Neuroprotective Activity of Melittin—The Main Component of Bee Venom—Against Oxidative Stress Induced by Aβ25–35 in In Vitro and In Vivo Models

Abstract

Melittin, a 26-amino acid peptide, is the main component of the venom of four honeybee species and exhibits neuroprotective actions. However, it is unclear how melittin ameliorates neuronal cells in oxidative stress and how it affects memory impairment in an in vivo model. We evaluated the neuroprotective effect of melittin on Aβ25–35-induced neuro-oxidative stress in both in vitro HT22 cells and in vivo animal model. Melittin effectively protected against HT22 cell viability and significantly deregulated the Aβ25–35-induced overproduction of intracellular reactive oxygen species. Western blot analysis showed that melittin suppressed cell apoptosis and regulated Bax/Bcl-2 ratio, as well as the expression of proapoptotic related factors: Apoptosis-inducing factor (AIF), Calpain, Cytochrome c (CytoC), Cleaved caspase-3 (Cleacas3). Additionally, melittin enhanced the antioxidant defense pathway by regulating the nuclear translocation of nuclear factor erythroid 2-like 2 (Nrf2) thus upregulated the production of the heme oxygenase-1 (HO-1), a major cellular antioxidant enzyme combating neuronal oxidative stress. Furthermore, melittin treatment activated the Tropomyosin-related kinase receptor B (TrkB)/cAMP Response Element-Binding (CREB)/Brain-derived neurotrophic factor (BDNF), contributing to neuronal neurogenesis, and regulating the normal function of synapses in the brain. In our in vivo experiment, melittin was shown to enhance the depleted learning and memory ability, a novel finding. A mouse model with cognitive deficits induced by Aβ25–35 intracerebroventricular injection was used. Melittin had dose-dependently enhanced neural-disrupted animal behavior and enhanced neurogenesis in the dentate gyrus hippocampal region. Further analysis of mouse brain tissue and serum confirmed that melittin enhanced oxidant–antioxidant balance, cholinergic system activity, and intercellular neurotrophic factors regulation, which were all negatively altered by Aβ25–35. Our study shows that melittin exerts antioxidant and neuroprotective actions against neural oxidative stress. Melittin can be a potential therapeutic agent for neurodegenerative disorders.

Deltamethrin induces apoptosis in cerebrum neurons of quail via promoting endoplasmic reticulum stress and mitochondrial dysfunction

“…AIF can be transported into the nucleus and cause DNA fragmentation 68 . AIF and Cyt C are both pro‐apoptotic factors 69 . These factors activate the caspase signaling pathway and undergo a series of enzyme‐linked reactions to apoptosis.…”

“…AIF and CytC are both pro-apoptotic factors 69. These factors activate the caspase signaling pathway and undergo a series of enzyme-linked reactions to apoptosis.…”

Pharmacokinetic improvement provided by microneedle patch in delivering bee venom, a case study in combating scopolamine-induced neurodegeneration in mouse model

“…Bee venom, thanks to research conducted across recent years, has been proven to have comprehensive anti-neurodegenerative effects (Moon et al, 2006 , 2007 ; Doo et al, 2012 ; Chung et al, 2015 ; Gu et al, 2015 ; Hwang et al, 2015 ; Im et al, 2016 ; Ye et al, 2016 ; Cai et al, 2017 ; Ham et al, 2019a, 2019b; Nguyen & Lee, 2021 ; Duc Nguyen et al, 2022 ). For instance, in terms of both in vitro and in vivo models, bee venom diminished LPS-induced proinflammatory cytokines GFAP, IBA-1, COX-2, and iNOS, having also resulted in a decrease in amyloid genesis and neuroinflammation.…”

“…In this study, melittin—a major component of bee venom—directly binds to the C-terminus of p50 where NLS is located and, as such, interrupts translocation of NF-κB (Gu et al, 2015 ; Im et al, 2016 ). Bee venom and melittin were also found to enhance neuro stress-induced conditions triggered by Amyloid beta in both in vitro and in vivo studies; this finding was significant since it exhibits the neuroprotective ability of the drug candidate in enhancing the intrinsic antioxidant defense barrier by promoting Nrf2 nuclear translocation and up regulating the antioxidative HO-1 enzyme production; as such, brain tissue redox balance was significantly fostered and subsequent brain-derived neurotrophic factors, inflammation regulations, and learning memory ability were all significantly restored (Nguyen & Lee, 2021 ; Duc Nguyen et al, 2022 ). Furthermore, in a report of vascular dementia is caused by ischemia and/or vascular brain lesions, bee venom had significantly recovered and restored the cognitive indexes and brain cells’ metabolisms (Cai et al, 2017 ).…”

“…For centuries, bee venom has been a therapeutic source for curing a diverse array of human disorders (Pucca et al, 2019 ; Kasozi et al, 2020 ); recently, the focus on bee venom as a therapy has gained steady interest from researchers and practitioners given bee venom’s anti-neurodegeneration ability, with recent studies have depicted bee venom’s significant anti-neurodegenerative properties via a wide-range of mechanisms (Moon et al, 2006 , 2007 ; Doo et al, 2012 ; Chung et al, 2015 ; Gu et al, 2015 ; Hwang et al, 2015 ; Im et al, 2016 ; Ye et al, 2016 ; Cai et al, 2017 ; Ham et al, 2019a, 2019b; Nguyen & Lee, 2021 ; Duc Nguyen et al, 2022 ).…”