Triple herbal extract DA-9805 exerts a neuroprotective effect via amelioration of mitochondrial damage in experimental models of Parkinson’s disease

Abstract

Moutan cortex, Angelica Dahurica root, and Bupleurum root are traditional herbal medicines used in Asian countries to treat various diseases caused by oxidative stress or inflammation. Parkinson’s disease (PD) has been associated with mitochondrial dysfunction, but no effective treatment for mitochondrial dysfunction has yet been identified. In this study we investigated the neuroprotective effects of the triple herbal extract DA-9805 in experimental models of PD. DA-9805 was prepared by extracting three dried plant materials (Moutan cortex, Angelica Dahurica root, and Bupleurum root in a 1:1:1 mixture) with 90% ethanol on a stirring plate for 24 h at room temperature and fingerprinted using high-performance liquid chromatography. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+), which both exert neurotoxic effects on dopaminergic neurons by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) complex I, were used to make experimental models of PD. In MPP+-treated SH-SY5Y cells, DA-9805 ameliorated the suppression of tyrosine hydroxylase expression and mitochondrial damage on OXPHOS complex 1 activity, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and oxygen consumption rate. In the MPTP-induced subacute PD model mice, oral administration of DA-9805 recovered dopamine content as well as bradykinesia, as determined by the rotarod test. DA-9805 protected against neuronal damage in the substantia nigra pars compacta (SNpc) and striatum. In both in vitro and in vivo models of PD, DA-9805 normalized the phosphorylation of AKT at S473 and T308 on the insulin signaling pathway and the expression of mitochondria-related genes. These results demonstrate that the triple herbal extract DA-9805 showed neuroprotective effects via alleviating mitochondria damage in experimental models of PD. We propose that DA-9805 may be a suitable candidate for disease-modifying therapeutics for PD.

DA-9805, a Herbal Mixture, Restores Motor Manifestations in 6-Hydroxydopamine-induced Parkinson’s Disease Mouse Model by Regulating Striatal Dopamine and Acetylcholine Levels

“…This result demonstrates a similar tendency to that noted in PD patients. However, DA-9805-induced recovery of the motor dysfunctions was only associated with a tendency to increase DA levels, which was particularly similar to the results of a previous study with MPTP-induced PD mice ( Jeong et al, 2018 ). However, striatal Ach showed the strongest correlation with rotarod latency times ( Table 1 and Figure 2B ).…”

“…A standardized DA-9805 (batch number: MB1603) was provided from Dong-A ST (Yong-in, South Korea). Condition for extraction and quality control of DA-9805 were described as reported methods previously ( Jeong et al, 2018 ). Briefly, same amounts of MRC, ADR, and BR were extracted at room temperature (20–25°C) for 24 h with 90% ethanol, evaporated and subsequently maintained at 4°C until use.…”

“…The neuroprotective effects of DA-9805 against neurotoxins MPTP or 6-hydroxydoapmine (6-OHDA) has previously been demonstrated in experimental PD models ( Jeong et al, 2018 ; Eo et al, 2019 ). However, there is a need to elucidate the therapeutic effects of administering DA-9805 post-treatment for PD symptoms, by regulating the levels of striatal neurotransmitters in 6-OHDA induced PD mice model.…”

Neurobehavioral and neuroprotective role of captopril in the rotenone model of rat Parkinsonism

“…(Fu et al, 2015) Herbal extracts like the moutan cortex, Angelica dahurica root, and bupleurum root also exerts neuroprotective action in PD. (Jeong et al, 2018) Many lavonoids are proposed to exhibit neuroprotective actions primarily through anti-oxidant mechanisms. (Magalingam et al, 2015) Apart from these, artemisia (Pal and Ghosh, 2018), isolongifolene (Balakrishnan et al, 2018), and caffeine (Khadrawy et al, 2017) and many other drugs have shown signi icant therapeutic roles in PD.…”

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“…CoQ10 and creatine [Figure 1D] combination therapy has been investigated in a MPTP mouse model of PD. [35] The researchers show that supplementation with these combined agents in mice through a diet with 2% creatine and 1% CoQ10 for 1 week before MPTP treatment (40 mg/kg body weight daily for 28 days through osmotic pumps) produced additive neuroprotective effects against dopamine depletion in the striatum and loss of tyrosine hydroxylase (TH) neurons in the SNpc, reduced lipid peroxidation and pathologic SNCA accumulation in SNpc neurons, and loss of DAergic neurons. Resveratrol [Figure 1E] is a well-known antioxidant that exerts extensive pharmacological effects including anti-inflammatory, anti-mutation, anti-tumor, and blood fat regulatory functions.…”