Dose-Dependent Neuroprotective Effect of Standardized Bee Venom Phospholipase A2 Against MPTP-Induced Parkinson’s Disease in Mice

Abstract

Parkinson’s disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons within the substantia nigra (SN). While the precise etiology of dopaminergic neuronal demise is elusive, multiple lines of evidence indicate that neuroinflammation is involved in the pathogenesis of PD. We have previously demonstrated that subcutaneous administration of bee venom (BV) phospholipase A 2 (bvPLA 2 ) suppresses dopaminergic neuronal cell death in a PD mouse model. In the present study, we established standardized methods for producing bvPLA 2 agent isolated from crude BV at good manufacturing practice (GMP) facility. The therapeutic efficacy of purified bvPLA2 agent was examined in MPTP-induced PD mice. Importantly, administration of purified bvPLA 2 in a dose-dependent manner reversed motor deficits in PD mice as well as inhibited loss of dopaminergic neurons within the SN of PD mice. The concentration-dependent action of standardized bvPLA 2 appeared to be related to the induction of CD4 + CD25 + Foxp3 + regulatory T cells (Tregs), which, in part, inhibits T helper 1 (Th1) and Th17 polarization and suppresses microglial activation in PD mice. Taken together, these results suggest that standardized bvPLA 2 purified from BV shows a neuroprotective effect against PD and thus has a potential target for treatment of PD.

Bee Venom: An Updating Review of Its Bioactive Molecules and Its Health Applications

“…As was mentioned before, bPLA2 has anti-inflammatory effects and induces protective effects against inflammatory conditions [117,148]. In a recent study, a mixture of 78% of bPLA2 and 15% of melittin was tested against PD in mice [49]. To initiate PD in mice, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model was used.…”

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

“…Kim et al (2019) administered 20 mg/kg of MPTP, intraperitoneally in male C57BL/6J mice and evaluated the purified bee venom phospholipase-A2 against MPTP-induced neurotoxicity. Bee venom phospholipase-A2 treatment defeated the motor deficits (pole test) and inhibited loss of dopaminergic neurons within the substantia nigra in a dose-dependent manner in PD mice [ 134 ]. Liu et al (2020) administered MPTP at 15 mg/kg intraperitoneally to female mice and evaluated the effect of ACT001 (a fumarate salt of dimethylaminomicheliolide and a derivative of parthenolide) against Parkinsonian abnormality in female BALB/c mice.…”

Bee Venom Phospholipase A2 Induces Regulatory T Cell Populations by Suppressing Apoptotic Signaling Pathway

“…The therapeutic effect of bvPLA2 extends to the treatment for neurodegenerative diseases including AD [32]. Previous studies demonstrated the neuroprotective effect of bvPLA2 against Parkinson's Disease [33] and AD [9]. The main action of bvPLA2 on a cellular level is the suppression of immune responses through the stimulation of dendritic cells, which ultimately leads to an increased function of Treg cells [20].…”

“…The area of the peak is used to measure the recovery of bvPLA2. The physical state of the final content of bvPLA2 was white powder and it was stored in freezing condition below −20 • C. It consisted of 93% of PLA2 and 7% of minor unknown constituents, as shown in previous report [33].…”

“…Phospholipase A2, from honey bee venom (Apis mellifera) was purchased from Sigma (St. Louis, MO, USA). The preparation process of the bvPLA2 is as follows [33,46]. The first step is isolation and purification, which involves dissolving raw BV in high performance liquid chromatography (HPLC) grade water at a concentration of 1 mg/mL; the second step is filtration, during which the diluted samples are applied to PTFE membrane filter (pore size 0.45 µm); the next step is concentration, during which the filtered mixtures are concentrated by a tangential flow filtration (TFF) system to reduce the volume.…”