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Lee, G. Melittin. Encyclopedia. Available online: (accessed on 11 December 2023).
Lee G. Melittin. Encyclopedia. Available at: Accessed December 11, 2023.
Lee, Gihyun. "Melittin" Encyclopedia, (accessed December 11, 2023).
Lee, G.(2021, November 21). Melittin. In Encyclopedia.
Lee, Gihyun. "Melittin." Encyclopedia. Web. 21 November, 2021.

Melittin, a 26-amino acid peptide, is the main component of the venom of four honeybee species and exhibits neuroprotective actions. Melittin alleviates HT22 in vivo and in vitro oxidative stress injury induced by Aβ25–35; For the first time, melittin has been reported to enhance cognitive function in a learning memory-deficit model; Melittin ameliorating mechanisms were observed via the nuclear translocation of Nrf2, stimulating 1-HO production and the regulation of the TrkB/CREB/BDNF pathway.

bee venom BDNF beta amyloid oxidative stress neurodegeneration melittin

1. Introduction

For centuries, bee venom therapy has been used to manage acute and chronic human diseases; recently, this focus has steadily gained more interest from researchers and practitioners for bee venom’s anti-neurodegeneration ability [1]. Melittin, a 26-amino acid peptide, is the dominant component in the venom of four most common honeybee species—Apis dorsataApis melliferaApis florea, and Apis cerena, which contain 95.8 ± 3.2%, 76.5 ± 1.9%, 66.3 ± 8.6%, and 56.8 ± 1.8% melittin, respectively [2][3].
Regarding neuroprotective effects, as evidenced by previous studies, melittin exhibits suppressive effects on the proinflammatory, and potentially pro-oxidative, response of BV2 microglia including the ability to reduce nitric oxide (NO) and inducible nitric oxide synthase (iNOS) by blocking LPS-induced activation of NF-κB7, suppressing the expression of COX-2/PGE2, resulting in anti-inflammatory properties [4]. Another study revealed that melittin stabilized pros and anti-apoptosis factor in SY5Y human neuroblastoma cells under stress induced by H2O2 [5].
As the primary component of honeybee venoms, melittin potential is high, and more research needs to be conducted on this compound to further explore its role in combating neurodegeneration. Neuro-oxidative stress ignited by beta amyloid (Aβ) in the human brain is a main trigger for the progression of neural disorder [6][7], and melittin’s protective capacity and mechanisms in this aspect are still unclear. Further, at an in-vivo level, the ability of melittin to convalesce deficit cognitive function remains elusive.
In previous cardiology and renal studies, melittin was reported to regulate the nuclear translocation of Nrf2, a key transcription factor that upregulates HO-1 expression [8][9]. HO-1 is a critical cellular antioxidant enzyme that normalizes redox balance in various disorders including in neurodegenerative oxidative stress [10]. A step from this, in an anti-neurodegeneration study, the TrkB/CREB/BDNF loop was also a companionable route that inter-connects and is commonly studied alongside cellular antioxidant aspects [10][11]. Therefore, we hypothesized that melittin also protects neuron cells such as HT22 against neurodegeneration induced by oxidative stress by regulating the Nrf2/HO-1, and TrkB/CREB/BDNF pathways; consequently, this substance has a high chance of exhibiting protection effects in a neurodegenerative cognitive induced in vivo model.

2. Protective Effect of Melittin on Oxidative Stress-Induced Apoptosis in HT-22 Cells

To determine the therapeutic window, we first identified the maximum safety concentrations; we tested melittin concentrations of 0.1–30 μM on HT22 cells and found that a concentration of 3 μM was the maximum safe concentration for our experiment (Figure 1A). Next, for protection effect against 7-μM Aβ25–35-induced stress, melittin (0.3–3 μM) exhibited observable dose-dependent effects; therefore, these concentrations were selected for further study (Figure 1B).
Figure 1. Screening for melittin maximum safety dosage and melittin protective effect against Aβ25–35 stress induced in HT22 cells. (A) Screening for maximum melittin safety concentration. The result indicated that 3 μM was the highest safety concentration of melittin to be studied. To conduct this experiment: Cells were seeded in 96-well plates; after incubation for 24 h, Melittin at different concentrations was introduced, and cell availability was examined after 24 h of incubation. (B) Protective effect of melittin against Aβ25–35 stress. The result indicated that 0.3 to 3 μM melittin was found to dosage-dependently ameliorate HT22 cell availability. To conduct this experiment: Cells were seeded in 96-well plates; after incubation for 24 h, melittin from 0.1 to 3 μM was introduced 1 h before Aβ25–35 (7 μM) challenge, and cell availability was examined after 24 h of incubation. Data are presented as the mean ± standard deviation values of triple determinations. # p < 0.01 vs. control * p < 0.05 and ** p < 0.01 vs. Aβ25–35 only-treated group.
Further experiments were conducted to elucidate the protective effect of melittin against HT22 cell apoptosis. Results revealed that 0.1 μM melittin did not exhibit statistically significant efficacy; however, at 1 and 3 μM, melittin markedly reduced the apoptosis level in HT22 cells by 3- and 4-fold, respectively (Figure 2A). Western blot results indicated that the Bax/Bcl-2 protein ratio was increased 2.5-fold once cells were introduced with Aβ25–35, this parameter was dosage dependently normalized by melittin. A step from that, other apoptosis-closely-associated proteins such as AIF, Calpain, CytoC, and CleaCas3 levels were all simultaneously normalized by melittin (Figure 2B) [11][12]. These results are indicators confirming the effect of melittin in protecting HT22 cells against Aβ25–35 stress-induced neuronal apoptosis.
Figure 2. Apoptosis-inhibitory effects of melittin on Aβ25–35 induced HT-22 cells. (A) Immunofluorescence analysis to determine the cellular apoptosis rate. The result indicated that melittin at 0.3 to 3 μM dosage-dependently ameliorated HT22 cell apoptosis under Aβ25–35 (7 μM) stress-induced conditions. To conduct this experiment: Seven hours after Aβ25–35 (7 μM) challenge in 96-well plates, immunofluorescence staining was carried out to exhibit live cells (blue, stained by CytoCalcein Violet 450), necrotic cells (red, indicated by 7-AAD staining), and apoptotic cells (green, Apopxin Green Indicator). (B) Western blot analysis of key apoptosis proteins. The result indicated that melittin at 0.3 to 3 μM dosage-dependently normalized the expression of pro and anti-apoptosis protein under Aβ25–35 stress challenge. To conduct this experiment: Seven hours after Aβ25–35 (7 μM) challenge in 6-well plates, cells were lysed, and western blot was performed. Data are presented as mean ± standard deviation values of triple determinations. # p < 0.01 vs. control * p < 0.05 and ** p < 0.01 vs. Aβ25–35 only-treated group.

3. Effects of Melittin on Aβ25–35-Induced Oxidative Stress

Melittin has previously been reported to possess antioxidant activity [2][8][9]. This suggests that the antioxidant properties of melittin can reduce the accumulation of intracellular ROS under Aβ25–35 oxidative stress-induced conditions [13]. We found that melittin, 1 and 3 μM, significantly reduced the cellular ROS levels (Figure 3A) by 2- and 3-fold, respectively. This further confirmed that 0.3 to 3 μM melittin dosage-dependently ameliorated the leakage of the key oxidative stress markers MDA and LDH. These excessive destructive cellular free radical sources can modify structure scaffolds and functional apparatus, which eventually increase protein carbonylation [14]. Protein carbonyl is a specific oxidative stress marker that is associated with various disease, including Alzheimer’s disease [15]. Our result indicated that 0.3 to 3 μM melittin exhibited a significant effect in down-regulating cellular protein carbonyl levels (Figure 3B).
Figure 3. Melittin regulates cellular oxidative stress induced by Aβ25–35 in HT22 cells. (A) Immunofluorescence analysis to determine the cellular ROS rate. The result indicated that melittin at 0.3 to 3 μM dosage-dependently normalized the expression of pro and anti-apoptosis proteins under Aβ25–35 stress challenge. To conduct this experiment: Seven hours after Aβ25–35 (7 μM) challenge in 96-well plates, immunofluorescence analysis by DCFDA staining was carried out. (B) Cellular MDA, LDH, and protein carbonyls levels. The result indicated that melittin at 0.3 to 3 μM dosage-dependently down-regulated MDA, LDH, and protein carbonyl parameters under Aβ25–35 stress challenge. To conduct this experiment: Seven hours after Aβ25–35 (7 μM) challenge in 6-well plates, kits measuring MDA, LDH, and protein carbonyls were used to determine the parameters. Data are presented as mean ± standard deviation values of triple determinations. # p < 0.01 vs. control * p < 0.05 and ** p < 0.01 vs. Aβ25–35 only-treated group.

4. Discussion

Neurodegenerative diseases, including Alzheimer which results in a decrease of human cognitive function, have become the main obstacles that degrade human life span and the overall wellbeing [16].
Through aging, Aβ is a product that naturally emerges and accumulates in the brain. Accumulated Aβ gradually forms aggregates with beta-sheet structures and has the capacity to alter the intercellular redox balance of neurons cells. This is considered a major cause of the onset of cognitive dysfunction [17][18][19]. Among Aβ variances, the Aβ25–35 fragment is the shortest segment of full-length Aβ142that can form a beta-sheet; this fragment was proven to have similar oxidative neurotoxicity output compared with the full-length Aβ142 [20]. With good solubility and stress-induced efficiency, interest in this undecapeptide Aβ25–35 has grown over the last decade [21].
In detail, both full-length and short Aβs were proven to form ion-like channels in cell membranes that promote Ca2+ influx, destabilize intercellular balance, and produce cellular oxidative stress [22][23][24]. Another source of oxidative stress arises as Aβ25–35 and Aβ142were also both found to cause mitochondrial abnormalities via the deactivation of mitochondrial complex IV [25][26][27][28]. In neurodegenerative progression, ROS overproduction from these important events causes damage to the cellular structure, increases MDA, LDH, and protein carbonyl levels, eventually initiates neuron cell death mechanisms, and promotes neuro-cognitive impairments [10][29][30]. Explaining this similar effect of Aβ2535 and Aβ1-42 is still a topic of debate, but the single methionine-35 located in both Aβs was mentioned as its redox states are significantly important for Aβ-correlated free radical oxidative stress and neurotoxicity causes [27][31][32][33].
In the in vitro study, our results demonstrated that Aβ25–35 induced injury in HT-22 cells, including massive ROS release, resulting in MDA and LDH leakage and increased protein carbonyl levels, which substantially reduced HT-22 cell viability. Melittin dramatically mitigated Aβ25–35-induced oxidative stress injury by reducing ROS, MDA, SOD, and eventually, the protein carbonyl levels. To further explain these phenomena, we examined the melittin effect on the generation of HO-1, an important component of the cellular antioxidant system. This protein expression is inducible and has been demonstrated to shield cells against oxidative damage [34]. HO-1 expression is regulated by Nrf2. In the primitive stage, Nrf2 is retained in the Nrf2-Keap1 complex, and activation of cellular protection mechanisms leads to the separation of Nrf2 from the complex and transfer to the nucleus. Nrf2 acts as a transcription factor in the antioxidant response element (ARE) gene region, which in turn upregulates the expression of the HO-1 gene [10][14]. Our results showed that under cellular stress-induced conditions, melittin markedly upregulated the nuclear translocation of Nrf2 and enhanced the overall production of antioxidant enzyme activity, suggesting that the beneficial effect of melittin on Aβ25–35-induced HT22 cell injury was attributed to its antioxidant properties. This is in line with the findings of previous studies indicating that melittin enhances Nrf2 nuclear translocation and subsequently upregulates the expression of important antioxidant genes such as HO-1 [8][9].
One other mechanism of melittin can be related to the TrkB/CREB/BDNF pathway, which is a commonly studied direction along with antioxidant aspects [11][12][35][36]. The activation of TrkB can lead to downstream enhancement of both cellular antioxidant defensive and brain-derived neurotrophic factor neuro-proliferative shields [10]. In our experiment, Aβ25–35 presence significantly depleted the TrkB/CREB/BDNF pathway. Remarkably, melittin induced p-TrkB activation, increased the amount of p-CREB transcription factor, and in turn upregulated the expression of BDNF [37]. Moreover, BDNF was examined to stimulate subsets of Trk receptors and can further protect neuronal cells from oxidative stress-induced cell death [38][39]. The grounds above suggested the mechanism on how melittin demonstrated the ability to protect neuron cell HT22 apoptosis induced by Aβ25–35, an protective effect which was confirmed by the normalization of Bax/Bcl-2 ration, apoptosis-inducing factor, Calpain, CytoC, and CleaCas3.
For in vivo research, the injection of Aβ25–35 into mice brains was a utilized as a mean to induce oxidative stress, initiating synaptic loss, suppressing neurogenesis, and resulting in cognitive impairments in animal experiments [21][40][41][42]. This model elicits a considerable degree of Alzheimer’s progression signs and neurodegeneration conditions in general [41].
In this study, melittin significantly enhanced the memory and learning abilities of cognitive impairment-induced animals, a novel finding. The neuroprocessing ability of mice is closely related to hippocampal physiology [43]. Among the many anatomical parts of the hippocampus, the dentate gyrus is commonly studied and plays a key role in the formation, recall, and discrimination of episodic memory [44]. The significant increase in neurogenesis in this region has proven the effect of melittin at an anatomical scale.
To further explore the antioxidant property of melittin, we measured ROS and MDA levels in the hippocampus and serum; the levels of these parameters were significantly increase due to Aβ25–35 ICV., and melittin treatment clearly decreased these oxidative stress markers. Our results showed melittin reduced the amount of NO accumulation and iNOS protein expression in the hippocampus, which indicates melittin’s effect in lowering neuronal-derived nitric oxide—a key element stimulating neural diseases [45][46].
Maintenance of the balance of the cholinergic system is necessary for normal memory function [47]. Previous studies have revealed that patients with Alzheimer’s disease have downregulated expression of mAChR 1; hence, it is an important neuroreceptor to study in the cholinergic system [47]. In the synaptic cleft, ACh binds to postsynaptic mAChRs, and the synaptic signal communicates sequentially with the cyclic adenosine monophosphate/protein kinase A/CREB signaling pathway via G-coupled protein receptors. This bridge reflects the reality that the cholinergic signaling system and intercellular neurotrophic factors are two reciprocal entities. The disruption of one can cause a negative effect on the other and they both synergistically facilitate the grounds for neuronal grow and brain normal cognitive functions [48]. In our study, downregulation of mAChR 1 expression by Aβ25–35 in hippocampal tissues was significantly normalized by melittin pretreatment. Excessive AChE activity leads to a decrease in the Ach level in hippocampal cholinergic synapses. Aβ25–35 ICV. injection augmented AChE activity by 1.5-fold in hippocampal tissue, whereas pretreatment with melittin completely attenuated the excessive activation of AChE and increased ACh levels. Regarding intercellular neurotrophic factors, the transcription factor CREB, which plays a key role in BDNF synthesis, is essential for memory and synaptic plasticity [49]. In line with the in vitro experiments, our in vivo results showed that melittin-treated mice also had increased hippocampal p-CREB and BDNF levels.
Therefore, through both in vivo and in vitro experiments, melittin had proved itself to be a drug candidate combating neurovegetative disease.
The drug administration route of melittin is often subcutaneous, which can cause adverse effects if over-dosed [50]. Although melittin exhibited the ability to recover cognitive function in neurodegenerative-induced models, its irritation properties should be alleviated, and an optimal dosage for humans should be determined. In other disease research with melittin, up-to-date recombinant technology and computational bioinformatics modified the specific amino acid sequences and created a specialized-engineered-melittin. This produced effective augmentation and enhanced drug delivery, which enabled melittin to event be intravenously injected and to target a specific group of malarian cells [51]. Such advances can alleviate the side effects of melittin and further increase the popularity of melittin treatment.


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