Surface Plasmon Resonance Assay
To analyze the PLA2 binding to CD206, we conducted surface plasmon resonance using a Biacore 2000 instrument . In brief, HBS-EP buffer was used for the sample dilution and analysis. The CM5 dextran sensor chip was activated with equal amounts of 0.2 M N-ethyl-Ncarbodiimide and 0.05 M N-hydroxysuccinimide. Recombinant human CD206 was immobilized in 10 mM sodium acetate buffer and then 1 M ethanolamine-hydrochloride to deactivate any excess N-hydroxysuccinimide esters. This coupling resulted in 8000 response units of the immobilized proteins per flow cell. To evaluate the binding, each PLA2 was diluted in HBS-EP buffer, analyzed at various concentrations, and passed over the sensor chip at a flow rate of 20 l/min. An activatedand-blocked flow cell without immobilized ligand was used to evaluate nonspecific binding. The immobilized surface was regenerated for subsequent measurements using 10 l 10 mM NaOH. The regeneration solution was passed over the immobilized surface until the surface plasmon resonance signal reached the initial background value before protein injection. For all of the samples, response curves were also recorded on control surfaces. The results were calculated after subtraction of the control values using the BIAevaluation 3.0 software .
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Are There Studies To Support This
In 2008, the study Bee Venom as a Neuroprotective Agent in Parkinsons Disease was published by The Michal J. Fox Parkinson Foundation, which supports clinical research on the use of bee venom against Parkinson at the Pitie-Salpetriere hospital in Paris.In a pre-clinical model of the disease, it was verified whether bee venom and one of its components, apamine, are able to stop or slow the loss of dopaminergic neurons, the neuronal cell type most severely affected in Parkinsons disease. They showed that regular bee venom injections are indeed able to slow the degeneration of dopaminergic neurons in the PD model used, and that this effect is partially due to apamine. However, the complete list of compounds responsible for this effect and the mechanism of action remain to be characterized.
in 2011, Kim JI et al, conducted the study Bee venom reduces neuroinflammation in the MPTP-Induced Model of Parkinsons Disease in mice, at the Department of Acupuncture and Moxibustion, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea. The conclusion was: These data suggest that BV injection may have a neuroprotective effect that attenuates the activation of the microglial response, which has implications for the treatment of PD.
There were no serious side effects reported, with the exception of one patient who reported itchiness.
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Bvpla2 Protects Dopaminergic Neurons Against Mptp Neurotoxicity In A Concentration
We further evaluated whether purified standard bvPLA2 exhibited a dose-dependent neuroprotection against neuronal degeneration of PD. Expectedly, the immunohistochemistry data revealed apoptotic cell death in H& E stained and loss of dopaminergic neurons in TH stained sections of MPTP-challenged mice . In contrast, there was a dramatic neuronal protection in SN of MPTP mice following bvPLA2 treatment in a dose-dependent manner. When administered at a comparative lower dose , bvPLA2 administration did not significantly rescue MPTP-induced neuronal loss. Similar results were observed in MPTP mice given with commercial bvPLA2 at a dose of 0.5 mg/kg. These data indicate that purified bvPLA2 effectively attenuated the loss of dopaminergic neurons associated with PD in a concentration-dependent way.
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How Could It Work
Many of the symptoms from Parkinsons develop when brain cells that make the brain chemical dopamine are destroyed. Why this happens isnt clear.
Researcher Seong-Uk Park, MD, who presented this paper, says acupuncture may help by increasing dopamine levels. Acupuncture may also enhance the effects of the Parkinsons drug L-dopa and lessen the drugs side effects, he says. Park is with the Stroke and Neurological Disorders Center, Kyung Hee University Hospital, Gangdong, Seoul, Korea.
The treatment involves injecting bee venom under the skin at an acupuncture point. Its thought this may help enhance and prolong the effects of stimulation of acupuncture points. So the mechanism of bee-venom acupuncture might be similar to those of acupuncture. Or there could be another effect due to the bee venom itself, Park says.
Another expert suggested that bee venom could act like botulinum toxin , causing a temporary paralysis of the muscles. Some Parkinsons symptoms include muscle spasms that can cause pain and trouble moving. Bee venom may help relax these muscles.
Acupuncture is quite commonly used for Parkinsons disease, but hard evidence of benefit is lacking, this man is reported as saying. Well, he cant say that now, can he?
The results are promising, but more research is needed before we can draw any firm conclusions, Park says. He says a second study is now under way, and its expected to be completed later this year.
Overview Of Bee Products
Bee workers of either Apis mellifera or Apis cerana speciesthe former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asiaproduce and store multiple bioactive substances Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive. They all possess multiple health-promoting properties due to their high content of natural antioxidants , peptides, rare lipids , vitamins, minerals, trace elements, and several bioactive substances . Research documents variability in the contents and effects of every single bee product, mainly due to variations in bee species, botanical origin, geographic location, season, extraction and handling procedures .
Figure 1. Bee products commonly involved in apitherapy along with common routes of admiration.
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Bee Venom Against Parkinsons Disease
This article is about protection from artificially induced Parkinsonism in mice. There is steady stream of such studies. These do not count as evidence that such a substance will improve actual Parkinsons in humans.
From 2016: In summary, our study did not evidence any clear symptomatic or disease-modifying effects of monthly bee venom injections over an 11 month period compared to placebo using a standard bee venom allergy desensitization protocol in PD patients. Of note, bee venom administration appeared safe in non-allergic patients. Given the increasingly strong preclinical rationale that SK channel blockade may be beneficial in treating PD short and long term, we believe that a larger study with less stringent exclusion criteria regarding IgE levels and ST is warranted. In particular, we feel that higher administration frequency and possibly higher individual doses of bee venom may reveal its potency in treating PD.
New Hope For Parkinsons Patient
According to Andreas Hartmann, it is important to remain cautious: Weve got a cocktail that seems to have satisfying effects, but there is a risk of potentially lethal allergic reactions. In France, more than a dozen people die each year from bee stings. So, should we intensively study apamin, the active substance in the venom, in order to synthetize it later as a medicine? Or should we analyze the bee venom as a whole and suppress the allergenic substances? Its not an easy answer, confesses Andreas Hartmann. Its possible that the allergenic elements contribute to the protection of dopaminergic neurons.
This discovery is a glimmer of hope in the search for treatments against Parkinsons disease. Even if many experiments still need to be carried out, the scientists are rather optimistic. Behind this unexpected case involving bees, there is real potential taking shape. And it doesnt stop with Parkinsons. Some data suggest that apitherapy, bee venom therapy, could have a positive impact on multiple sclerosis. If you thought that killing bees could lead to the end of the world, you might also say that saving them could mean treating, and, thus, saving, humans.
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Apitherapy For Neurodegenerative Disorders
Alzheimers disease and Parkinsons disease are the most common age-related neurodegenerative diseases. Research shows that both disorders develop as a result of a chronic inflammatory condition that involves neurons and glial cells . Glial overactivity promotes the expression of pathogenic genes that underly Alzheimers disease and Parkinsons disease such as APOE and alpha-synuclein , respectively. These genes further inflammation and oxidative stress both in neurons and in the blood brain barrier promoting the passage of neurotoxic molecules from the system circulation to neurons . Intraneuronal accumulation of the toxic amyloid beta peptides along with the uncontrolled release of inflammatory mediators and associated free radicals by dysfunctional glial cells potentiate the development of pours in mitochondrial membrane resulting in the release of molecules that activate cellular apoptosis . Research denotes that the origin of inflammation in most disorders including Alzheimers disease and Parkinsons disease is gut microbial alteration, which causes aberrations in the intestinal membrane allowing the passage of bacterial toxins to the systemic circulation and subsequently to the brain to stimulate neuroinflammation .
Animals And Experimental Design
In the current study, we handled the animals consistently in accordance with the ARRIVE guidelines. On October 29, 2019, the institutional Ethics Committee at NODCAR and Faculty of Pharmacy, Cairo University, approved all animal procedures. All experiments were carried out in accordance with the authorized experimental protocols and the Guide for Care and Use of Laboratory animals of The National Organization for Drug Control and Research . For all conducted experiments, a total of 30 male rats, three-month-old were used. All rats were housed in standardized cages in groups of 23 per cage, in a room with controlled temperature , humidity and luminosity , with food and tap water provided ad libitum. We randomly divided the experimental rats into five groups with six animals per group as following:
After 24 h of last dosing of different therapies, all animals were deeply anesthetized with 2 mg pentobarbital then transcardially perfused with 200 ml of heparinized saline, followed by 250 ml of 4% paraformaldehyde in PBS. The brain was then surgically removed for further processing.
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Special Precautions And Warnings
When given as a shotLIKELY SAFEtrouble breathingheart palpitationslow blood pressureanaphylaxisPOSSIBLY SAFEWhen applied to the skinPregnancy and breast-feedingPOSSIBLY SAFEhealthcarePOSSIBLY UNSAFEmiscarriageAuto-immune diseases such as multiple sclerosis , lupus , rheumatoid arthritis , or other conditionsimmune system
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Apitherapy For Insulin Resistance
Insulin is a multifunctional hormone that is mainly responsible for cellular glucose uptake. Its signaling pathway interacts with a variety of other signaling cascades and affects their functioning within every single cell in the body . Insulin resistance and glucose intolerance increase during old age evoking conversions in muscle fibers from type-1 to type-2 inclined in muscle loss . Glucose metabolism and insulin contribute to Ach synthesis by controlling the activity of choline acetyltransferase . On the other hand, cerebral insulin resistance develops in old as well as obese individuals due to depletion of adiponectinan adipose tissue-derived adipokine that regulates neurogenesis and the metabolism of lipids and glucose . Alterations in nutrient supply to the brain are associated with increased production of free radicals and active glycation products, which accelerate inflammation in brain cell leading to neurodegeneration . Several studies show that bee products express potent hypoglycemic activities. For example, positive effects of whole royal jelly and royal jelly acid on skeletal muscle are associated improved insulin signaling and translocation of glucose transporter 4 to the cell surface for glucose uptake .
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Attenuation Of Neuroinflammation And Microglial Activation
Abnormal microglial activation is a pathological hallmark in neurodegenerative diseases, including PD and AD . Experimental activation of BV2 microglial cells , using bacterial lipopolysaccharide , increases the expression of tumor necrosis factor and inducible nitric oxide synthase , promoting neuroinflammation and nitric oxide -mediated neuronal death . Moreover, activated microglia can generate superoxide free radicals
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Bvpla2 Is A Regulator Of Peripheral Regulatory T Cell Differentiation
Growing body of evidence supported the role of regulatory T cells in the disease progression of PD both in human PD patients and animal models of PD . Here, we speculated that the action of purified standard bvPLA2 on improving sensorimotor function in PD mice may be related to the induction of Tregs in the periphery.
To address our hypothesis, we first measured the cellular proportions of Tregs in MPTP mice after treatment with different doses of bvPLA2 . In fact, no significant difference in CD4+CD25+Foxp3+ Treg populations was detected between control and MPTP mice on 7 days after MPTP challenge . Importantly, administration of bvPLA2 at a concentration of 0.1 and 0.5 mg/kg induced an increase in the number of splenic Tregs on MPTP-treated mice, when compared with mice treated with MPTP only. Whereas lower doses of bvPLA2 induced no significant differences in the population of Treg cells. Similarly, commercial bvPLA2 stimulated Treg induction in the periphery with no significant difference compared with purified standard bvPLA2 . All these findings support the notion that bvPLA2 induces the expansion of CD4+CD25+Foxp3+ Treg in the periphery in PD, which can suppress the inflammatory response.
Morphological Characterization And Size Distribution
Determination of the zeta potential of DA-nanoparticles is extremely valuable as it provides an idea about the prepared suspension stability. It was observed that the prepared DA- nanoparticles remained stable for more than several weeks, with no signs of aggregation or precipitation. In our case, the values of zeta potential for the prepared nanoparticles with respect to time are specified in . In different times, the zeta potential ranged from 10.4 to 12.0 nm which is adequate for crossing the blood brain barrier. The prepared DA-nanoparticles preserved their characteristics when stored at room temperature. When the temperature was increased from 4 to 50 °C over a period of 90 days, the hydrodynamic size of the nanoparticles remained stable. However, when the temperature was raised after 90 days, the nanoparticles agglomerated indicating the possibility of storing this formula at room temperature .
Table 1 Variations in DA-nanoparticles characteristics with respect to time.
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Ex Vivo Treg Suppression Assay
Using magnetic bead separation , CD4+CD25+ and CD4+CD25 T cells were isolated from spleens obtained from the Foxp3EGFP mice that had received PBS or bvPLA2 as previously described . CD4+CD25 T cells from PBS-treated mice were labeled with eFluor 670 fluorescent dye , plated at a density of 2 × 105 cells/well or 1.6 × 105 cells/well in 96-well round-bottom plates and activated with 2 g/ml soluble anti-CD3 and 6 g/ml soluble anti-CD28 Ab. CD4+CD25+ Tregs from PBS- or bvPLA2-treated mice were added at a density of 0.4 × 105 cells/well. The cultures were incubated for 4 d, and the percentage of mean fluorescence intensity of responder cells was measured. Following the acquisition of sample data on the FACSCalibur flow cytometer , the sample results were generated in graphical and tabular formats using FlowJo software .
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Locomotor And Exploratory Activity
In the open-field test, the administration of BV at a dose of 1.2 mg/kg caused a significant reduction in the number of crossings compared to the other treatments. The same result was observed after the administration of haloperidol. This effect was not observed when the treatments were associated . When rearing was examined, both doses of bee venom and treatment with haloperidol resulted in a significant reduction compared to that seen in controls . The reduction remained significant when the lowest dose of BV was preceded by haloperidol, but the effect was reversed in the group receiving 1.2 mg/kg of BV . In addition, there was a significant decrease in grooming behavior after 1.2 mg/kg of BV compared to the saline group .
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Standardization Of The Manufacturing Process Of Bee Venom Pla2
In the present study, we developed standardized methods for preparing bvPLA2 from active components of European honeybee, Apis mellifera . To purify the crude BV, the extract was ultra-filtrated and subsequently concentrated to increase the yield of bvPLA2, as well as to remove undesirable products. Purified standard bvPLA2 were identified and separated using RP-HPLC system with a C18 column . Commercial standard bvPLA2 was also used to identify the separation profiles of purified bvPLA2 and determine the content of purified of bvPLA2. Additionally, the bioactivity test was carried out to test specific PLA2 activity . To ensure that purified bvPLA2 was safe, we performed the quality control tests, resulting in that it had an allowable endotoxin level approved by US Food and Drug Administration . Therefore, based on these observations, we considered this purified bvPLA2 as properly manufactured and standardized agent.
Table 1. Endotoxin analysis of purified standard bee venom phospholipase A2 .
Bvpla2 Inhibits The Expansion Of Th1 And Th17 Effector Cells That Are Associated With Pd
Since the balance of CD4+ T cell subsets is highly correlated with disease activity in PD , we further explored whether T helper subset balance was altered in PD. As shown in Figure 4, we assessed the differentiation of T helper cells based on their cytokine signature: IFN–secreting Th1, IL-4-secreting Th2 and IL-17A-producing Th17 cells . Obviously, MPTP treatment increased IFN–secreting Th1 cells, but not IL-4-secreting Th2, indicating a shifted Th1/Th2 balance towards Th1 in PD mice . Additionally, we asked whether purified standard bvPLA2 could reverse the altered balance of Th subsets in PD mice. Impressively, bvPLA2 treatment significantly reduced the secretion of the two pro-inflammatory cytokines IFN- and IL-17A in a dose-dependent fashion . Commercial bvPLA2 injection also exhibited a similar suppressive effect on Th1- and Th17-polarizing cytokines associated with PD. These results showed that specific CD4+ T subsets, including Th1 and Th17 cells, were markedly differentiated in PD induced by MPTP. Impressively, purified standard bvPLA2 in a dose-dependent manner suppressed MPTP-mediated imbalance of CD4+ T cell subsets.
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