Anthocyanins abrogate glutamate-induced AMPK activation, oxidative stress, neuroinflammation, and neurodegeneration in postnatal rat brain

Abstract

BackgroundGlutamate-induced excitotoxicity, oxidative damage, and neuroinflammation are believed to play an important role in the development of a number of CNS disorders. We recently reported that a high dose of glutamate could induce AMPK-mediated neurodegeneration in the postnatal day 7 (PND7) rat brain. Yet, the mechanism of glutamate-induced oxidative stress and neuroinflammation in the postnatal brain is not well understood. Here, we report for the first time the mechanism of glutamate-induced oxidative damage, neuroinflammation, and neuroprotection by polyphenolic anthocyanins in PND7.MethodsPND7 rat brains, SH-SY5Y, and BV2 cells treated either alone with glutamate or in combination with anthocyanins and compound C were examined with Western blot and immunofluorescence techniques. Additionally, reactive oxygen species (ROS) assay and other ELISA kit assays were employed to know the therapeutic efficacy of anthocyanins against glutamate.ResultsA single injection of glutamate to developing rats significantly increased brain glutamate levels, activated and phosphorylated AMPK induction, and inhibited nuclear factor-E2-related factor 2 (Nrf2) after 2, 3, and 4 h in a time-dependent manner. In contrast, anthocyanin co-treatment significantly reduced glutamate-induced AMPK induction, ROS production, neuroinflammation, and neurodegeneration in the developing rat brain. Most importantly, anthocyanins increased glutathione (GSH and GSSG) levels and stimulated the endogenous antioxidant system, including Nrf2 and heme oxygenase-1 (HO-1), against glutamate-induced oxidative stress. Interestingly, blocking AMPK with compound C in young rats abolished glutamate-induced neurotoxicity. Similarly, all these experiments were replicated in SH-SY5Y cells by silencing AMPK with siRNA, which suggests that AMPK is the key mediator in glutamate-induced neurotoxicity.ConclusionsHere, we report for the first time that anthocyanins can potentially decrease glutamate-induced neurotoxicity in young rats. Our work demonstrates that glutamate is toxic to the developing rat brain and that anthocyanins can minimize the severity of glutamate-induced neurotoxicity in an AMPK-dependent manner.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0752-y) contains supplementary material, which is available to authorized users.

Metabolic Stress Alters Antioxidant Systems, Suppresses the Adiponectin Receptor 1 and Induces Alzheimer’s Like Pathology in Mice Brain

“…Of note, AMPK is a major downstream molecule of APN signaling. In general, AMPK acts as the cellular energy or fuel sensor responsible for the maintenance of cellular energy homeostasis in the body and is normally activated in response to an increase in the intracellular AMP/ATP ratio [73][74][75], e.g., the depletion of cellular energy by stress, starvation, hypoxia, or other means causes an increase in intracellular AMP and thereby, allosterically activates AMPK through phosphorylation of its α-subunit at Thr-172 by upstream kinases [76]. Reduced circulating APN levels have been observed in aged obese individuals and obese patients with type 2 diabetes mellitus [77,78].…”

Evaluation of Polyphenol Anthocyanin-Enriched Extracts of Blackberry, Black Raspberry, Blueberry, Cranberry, Red Raspberry, and Strawberry for Free Radical Scavenging, Reactive Carbonyl Species Trapping, Anti-Glycation, Anti-β-Amyloid Aggregation, and Microglial Neuroprotective Effects

“…Published data suggest that the neuroprotective effects of berry fruits are associated with their polyphenolic compounds, particularly, anthocyanins [ 37 , 38 ]. For instance, anthocyanins have been reported to protect against inflammatory and oxidative stress mediated neuroinflammation and neurodegeneration in adult mouse cortex [ 39 ], as well as in brains of postnatal rats [ 40 ], and rats fed a high-fat diet [ 41 ]. In light of these data, we designed the current study to evaluate the potential neuroprotective effects of polyphenolic-enriched extracts of six common edible berries, namely, blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry.…”

Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review

“…Long-lasting neuroinflammation and oxidative stress are the other pathological processes involved in brain aging and neurodegeneration (Lee et al, 2008;Mishra et al, 2016;Shah et al, 2016). It has been reported that neuroinflammation is a key player in various neurological disorders, including neurodegenerative illnesses and CNS injury (Chen et al, 2016;Yang and Zhou, 2018).…”