Cordycepin Exerts Neuroprotective Effects via an Anti-Apoptotic Mechanism based on the Mitochondrial Pathway in a Rotenone-Induced Parkinsonism Rat Model

Background: Cordycepin (Cor), one of the major bioactive components of the traditional Chinese medicine Cordyceps militaris, has been used in clinical practice for several years. However, its neuroprotective effect remains unknown. Aim: The purpose of the study was to evaluate the neuroprotective effects of Cor using a rotenoneinduced Parkinson’s Disease (PD) rat model and to delineate the possible associated molecular mechanisms. Methods: In vivo, behavioural tests were performed based on the 10-point scale and grid tests. Levels of dopamine and its metabolites in the striatum and the numbers of TH-positive neurons in the Substantia Nigra pars compacta (SNpc) were investigated by high-performance liquid chromatography with electrochemical detection and immunohistochemical staining, respectively. In vitro, cell apoptosis rates and Mitochondrial Membrane Potential (MMP) were analysed by flow cytometry and the mRNA and protein levels of Bax, Bcl-2, Bcl-xL, Cytochrome c (Cyt-c), and caspase-3 were determined by quantitative real-time PCR and western blotting. Results: Showed that Cor significantly improved dyskinesia, increased the numbers of TH-positive neurons in the SNpc, and maintained levels of dopamine and its metabolites in the striatum in rotenone- induced PD rats. We also found that apoptosis was suppressed and the loss of MMP was reversed with Cor treatment. Furthermore, Cor markedly down-regulated the expression of Bax, upregulated Bcl-2 and Bcl-xL, inhibited the activation of caspase-3, and decreased the release of Cyt-c from the mitochondria to the cytoplasm, as compared to those in the rotenone-treated group. Conclusion: Therefore, Cor protected dopamine neurons against rotenone-induced apoptosis by improving mitochondrial dysfunction in a PD model, demonstrating its therapeutic potential for this disease.

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Resveratrol as a Therapeutic Agent for Alzheimer’s Disease

BioMed Research International ◽

10.1155/2014/350516 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 50

Author(s):

Teng Ma ◽

Meng-Shan Tan ◽

Jin-Tai Yu ◽

Lan Tan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Therapeutic Agent ◽

Red Wine ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Neuroprotective Effects

Alzheimer’s disease (AD) is the most common cause of dementia, but there is no effective therapy till now. The pathogenic mechanisms of AD are considerably complex, including Aβaccumulation, tau protein phosphorylation, oxidative stress, and inflammation. Exactly, resveratrol, a polyphenol in red wine and many plants, is indicated to show the neuroprotective effect on mechanisms mostly above. Recent years, there are numerous researches about resveratrol acting on AD in many models, both in vitro and in vivo. However, the effects of resveratrol are limited by its pool bioavailability; therefore researchers have been trying a variety of methods to improve the efficiency. This review summarizes the recent studies in cell cultures and animal models, mainly discusses the molecular mechanisms of the neuroprotective effects of resveratrol, and thus investigates the therapeutic potential in AD.

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Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson’s disease

Molecular Biology of the Cell ◽

10.1091/mbc.e15-06-0415 ◽

2015 ◽

Vol 26 (24) ◽

pp. 4478-4491 ◽

Cited By ~ 19

Author(s):

BK. Binukumar ◽

Varsha Shukla ◽

Niranjana D. Amin ◽

Philip Grant ◽

M. Bhaskar ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Neuroprotective Effect ◽

Selective Inhibition ◽

Motor Dysfunction ◽

Dopamine Neurons ◽

Dopamine Depletion ◽

Neuroprotective Effects

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease.

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Pharmacological Antagonism of Kainate Receptor Rescues Dysfunction and Loss of Dopamine Neurons in a Mouse Model of Human Parkin-induced Toxicity

10.21203/rs.3.rs-36149/v1 ◽

2020 ◽

Author(s):

Maria Regoni ◽

Stefano Cattaneo ◽

Daniela Mercatelli ◽

Salvatore Novello ◽

Alice Passoni ◽

...

Keyword(s):

Mouse Model ◽

Neuroprotective Effect ◽

Chronic Administration ◽

Dopamine Neurons ◽

Kainate Receptors ◽

Substantia Nigra Pars Compacta ◽

Gene Encoding ◽

Neuroprotective Therapy

Abstract BackgroundMutations in the PARK2 gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP), a neurodegenerative disease characterized by dysfunction and death of dopamine (DA) neurons in the substantia nigra pars compacta. Since a neuroprotective therapy for ARJP does not exist, research efforts aimed at discovering potential targets for neuroprotection are critically needed.A previous study demonstrated that loss of parkin function or expression of parkin mutants associated with ARJP causesan accumulation of glutamate kainate receptors (KARs) in human brain tissues and an increase of KAR-mediated currents in neuronsin vitro. MethodsBased on the hypothesisthat such KAR hyper-activation may contribute to the death of nigralDA neurons, we investigated the effect of KAR antagonism on the DA neuron dysfunction and death that occur in the parkinQ311X mouse, a model of human parkin-induced toxicity. ResultsWe found that early accumulation of KARs occurs in the DA neurons of the parkinQ311X mouse model and that chronic administration of the KAR antagonist UBP310 prevents DA neuron loss. This neuroprotective effect was associated with rescue of the abnormal firing rate of nigral DA neurons and downregulation of GluK2, the key KAR subunit. ConclusionsThis study provides novel evidence ofa causal role of glutamate KARs in the DA neuron dysfunction and loss occurring in a mouse model of human parkin-induced toxicity. Our results support KAR as a potential target in the development of a neuroprotective therapy for ARJP.

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Neuroprotective effects of Shende’an tablet in the Parkinson’s disease model

10.21203/rs.3.rs-29059/v3 ◽

2021 ◽

Author(s):

Xiao Yan Sheng ◽

Shui Yuan Yang ◽

Xiao Min Wen ◽

Xin Zhang ◽

Yong Feng Ye ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Pc12 Cells ◽

Motor Behavior ◽

Neuroprotective Effect ◽

Signal Pathway ◽

Dopamine Neurons ◽

Therapeutic Modality ◽

Neuroprotective Effects

Abstract Background: Shende’an tablet (SDA) is a newly capsuled Chinese herbal formula derived from the Chinese traditional medicine Zhengan Xifeng Decoction which is approved for the treatment of neurasthenia and insomnia in China. This study aimed to investigate the neuroprotective effects of SDA against Parkinson’s disease (PD) in vitro and in vivo.Methods: In the present work, the neuroprotective effects and mechanism of SDA were evaluated in the cellular PD model. Male C57BL/6J mice were subject to a partial MPTP lesion alongside treatment with SDA. Behavioural test and tyrosine-hydroxylase immunohistochemistry were used to evaluate nigrostriatal tract integrity. HPLC analysis and Western blotting were used to assess the effect of SDA on dopamine metabolism and the expression of HO-1, PGC-1α and Nrf2, respectively.Results: Our results demonstrated that SDA had neuroprotective effect in dopaminergic PC12 cells with 6-OHDA lesion. It had also displayed efficient dopaminergic neuronal protection and motor behavior alleviation properties in MPTP-induced PD mice. In the PC12 cells and MPTP-induced Parkinson’s disease animal models, SDA was highly efficacious in α-synuclein clearance associated with the activation of PGC-1α/Nrf2 signal pathway.Conclusion: SDA demonstrated potential as a future therapeutic modality in PD through protecting dopamine neurons and alleviating the motor symptoms, mediated by the activation of PGC-1α/Nrf2 signal pathway.

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Valproic Acid Protects Primary Dopamine Neurons from MPP+-Induced Neurotoxicity: Involvement of GSK3βPhosphorylation by Akt and ERK through the Mitochondrial Intrinsic Apoptotic Pathway

BioMed Research International ◽

10.1155/2017/8124501 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Chi Zhang ◽

Xianrui Yuan ◽

Zhongliang Hu ◽

Songlin Liu ◽

Haoyu Li ◽

...

Keyword(s):

Valproic Acid ◽

Molecular Mechanisms ◽

Glycogen Synthase ◽

Neurological Diseases ◽

Neuroprotective Effect ◽

Dopamine Neurons ◽

Intrinsic Apoptotic Pathway ◽

Apoptotic Pathway ◽

Neuroprotective Effects ◽

Mitogen Activated Protein

Valproic acid (VPA), a drug widely used to treat manic disorder and epilepsy, has recently shown neuroprotective effects in several neurological diseases, particularly in Parkinson’s disease (PD). The goal of the present study was to confirm VPA’s dose-dependent neuroprotective propensities in the MPP+model of PD in primary dopamine (DA) neurons and to investigate the underlying molecular mechanisms using specific mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase- (PI3K-) Akt signaling inhibitors. VPA reversed MPP+-induced mitochondrial apoptosis and counteracted MPP+-induced extracellular signal-regulated kinase (ERK) and Akt repression and inhibited glycogen synthase kinase 3β(GSK3β) activation through induction of GSK3βphosphorylation. Moreover, inhibitors of the PI3K and MAPK pathways abolished GSK3βphosphorylation and diminished the VPA-induced neuroprotective effect. These findings indicated that VPA’s neuroprotective effect in the MPP+-model of PD is associated with GSK3βphosphorylation via Akt and ERK activation in the mitochondrial intrinsic apoptotic pathway. Thus, VPA may be a promising therapeutic candidate for clinical treatment of PD.

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The neuroprotective effect of nicotine in Parkinson’s disease models is associated with inhibiting PARP-1 and caspase-3 cleavage

PeerJ ◽

10.7717/peerj.3933 ◽

2017 ◽

Vol 5 ◽

pp. e3933 ◽

Cited By ~ 14

Author(s):

Justin Y.D. Lu ◽

Ping Su ◽

James E.M. Barber ◽

Joanne E. Nash ◽

Anh D. Le ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Neuroprotective Effect ◽

Future Research ◽

Neuroprotective Effects ◽

Α7 Nachr ◽

Parp 1

Clinical evidence points to neuroprotective effects of smoking in Parkinson’s disease (PD), but the molecular mechanisms remain unclear. We investigated the pharmacological pathways involved in these neuroprotective effects, which could provide novel ideas for developing targeted neuroprotective treatments for PD. We used the ETC complex I inhibitor methylpyridinium ion (MPP+) to induce cell death in SH-SY5Y cells as a cellular model for PD and found that nicotine inhibits cell death. Using choline as a nicotinic acetylcholine receptor (nAChR) agonist, we found that nAChR stimulation was sufficient to protect SH-SY5Y cells against cell death from MPP+. Blocking α7 nAChR with methyllycaconitine (MLA) prevented the protective effects of nicotine, demonstrating that these receptors are necessary for the neuroprotective effects of nicotine. The neuroprotective effect of nicotine involves other pathways relevant to PD. Cleaved Poly (ADP-ribose) polymerase-1 (PARP-1) and cleaved caspase-3 were decreased by nicotine in 6-hydroxydopamine (6-OHDA) lesioned mice and in MPP+-treated SH-SY5Y cells. In conclusion, our data indicate that nicotine likely exerts neuroprotective effects in PD through the α7 nAChR and downstream pathways including PARP-1 and caspase-3. This knowledge could be pursued in future research to develop neuroprotective treatments for PD.

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A review on chemistry, source and therapeutic potential of lambertianic acid

Zeitschrift für Naturforschung C ◽

10.1515/znc-2020-0267 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Md Shahinozzaman ◽

Moutushi Islam ◽

Bristy Basak ◽

Arifa Sultana ◽

Rashiduzzaman Emran ◽

...

Keyword(s):

Molecular Mechanisms ◽

Therapeutic Potential ◽

Bioactive Compound ◽

Cancer Cell Proliferation ◽

Neuroprotective Effects ◽

Potential Health ◽

Anticancer Properties ◽

Toxicological Profile ◽

Lambertianic Acid

Abstract Lambertianic acid (LA) is a diterpene bioactive compound mainly purified from different species of Pinus. It is an optical isomer of another natural compound daniellic acid and was firstly purified from Pinus lambertiana. LA can be synthesized in laboratory from podocarpic acid. It has been reported to have potential health benefits in attenuating obesity, allergies and different cancers including breast, liver, lung and prostate cancer. It exhibits anticancer properties through inhibiting cancer cell proliferation and survival, and inducing apoptosis, targeting major signalling components including AKT, AMPK, NFkB, COX-2, STAT3, etc. Most of the studies with LA were done using in vitro models, thus warranting future investigations with animal models to evaluate its pharmacological effects such as antidiabetic, anti-inflammatory and neuroprotective effects as well as to explore the underlying molecular mechanisms and toxicological profile. This review describes the chemistry, source, purification and therapeutic potentials of LA and it can therefore be a suitable guideline for any future study with LA.

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Resveratrol and Neuroprotection: Impact and Its Therapeutic Potential in Alzheimer's Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2020.619024 ◽

2020 ◽

Vol 11 ◽

Author(s):

Md. Habibur Rahman ◽

Rokeya Akter ◽

Tanima Bhattacharya ◽

Mohamed M. Abdel-Daim ◽

Saad Alkahtani ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Tau Proteins ◽

Amyloid Peptides ◽

Work Done

Alzheimer’s disease (AD) is a progressive cortex and hippocampal neurodegenerative disease which ultimately causes cognitively impaired decline in patients. The AD pathogen is a very complex process, including aggregation of Aβ (β-amyloid peptides), phosphorylation of tau-proteins, and chronic inflammation. Exactly, resveratrol, a polyphenol present in red wine, and many plants are indicated to show the neuroprotective effect on mechanisms mostly above. Resveratrol plays an important role in promotion of non-amyloidogenic cleavage of the amyloid precursor protein. It also enhances the clearance of amyloid beta-peptides and reduces the damage of neurons. Most experimental research on AD and resveratrol has been performed in many species, both in vitro and in vivo, during the last few years. Nevertheless, resveratrol’s effects are restricted by its bioavailability in the reservoir. Therefore, scientists have tried to improve its efficiency by using different methods. This review focuses on recent work done on the cell and animal cultures and also focuses on the neuroprotective molecular mechanisms of resveratrol. It also discusses about the therapeutic potential onto the treatment of AD.

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Effects of GLP-1 Receptor Activation on a Pentylenetetrazole—Kindling Rat Model

Brain Sciences ◽

10.3390/brainsci9050108 ◽

2019 ◽

Vol 9 (5) ◽

pp. 108 ◽

Cited By ~ 6

Author(s):

Abdelaziz M. Hussein ◽

Mohamed Eldosoky ◽

Mohamed El-Shafey ◽

Mohamed El-Mesery ◽

Khaled M. Abbas ◽

...

Keyword(s):

Oxidative Stress ◽

Rat Model ◽

Caspase 3 ◽

Neuroprotective Effect ◽

Receptor Activation ◽

Sprague Dawley ◽

Neuroprotective Effects ◽

Ptz Kindling ◽

Markers Of Oxidative Stress ◽

Brain Tissues

Objectives: To study the possible anti-seizure and neuroprotective effect of glucagon like peptide 1 (GLP1) analogue (liraglutide) in a pentylenetetrazole (PTZ) induced kindled rat model and its underlying mechanisms. Methods: Thirty Sprague Dawley rats were allocated into 3 equal groups; i) Normal group: normal rats received normal saline, ii) PTZ (kindling) group: received PTZ (50 mg/Kg intraperitoneally (i.p.)) every other day for 2 weeks and iii) PTZ + GLP1 group: same as the PTZ group but rats received liraglutide (75 µg/kg i.p. daily) for 2 weeks before PTZ injection. Seizure severity score, seizure latency and duration were assessed. Also, the expression of caspase-3 (apoptotic marker) and β-catenin (Wnt pathway) by western blotting, markers of oxidative stress (GSH, CAT and MDA) by biochemical assay and the expression of LC3 (marker of autophagy) and heat shock protein 70 (Hsp70) by immunostaining were assessed in hippocampal regions of brain tissues. Results: PTZ caused a significant increase in Racine score and seizure duration with a significant decrease in seizure latency. These effects were associated with a significant increase in MDA, β-catenin, caspase-3, Hsp70 and LC3 in brain tissues (p < 0.05). Meanwhile, liraglutide treatment caused significant attenuation in PTZ-induced seizures, which were associated with significant improvement in markers of oxidative stress, reduction in LC3, caspase-3 and β-catenin and marked increase in Hsp70 in hippocampal regions (p < 0.05). Conclusion: Activation of GLP1R might have anticonvulsant and neuroprotective effects against PTZ-induced epilepsy. These effects could be due to suppression of oxidative stress, apoptosis and autophagy and upregulation of Hsp70.

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Neuroprotective effects of Shende’an tablet in the Parkinson’s disease model

Chinese Medicine ◽

10.1186/s13020-021-00429-y ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Xiaoyan Sheng ◽

Shuiyuan Yang ◽

Xiaomin Wen ◽

Xin Zhang ◽

Yongfeng Ye ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Pc12 Cells ◽

Motor Behavior ◽

Neuroprotective Effect ◽

Signal Pathway ◽

Dopamine Neurons ◽

Therapeutic Modality ◽

Neuroprotective Effects

Abstract Background Shende’an tablet (SDA) is a newly capsuled Chinese herbal formula derived from the Chinese traditional medicine Zhengan Xifeng Decoction which is approved for the treatment of neurasthenia and insomnia in China. This study aimed to investigate the neuroprotective effects of SDA against Parkinson’s disease (PD) in vitro and in vivo. Methods In the present work, the neuroprotective effects and mechanism of SDA were evaluated in the cellular PD model. Male C57BL/6J mice were subject to a partial MPTP lesion alongside treatment with SDA. Behavioural test and tyrosine-hydroxylase immunohistochemistry were used to evaluate nigrostriatal tract integrity. HPLC analysis and Western blotting were used to assess the effect of SDA on dopamine metabolism and the expression of HO-1, PGC-1α and Nrf2, respectively. Results Our results demonstrated that SDA had neuroprotective effect in dopaminergic PC12 cells with 6-OHDA lesion. It had also displayed efficient dopaminergic neuronal protection and motor behavior alleviation properties in MPTP-induced PD mice. In the PC12 cells and MPTP-induced Parkinson’s disease animal models, SDA was highly efficacious in α-synuclein clearance associated with the activation of PGC-1α/Nrf2 signal pathway. Conclusions SDA demonstrated potential as a future therapeutic modality in PD through protecting dopamine neurons and alleviating the motor symptoms, mediated by the activation of PGC-1α/Nrf2 signal pathway.

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