12,45]. Here, scopolamine decreased the expression levels of BDNF, p-TrkB, and p-Akt in the brain, whereas EAEP significantly restored the scopolamine-induced memory deficits.…”

“…These results suggest that the memory-enhancing effect of EAEP in scopolamine-induced memory impairment may be associated with modulation of the cholinergic nervous system. The most noticeable biological change in AD patients was the reduction in ACh levels in the hippocampus and cortex of the brain [11,12,53,54]. Thus, the mechanism of the memory-enhancing effect of EAEP on the cholinergic nervous system was assessed in brain tissue.…”

“…Of note, the effect of EAEP on the BDNF/TrkB/Akt pathway was examined, since the BDNF/TrkB/Akt pathway is known to modulate the growth and complexity of dendrites and play a critical role in learning and memory formation processes [9,11,12,59,60]. BDNF, a neurotrophic factor, activates TrkB, a BDNF receptor, and enhances synaptic plasticity, memory formation, and the persistence of memory storage.…”

Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System

“…PPE also increased the phosphorylations of MAPKs (p38, ERK, JNK), PI3K, Akt and p65, decreased NF-κB level and enhanced the nuclear translocation of Nrf2 and the expressions of HO-1 and SOD (Byun et al, 2018). 3,3 -Diindolylmethane is a metabolite of indole-3-carbinol found in Brassicaceae family and was found to attenuate OS in glutamate-induced HT-22 cells by activating the TrkB/Akt pathway (Lee et al, 2019). 3,3 -Diindolylmethane metabolite attenuated the expressions of Bax, cytochrome c, cleaved caspase-3, and AIF (apoptosis-inducing factor), and increased Bcl-2 expression, the phosphorylations of TrkB, Akt, and CREB, and the expressions of HO-1, GCLC, NQO-1, and GPx (Lee et al, 2019).…”

Antioxidants Properties of Natural Products: A Themed Issue in Honor of Professor Isabel C.F.R. Ferreira

“…Molecular mechanisms involved in the biological effects of quercetin were studied by Ayuda-Durán et al [20], using Caenorhabditis elegans as a model organism with different methodological approaches. Lee et al [21] assessed the 3,3 -Diindolylmethane, a metabolite of indole-3-carbinol present in Brassicaceae vegetables, regarding its potential for prevention and therapy of neurodegenerative diseases. The authors evaluated in vitro effects of this compound against oxidative stress-induced issues.…”