Neuroprotective and Anti-Inflammatory Effects of Evernic Acid in an MPTP-Induced Parkinson’s Disease Model

Oxidative stress, mitochondrial dysfunction, and neuroinflammation are strongly associated with the pathogenesis of Parkinson’s disease (PD), which suggests that anti-oxidative and anti-inflammatory compounds might provide an alternative treatment for PD. Here, we evaluated the neuroprotective effects of evernic aid (EA), which was screened from a lichen library provided by the Korean Lichen Research Institute at Sunchon National University. EA is a secondary metabolite generated by lichens, including Ramalina, Evernia, and Hypogymnia, and several studies have described its anticancer, antifungal, and antimicrobial effects. However, the neuroprotective effects of EA have not been studied. We found that EA protected primary cultured neurons against 1-methyl-4-phenylpyridium (MPP+)-induced cell death, mitochondrial dysfunction, and oxidative stress, and effectively reduced MPP+-induced astroglial activation by inhibiting the NF-κB pathway. In vivo, EA ameliorated MPTP-induced motor dysfunction, dopaminergic neuronal loss, and neuroinflammation in the nigrostriatal pathway in C57BL/6 mice. Taken together, our findings demonstrate that EA has neuroprotective and anti-inflammatory effects in PD models and suggest that EA is a potential therapeutic candidate for PD.

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Oxidative Stress, Mitochondrial Dysfunction, and Neuroprotection of Polyphenols with Respect to Resveratrol in Parkinson’s Disease

Biomedicines ◽

10.3390/biomedicines9080918 ◽

2021 ◽

Vol 9 (8) ◽

pp. 918

Author(s):

Heng-Chung Kung ◽

Kai-Jung Lin ◽

Chia-Te Kung ◽

Tsu-Kung Lin

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Dynamics ◽

Critical Role ◽

Neuronal Loss ◽

Ros Generation ◽

Neuroprotective Effects ◽

Dopaminergic Neuronal Loss

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss. The exact pathogenesis of PD is complex and not yet completely understood, but research has established the critical role mitochondrial dysfunction plays in the development of PD. As the main producer of cytosolic reactive oxygen species (ROS), mitochondria are particularly susceptible to oxidative stress once an imbalance between ROS generation and the organelle’s antioxidative system occurs. An overabundance of ROS in the mitochondria can lead to mitochondrial dysfunction and further vicious cycles. Once enough damage accumulates, the cell may undergo mitochondria-dependent apoptosis or necrosis, resulting in the neuronal loss of PD. Polyphenols are a group of natural compounds that have been shown to offer protection against various diseases, including PD. Among these, the plant-derived polyphenol, resveratrol, exhibits neuroprotective effects through its antioxidative capabilities and provides mitochondria protection. Resveratrol also modulates crucial genes involved in antioxidative enzymes regulation, mitochondrial dynamics, and cellular survival. Additionally, resveratrol offers neuroprotective effects by upregulating mitophagy through multiple pathways, including SIRT-1 and AMPK/ERK pathways. This compound may provide potential neuroprotective effects, and more clinical research is needed to establish the efficacy of resveratrol in clinical settings.

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Neuroprotective Effects of Gagam-Sipjeondaebo-Tang, a Novel Herbal Formula, against MPTP-Induced Parkinsonian Mice and MPP+-Induced Cell Death in SH-SY5Y Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/2420809 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Jade Heejae Ko ◽

Ju-Hee Lee ◽

Bobin Choi ◽

Ju-Yeon Park ◽

Young-Won Kwon ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Mitochondrial Dysfunction ◽

Apoptotic Cell ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Motor Dysfunction ◽

Herbal Formula ◽

Neuroprotective Effects

Parkinson’s disease is a neurodegenerative disease characterized by progressive cell death of dopaminergic neuron and following neurological disorders. Gagam-Sipjeondaebo-Tang (GST) is a novel herbal formula made of twelve medicinal herbs derived from Sipjeondaebo-Tang, which has been broadly used in a traditional herbal medicine. In the present study, we investigated the effects of GST against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor abnormalities in mice and 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in SH-SY5Y cell. First, we found that GST alleviated motor dysfunction induced by MPTP, and the result showed dopaminergic neurons recovery in substantia nigra. In the cell experiment, pretreatment with GST increased the cell viability and attenuated apoptotic cell death in MPP+-treated SH-SY5Y cells. GST also inhibited reactive oxygen species production and restored the mitochondrial membrane potential loss, which were induced by MPP+. Furthermore, GST extract significantly activated ERK and Akt, cell survival-related proteins, in SH-SY5Y cells. The effect of GST preventing mitochondrial dysfunction was antagonized by pretreatment of PD98059 and LY294002, selective inhibitors of ERK and Akt, respectively. Taken together, GST alleviated abnormal motor functions and recovered neuronal cell death, mitochondrial dysfunction, possibly via ERK and Akt activation. Therefore, we suggest that GST may be a candidate for the treatment and prevention of Parkinson’s disease.

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Neuroprotective Effects of Lindleyin on Hydrogen Peroxide-Induced Cell Injury and MPTP-Induced Parkinson’s Disease in C57BL/6 Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/2938432 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Jin-Jie Zhang ◽

Xiao-Rong Shi ◽

Wen-Wen Lv ◽

Xiao-Long Zhou ◽

Ying-Dong Sun ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Hydrogen Peroxide ◽

Parkinson's Disease ◽

Cell Injury ◽

In Vivo Studies ◽

Antioxidant Enzyme Activities ◽

Apoptotic Pathway ◽

Neuroprotective Effects

Oxidative stress (OS) is a crucial factor influencing the development of Parkinson’s disease (PD). Here we first reported that Lindleyin (Lin), one of the major components of rhubarb, possessed neuroprotective effects against H2O2-induced SH-SY5Y cell injury and MPTP-induced PD of C57BL/6 mice. The results showed that Lin can decrease cell death and apoptotic rate induced by H2O2 through inhibiting mitochondrial apoptotic pathway and increasing the activities of SOD, GSH-Px, and CAT as well as decreasing the level of MDA. In addition, in vivo studies showed that oral administration of Lin (5 or 20 mg/kg) showed significant change in motor function deficits, antioxidant enzyme activities, apoptotic pathway, and tyrosine hydroxylase expression. Our results reveal that Lin might be a promising anti-PD agent by reducing OS and apoptosis.

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The Neuroprotective Effects of Cannabis-Derived Phytocannabinoids and Resveratrol in Parkinson’s Disease: A Systematic Literature Review of Pre-Clinical Studies

Brain Sciences ◽

10.3390/brainsci11121573 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1573

Author(s):

Samay Prakash ◽

Wayne G. Carter

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Unmet Need ◽

Neuroprotective Agents ◽

Eligibility Criteria ◽

Neuroprotective Effects ◽

In Vivo Models ◽

Anti Inflammatory ◽

Nigral Degeneration

Currently, there are no pharmacological treatments able to reverse nigral degeneration in Parkinson’s disease (PD), hence the unmet need for the provision of neuroprotective agents. Cannabis-derived phytocannabinoids (CDCs) and resveratrol (RSV) may be useful neuroprotective agents for PD due to their anti-oxidative and anti-inflammatory properties. To evaluate this, we undertook a systematic review of the scientific literature to assess the neuroprotective effects of CDCs and RSV treatments in pre-clinical in vivo animal models of PD. The literature databases MEDLINE, EMBASE, PsychINFO, PubMed, and Web of Science core collection were systematically searched to cover relevant studies. A total of 1034 publications were analyzed, of which 18 met the eligibility criteria for this review. Collectively, the majority of PD rodent studies demonstrated that treatment with CDCs or RSV produced a significant improvement in motor function and mitigated the loss of dopaminergic neurons. Biochemical analysis of rodent brain tissue suggested that neuroprotection was mediated by anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms. This review highlights the neuroprotective potential of CDCs and RSV for in vivo models of PD and therefore suggests their potential translation to human clinical trials to either ameliorate PD progression and/or be implemented as a prophylactic means to reduce the risk of development of PD.

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KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson’s Disease

Neurotherapeutics ◽

10.1007/s13311-021-01097-4 ◽

2021 ◽

Author(s):

Min-Ho Nam ◽

Jong-Hyun Park ◽

Hyo Jung Song ◽

Ji Won Choi ◽

Siwon Kim ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Therapeutic Potential ◽

Motor Dysfunction ◽

Monoamine Oxidase B ◽

Nigrostriatal Pathway ◽

Neuroprotective Effects ◽

Mao B ◽

6 Hydroxydopamine ◽

Mptp Model

AbstractMonoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson’s disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.

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α-Bisabolol, a Dietary Bioactive Phytochemical Attenuates Dopaminergic Neurodegeneration through Modulation of Oxidative Stress, Neuroinflammation and Apoptosis in Rotenone-Induced Rat Model of Parkinson’s Disease

Biomolecules ◽

10.3390/biom10101421 ◽

2020 ◽

Vol 10 (10) ◽

pp. 1421 ◽

Cited By ~ 1

Author(s):

Hayate Javed ◽

M. F. Nagoor Meeran ◽

Sheikh Azimullah ◽

Lujain Bader Eddin ◽

Vivek Dhar Dwivedi ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Proinflammatory Cytokines ◽

Rat Model ◽

Inflammatory Mediators ◽

Dopaminergic Neurons ◽

Neuroprotective Effects ◽

Dopaminergic Neurodegeneration

Rotenone (ROT), a plant-derived pesticide is a well-known environmental neurotoxin associated with causation of Parkinson’s disease (PD). ROT impairs mitochondrial dysfunction being mitochondrial complex-I (MC-1) inhibitor and perturbs antioxidant-oxidant balance that contributes to the onset and development of neuroinflammation and neurodegeneration in PD. Due to the scarcity of agents to prevent the disease or to cure or halt the progression of symptoms of PD, the focus is on exploring agents from naturally occurring dietary phytochemicals. Among numerous phytochemicals, α-Bisabolol (BSB), natural monocyclic sesquiterpene alcohol found in many ornamental flowers and edible plants garnered attention due to its potent pharmacological properties and therapeutic potential. Therefore, the present study investigated the neuroprotective effects of BSB in a rat model of ROT-induced dopaminergic neurodegeneration, a pathogenic feature of PD and underlying mechanism targeting oxidative stress, inflammation and apoptosis. BSB treatment significantly prevented ROT-induced loss of dopaminergic neurons and fibers in the substantia nigra and striatum respectively. BSB treatment also attenuated ROT-induced oxidative stress evidenced by inhibition of MDA formation and GSH depletion as well as improvement in antioxidant enzymes, SOD and catalase. BSB treatment also attenuated ROT-induced activation of the glial cells as well as the induction and release of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) and inflammatory mediators (iNOS and COX-2) in the striatum. In addition to countering oxidative stress and inflammation, BSB also attenuated apoptosis of dopaminergic neurons by attenuating downregulation of anti-apoptotic protein Bcl-2 and upregulation of pro-apoptotic proteins Bax, cleaved caspases-3 and 9. Further, BSB was observed to attenuate mitochondrial dysfunction by inhibiting mitochondrial lipid peroxidation, cytochrome-C release and reinstates the levels/activity of ATP and MC-I. The findings of the study demonstrate that BSB treatment salvaged dopaminergic neurons, attenuated microglia and astrocyte activation, induction of inflammatory mediators, proinflammatory cytokines and reduced the expression of pro-apoptotic markers. The in vitro study on ABTS radical revealed the antioxidant potential of BSB. The results of the present study are clearly suggestive of the neuroprotective effects of BSB through antioxidant, anti-inflammatory and anti-apoptotic properties in ROT-induced model of PD.

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Increased Activity of Tyrosine Hydroxylase Leads to Elevated Amphetamine Response and Markers of Oxidative Stress in Transgenic Mice

10.1101/188318 ◽

2017 ◽

Cited By ~ 1

Author(s):

Laura M. Vecchio ◽

M. Kristel Bermejo ◽

Amy Dunn ◽

Marija Milenkovic ◽

Nikhil Urs ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Tyrosine Hydroxylase ◽

Dopamine Synthesis ◽

Dopamine Turnover ◽

Nigrostriatal Pathway ◽

Adult Mice

AbstractIn Parkinson’s disease, noradrenergic cells of the locus coeruleus and dopamine cells within the nigrostriatal pathway undergo profound degeneration. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the production of all catecholamines, including dopamine and noradrenaline, and is selectively expressed in the cells that produce these neurotransmitters. In vitro studies have previously shown that the TH-synthetic system can contribute to the formation of reactive oxygen species. In addition, animal models of dopamine mishandling demonstrated that free dopamine is neurotoxic. To examine how increased TH activity might influence catecholamine systems in vivo, we generated TH-overexpressing mice (TH-HI) with six total copies of the TH murine gene. A commensurate increase in TH mRNA produced a threefold increase in both total TH protein and phosphorylated TH levels. We found an increased rate of dopamine synthesis in both young and adult mice, reflected by the accumulation of L-DOPA following NSD-1015 administration, as well as elevated dopamine tissue content in young mice and an increased presence of dopamine metabolites at both ages. Adult mice show no difference in baseline locomotor behaviour compared to wildtype littermates, but a have potentiated response to amphetamine. In addition to elevated dopamine turnover in the striatum, TH-HI mice show reduced levels of glutathione and increased levels of cysteinylated catechols. These results indicate that a heightened level of active TH can produce oxidative stress, and may represent a source of toxicity that is specific to catecholamine cells, which are most vulnerable to degeneration in Parkinson’s disease.

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Anti-Inflammatory Effects of the Novel Barbiturate Derivative MHY2699 in an MPTP-Induced Mouse Model of Parkinson’s Disease

Antioxidants ◽

10.3390/antiox10111855 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1855

Author(s):

Seulah Lee ◽

Yeon Ji Suh ◽

Yujeong Lee ◽

Seonguk Yang ◽

Dong Geun Hong ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Cell Activation ◽

Motor Dysfunction ◽

Dopamine Neurons ◽

Neuroprotective Effects ◽

Glial Cell Activation ◽

Anti Inflammatory ◽

Neuroprotective Treatment

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, and is caused by the death of dopamine neurons and neuroinflammation in the striatum and substantia nigra. Furthermore, the inflammatory response in PD is closely related to glial cell activation. This study examined the neuroprotective effects of the barbiturate derivative, MHY2699 [5-(4-hydroxy 3,5-dimethoxybenzyl)-2 thioxodihydropyrimidine-4,6(1H,5H)-dione] in a mouse model of PD. MHY2699 ameliorated MPP⁺-induced astrocyte activation and ROS production in primary astrocytes and inhibited the MPP⁺-induced phosphorylation of MAPK and NF-κB. The anti-inflammatory effects of MHY2699 in protecting neurons were examined in an MPTP-induced mouse model of PD. MHY2699 inhibited MPTP-induced motor dysfunction and prevented dopaminergic neuronal death, suggesting that it attenuated neuroinflammation. Overall, MHY2699 has potential as a neuroprotective treatment for PD.

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Corynoxine Protects Dopaminergic Neurons Through Inducing Autophagy and Diminishing Neuroinflammation in Rotenone-Induced Animal Models of Parkinson’s Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2021.642900 ◽

2021 ◽

Vol 12 ◽

Author(s):

Leilei Chen ◽

Yujv Huang ◽

Xing Yu ◽

Jiahong Lu ◽

Wenting Jia ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Animal Models ◽

Dopaminergic Neurons ◽

Cell Model ◽

Neuronal Loss ◽

Motor Dysfunction ◽

Neuroprotective Effects ◽

Drug Candidates ◽

Low Dosage

Recent studies have shown that impairment of autophagy is related to the pathogenesis of Parkinson’s disease (PD), and small molecular autophagy enhancers are suggested to be potential drug candidates against PD. Previous studies identified corynoxine (Cory), an oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.) Jacks, as a new autophagy enhancer that promoted the degradation of α-synuclein in a PD cell model. In this study, two different rotenone-induced animal models of PD, one involving the systemic administration of rotenone at a low dosage in mice and the other involving the infusion of rotenone stereotaxically into the substantia nigra pars compacta (SNpc) of rats, were employed to evaluate the neuroprotective effects of Cory. Cory was shown to exhibit neuroprotective effects in the two rotenone-induced models of PD by improving motor dysfunction, preventing tyrosine hydroxylase (TH)-positive neuronal loss, decreasing α-synuclein aggregates through the mechanistic target of the rapamycin (mTOR) pathway, and diminishing neuroinflammation. These results provide preclinical experimental evidence supporting the development of Cory into a potential delivery system for the treatment of PD.

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Differential mitochondrial roles for α-synuclein in DRP1-dependent fission and PINK1/Parkin-mediated oxidation

Cell Death and Disease ◽

10.1038/s41419-021-04046-3 ◽

2021 ◽

Vol 12 (9) ◽

Author(s):

Thomas J. Krzystek ◽

Rupkatha Banerjee ◽

Layne Thurston ◽

JianQiao Huang ◽

Kelsey Swinter ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Dynamics ◽

Dependent Manner ◽

Shape Distribution ◽

Mitochondrial Homeostasis ◽

C Terminus

AbstractMitochondria are highly dynamic organelles with strict quality control processes that maintain cellular homeostasis. Within axons, coordinated cycles of fission-fusion mediated by dynamin related GTPase protein (DRP1) and mitofusins (MFN), together with regulated motility of healthy mitochondria anterogradely and damaged/oxidized mitochondria retrogradely, control mitochondrial shape, distribution and size. Disruption of this tight regulation has been linked to aberrant oxidative stress and mitochondrial dysfunction causing mitochondrial disease and neurodegeneration. Although pharmacological induction of Parkinson’s disease (PD) in humans/animals with toxins or in mice overexpressing α-synuclein (α-syn) exhibited mitochondrial dysfunction and oxidative stress, mice lacking α-syn showed resistance to mitochondrial toxins; yet, how α-syn influences mitochondrial dynamics and turnover is unclear. Here, we isolate the mechanistic role of α-syn in mitochondrial homeostasis in vivo in a humanized Drosophila model of Parkinson’s disease (PD). We show that excess α-syn causes fragmented mitochondria, which persists with either truncation of the C-terminus (α-syn1–120) or deletion of the NAC region (α-synΔNAC). Using in vivo oxidation reporters Mito-roGFP2-ORP1/GRX1 and MitoTimer, we found that α-syn-mediated fragments were oxidized/damaged, but α-syn1–120-induced fragments were healthy, suggesting that the C-terminus is required for oxidation. α-syn-mediated oxidized fragments showed biased retrograde motility, but α-syn1–120-mediated healthy fragments did not, demonstrating that the C-terminus likely mediates the retrograde motility of oxidized mitochondria. Depletion/inhibition or excess DRP1-rescued α-syn-mediated fragmentation, oxidation, and the biased retrograde motility, indicating that DRP1-mediated fragmentation is likely upstream of oxidation and motility changes. Further, excess PINK/Parkin, two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, rescued α-syn-mediated membrane depolarization, oxidation and cell death in a C-terminus-dependent manner, suggesting a functional interaction between α-syn and PINK/Parkin. Taken together, our findings identify distinct roles for α-syn in mitochondrial homeostasis, highlighting a previously unknown pathogenic pathway for the initiation of PD.

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