Wuzi Yanzong pill attenuates MPTP-induced Parkinson's Disease via PI3K/Akt signaling pathway.

Wuzi Yanzong Pill (WYP) was found to play a protective role on nerve cells and neurological diseases, however the molecular mechanism is unclear. To understand the molecular mechanisms that underly the neuroprotective effect of WYP on dopaminergic neurons in Parkinson's disease (PD). PD mouse model was induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Gait and hanging tests were used to assess motor behavioral function. Immunofluorescence assay was used to determine TH-positive neurons in substantia nigra (SN). Apoptosis, dopamine and neurotrophic factors as well as expression of PI3K/Akt pathway were detected by TUNEL staining, ELISA and western blotting, respectively. First, it was observed that WYP intervention improved abnormal motor function in MPTP-induced PD model, alleviated the loss of TH+ neurons in SN, and increased dopamine content in brain, revealing a potential protective effect. Second, network pharmacology was used to analyze the possible targets and pathways of WYP action in the treatment of PD. A total of 126 active components related to PD were screened in WYP, and the related core targets included ALB, GAPDH, Akt1, TP53, IL6 and TNF. Particularly, the effect of WYP on PD may be medicate through PI3K/Akt signaling pathway and apoptotic regulation. The WYP treated PD mice had higher expression of p-PI3K, p-Akt and Bcl-2 but lower expression of Bax and cleaved caspase-3 than the non-WYP treated PD mice. Secretion of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) were also increased in the treated mice. WYP may inhibit apoptosis and increase the secretion of neurotrophic factor via activating PI3K/ Akt signaling pathway, thus protecting the loss of dopamine neurons in MPTP-induced PD mice.

Conveyance of cortical pacing for parkinsonian tremor-like hyperkinetic behavior by subthalamic dysrhythmia.

Parkinson's disease is characterized by both hypokinetic and hyperkinetic symptoms. While increased subthalamic burst discharges have a direct causal relationship with the hypokinetic manifestations (e.g., rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g., resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed to be autonomous or less responsive to synaptic input, thereby interrupting the information flow. We, however, demonstrate that subthalamic burst discharges are dependent on cortical glutamatergic synaptic input, which is enhanced by A-type K+ channel inhibition. Excessive top-down-triggered subthalamic burst discharges then drive highly correlative activities bottom-up in the motor cortices and skeletal muscles. This leads to hyperkinetic behaviors such as tremors, which are effectively ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges play an imperative role in cortico-subcortical information relay, and they critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms.

Neuroprotective effects of garlic extract on dopaminergic neurons of substantia nigra in a rat model of Parkinson's disease: motor and non-motor outcomes.

Parkinson's disease (PD) is a common and severe neurodegenerative disorder associated with a selective loss of dopaminergic neurons in substantia nigra pars compacta. The crucial role of oxidative stress and inflammation in PD onset and progression is evident. It has been proven that garlic extract (GE) protects the cells from oxidative stress, inflammation, mitochondrial dysfunction and apoptosis. That is, we aimed to investigate if GE reveals protective features on the preclinical model of PD. The study has been designed to evaluate both preventive (GE administered before 6-OHDA injection) and therapeutic (GE administered after 6-OHDA injection) effects of GE on the animal model. Forty male Wistar rats were divided into 4 groups including control, lesion, treatment I (received GE before 6-OHDA injection) and treatment II (received GE both before and after 6-OHDA injection). At the end of treatment, hanging, rotarod, open field and passive avoidance tests as well as immunohistochemistry were performed to evaluate the neuroprotective effects of garlic against PD. Our immunohistochemistry analysis revealed that the tyrosine hydroxylase positive cells (TH+) in GE treated groups were significantly higher (p˂0.001) than the lesion group. The motor deficiency significantly improved in hanging, rotarod, open-field and apomorphine-induced rotational tests. We observed an attenuation in memory impairment induced by PD on GE treated group. Therefore, we found that GE protects dopaminergic neurons in 6-OHDA-induced neurotoxicity and ameliorates movement disorders and behavioral deficits.

Neuroprotective potential of cinnamon and its metabolites in Parkinson's disease: Mechanistic insights, limitations, and novel therapeutic opportunities.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder with obscure etiology and no disease-modifying therapy to date. Hence, novel, safe, and low cost-effective approaches employing medicinal plants are currently receiving increased attention. A growing body of evidence has revealed that cinnamon, being widely used as a spice of unique flavor and aroma, may exert neuroprotective effects in several neurodegenerative diseases, including PD. In vitro evidence has indicated that the essential oils of Cinnamomum species, mainly cinnamaldehyde and sodium benzoate may protect against oxidative stress-induced cell death, reactive oxygen species generation, and autophagy dysregulation, thus acting in a potentially neuroprotective manner. In vivo evidence has demonstrated that oral administration of cinnamon powder and sodium benzoate may protect against dopaminergic cell death, striatal neurotransmitter dysregulation, and motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models of PD. The underlying mechanisms of its action include autophagy regulation, antioxidant effects, upregulation of Parkin, DJ-1, glial cell line-derived neurotrophic factor, as well as modulation of the TLR/NF-κB pathway and inhibition of the excessive proinflammatory responses. In addition, in vitro and in vivo studies have shown that cinnamon extracts may affect the oligomerization process and aggregation of α-synuclein. Herein, we discuss recent evidence on the novel therapeutic opportunities of this phytochemical against PD, indicating additional mechanistic aspects that should be explored, and potential obstacles/limitations that need to be overcome, for its inclusion in experimental PD therapeutics.

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.

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-1ß, 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.

Induction of Autophagy by Vasicinone Protects Neural Cells from Mitochondrial Dysfunction and Attenuates Paraquat-Mediated Parkinson's Disease Associated α-Synuclein Levels.

Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson's disease (PD). Vasicinone is a quinazoline alkaloid from Adhatoda vasica. Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases α-synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.

Amelioration of motor and non-motor deficits and increased striatal APoE levels highlight the beneficial role of pistachio supplementation in rotenone-induced rat model of PD.

Pistachio contains polyphenolic compounds including flavonoids and anthocyanins which have antioxidant and antiinflammatory activity. Present study was aimed to evaluate the protective effects of pistachio on neurobehavioral and neurochemical changes in rats with Parkinson's disease (PD). Animal model of PD was induced by the injection of rotenone (1.5 mg/kg/day, s.c.) for 8 days. Pistachio (800 mg/kg/day, p.o.) was given for two weeks in both pre- and post-treatment. At the end of treatment brain was dissected out and striatum was isolated for biochemical and neurochemical analysis. Memory was assessed by Morris water maze (MWM) and novel object recognition (NOR) test while open field test (OFT), Kondziela inverted screen test (KIST), pole test (PT), beam walking test (BWT), inclined plane test (IPT) and footprint (FP) test were used to observe motor behavior. Rotenone administration significantly (p < 0.01) impaired the memory but pistachio in both pre- and post-treatment groups significantly (p < 0.01) improved memory performance. Rotenone-induced motor deficits were significantly attenuated in both pre- and post-pistachio treatment. Increased oxidative stress and decreased DA and 5-HT levels induced by rotenone were also significantly attenuated by pistachio supplementation. Furthermore, raised apolipoprotein E (APoE) levels in rotenone injected rats were also normalized following treatment with pistachio. Present findings show that pistachio possesses neuroprotective effects and improves memory and motor deficits via increasing DA levels and improving oxidative status in brain.

Effects of Electroacupuncture on Metabolic Changes in Motor Cortex and Striatum of 6-Hydroxydopamine-Induced Parkinsonian Rats.

OBJECTIVE: To explore the possible underlying mechanism by investigating the effect of electroacupuncture (EA) treatment on the primary motor cortex and striatum in a unilateral 6-hydroxydopamine (6-OHDA) induced rat Parkinson's disease (PD) model. METHODS: Male Sprague-Dawley rats were randomly divided into sham group (n=16), model group (n=14), and EA group (n=14). EA stimulation at Dazhui (GV 14) and Baihui (GV20) was applied to PD rats in the EA group for 4 weeks. Behavioral tests were conducted to evaluate the effectiveness of EA treatment. Metabolites were detected by 7.0 T proton nuclear magnetic resonance. RESULTS: Following 4 weeks of EA treatment in PD model rats, the abnormal behavioral impairment induced by 6-OHDA was alleviated. In monitoring changes in metabolic activity, ratios of myoinositol/creatine (Cr) and N-acetyl aspartate (NAA)/Cr in the primary motor cortex were significantly lower at the injected side than the non-injected side in PD rats (P=0.024 and 0.020). The ratios of glutamate + glutamine (Glx)/Cr and NAA/Cr in the striatum were higher and lower, respectively, at the injected side than the non-injected side (P=0.046 and 0.008). EA treatment restored the balance of metabolic activity in the primary motor cortex and striatum. In addition, the taurine/Cr ratio and Glx/Cr ratio were elevated in the striatum of PD model rats compared to sham-lesioned rats (P=0.026 and 0.000). EA treatment alleviated the excessive glutamatergic transmission by down-regulating the striatal Glx/Cr ratio (P=0.001). The Glx/Cr ratio was negatively correlated with floor plane spontaneous locomotion in PD rats (P=0.027 and P=0.0007). CONCLUSIONS: EA treatment is able to normalize the metabolic balance in the primary motor cortex and striatum of PD rats, which may contribute to its therapeutic effect on motor deficits. The striatal Glx/Cr ratio may serve as a potential indicator of PD and a therapeutic target of EA treatment.

Neuroprotective effects of Bacopa monnieri in Parkinson's disease model.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra region and the presence of α-synuclein aggregates in the striatum and surrounding areas of brain. Evidences suggest that neuroinflammation plays a role in the progression of PD. We examined the neuro-protective effects of Bacopa monnieri (BM) in regulating neuroinflammation. Administration of BM suppressed the level of pro-inflammatory cytokines, decreased the levels of α-synuclein, and reduced reactive oxygen species (ROS) generation in PD animal model. Pre-treatment of BM showed more prominent results as compare to co- and post-treatment. Results suggest that Bacopa can limit inflammation in the different areas of brain, thus, offers a promising source of novel therapeutics for the treatment of many CNS disorders.

Potential therapeutic effects of antagonizing adenosine A2A receptor, curcumin and niacin in rotenone-induced Parkinson's disease mice model.

Parkinson's disease (PD) is the second common age-related neurodegenerative disease. It is characterized by control loss of voluntary movements control, resting tremor, postural instability, bradykinesia, and rigidity. The aim of the present work is to evaluate curcumin, niacin, dopaminergic and non-dopaminergic drugs in mice model of Parkinson's disease through behavioral, biochemical, genetic and histopathological observations. Mice treated with rotenone rerecorded significant increase in adenosine A2A receptor (A2AR) gene expression, α synuclein, acetylcholinesterase (AchE), malondialdehyde (MDA), angiotensin-II (Ang-II), c-reactive protein (CRP), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels as compared with the control group. While, significant decrease in dopamine (DA), norepinephrine (NE), serotonin (5-HT), superoxide dismutase (SOD), reduced glutathione (GSH), ATP, succinate and lactate dehydrogenases (SDH &LDH) levels were detected. Treatment with curcumin, niacin, adenosine A2AR antagonist; ZM241385 and their combination enhanced the animals' behavior and restored all the selected parameters with variable degrees of improvement. The brain histopathological features of hippocampal and substantia nigra regions confirmed our results. In conclusion, the combination of curcumin, niacin and ZM241385 recorded the most potent treatment effect in Parkinsonism mice followed by ZM241385, as a single treatment. ZM241385 succeeded to antagonize adenosine A2A receptor by diminishing its gene expression and ameliorating all biochemical parameters under investigation. The newly investigated agent; ZM241385 has almost the same pattern of improvement as the classical drug; Sinemet®. This could shed the light to the need of detailed studies on ZM241385 for its possible role as a promising treatment against PD. Additionally, food supplements such as curcumin and niacin were effective in Parkinson's disease eradication.

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. AIMS: 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.

Effects of bromelain on motor responses following intra-medial forebrain bundle 6-OHDA injection in rat model of parkinsonism.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The conventional therapeutic measures which include the widely used L-DOPA therapy, are inefficient especially when dopamine loss is severe, and the physical symptoms are full blown. Since neuroinflammation is a core feature of PD, this raised the question of whether early treatment with an anti-inflammatory agent may provide a more efficient intervention for PD. In this study, we investigated the effect of bromelain (an anti-inflammatory drug) on motor responses and dopamine levels in a parkinsonian rat model. Male Sprague-Dawley rats were lesioned stereotaxically with the neurotoxin 6-OHDA. The anti-inflammatory agent, bromelain (40 mg/kg i.p) was used to treat a subset of the rats prior to or 24 h post 6-OHDA lesion. Locomotor activity was assessed after 6-OHDA injection, using the cylinder and step tests. The cortical and striatal concentrations of dopamine were also measured. 6-OHDA injection resulted in marked motor impairment which was prevented by pretreatment with bromelain prior to the lesion. Also, the injection of 6-OHDA into the medial forebrain bundle resulted in a significant reduction in dopamine concentration in the striatum and PFC. Bromelain treatment did not alter the suppression of cortical and striatal dopamine levels. Pre-treatment with bromelain reduced the motor dysfunction in the parkinsonian rat model of PD. The efficacy of treatment with bromelain does not appear to be via preservation of the dopaminergic system. The efficacy of bromelain in 6-OHDA injected rats still remains unclear.

Prophylactic neuroprotective propensity of Crocin, a carotenoid against rotenone induced neurotoxicity in mice: behavioural and biochemical evidence.

Previously we have demonstrated the potential neuroprotective propensity of saffron and Crocin (CR) employing a Drosophila model of Parkinsonism. Rotenone (ROT) has been extensively used as a model neurotoxin to induce Parkinson's disease (PD) like symptoms in mice. In the present study, as a proof of concept we evaluated the efficacy of CR prophylaxis (25 mg/ kg bw/d, 7d) to attenuate ROT(0.5 mg/Kg bw/d,7d) -induced neurotoxic effects in male mice focussing on neurobehavioural assessments and biochemical determinants in the striatum. CR prophylaxis significantly alleviated ROT-induced behavioural alterations such as increased anxiety, diminished exploratory behaviour, decreased motor co-ordination, and grip strength. Concomitantly, we evidenced diminution of oxidative stress markers, enhanced levels of antioxidant enzyme and mitochondrial enzyme function in the striatal region. Further, varying degree of restoration of cholinergic function, dopamine and α-synuclein levels were discernible suggesting the possible mechanism/s of action of CR in this model. Based on our earlier data in flies and in worm model, we propose its use as an adjuvant therapeutic agent in oxidative stress-mediated neurodegenerative conditions such as PD.

Attenuation of Endoplasmic Reticulum Stress, Impaired Calcium Homeostasis, and Altered Bioenergetic Functions in MPP+-Exposed SH-SY5Y Cells Pretreated with Rutin.

Parkinson's disease (PD) is a common neurodegenerative disorder that affects approximately 1% of the population over the age of 65 years. While treatment options for PD are limited, reports show that plant-derived bioactive compounds such as rutin possess numerous pharmacological benefits, including antioxidant and antiapoptotic activities. This study aimed to investigate the potential role of rutin in MPP+-treated SH-SY5Y neuroblastoma cells, an established cell model of PD. Our findings reveal increased concentrations of Ca2+ and endoplasmic reticulum (ER) stress as well as impaired mitochondrial membrane potential and bioenergetic status in SH-SY5Y cells treated with MPP+ only. This is demonstrated by a significant reduction in the expression levels of BiP, significantly reduced basal respiration, maximal respiration, and spare respiratory capacity as well as a significant increase in the expression levels of CHOP; however, these effects were significantly attenuated following pretreatment with rutin. Also, rutin significantly improved basal and compensatory glycolysis as a response to an impaired oxidative phosphorylation system triggered by MPP+, characterized by deficient ATP production. In conclusion, our findings provide the first evidence on the ability of rutin to maintain Ca2+ homeostasis, inhibit ER stress, and protect the mitochondria in MPP+-treated SH-SY5Y cells.

Design, Synthesis, and Biological Evaluation of Phenol Bioisosteric Analogues of 3-Hydroxymorphinan.

The neuroprotective agent 3-hydroxymorphinan (3-HM) is a well-documented and highly safe therapeutic intervention for the inflammatory-related effects of Parkinson's disease (PD). However, the bioavailability of 3-HM is very low due to the rapid first-pass metabolism of the phenolic moiety. In the present study, we sought to improve the metabolic stability and overall pharmacokinetic profile of 3-HM. Based on an iterative design process that a suitably arranged heterocycle with an NH group would serve as the metabolically stable isostere of the phenolic group, we designed and synthesized two analogues of 3-HM. Benzimidazolone compound 8 (imidazolone-morphinan) was comparable in activity to 3-HM against lipopolysaccharide (LPS)-induced inflammatory responses in microglial BV2 cells and in vivo animal experiments (MPTP-induced PD mouse model). Moreover, the in vitro study showed that imidazolone-morphinan was non-toxic to microglia, indicating its high safety. Considering the favourable and unique preclinical profiles, compound 8 was nominated as a candidate for further clinical development.

Calycosin attenuates MPTP-induced Parkinson's disease by suppressing the activation of TLR/NF-κB and MAPK pathways.

Parkinson is the second common neurodegenerative disease. The characteristics of Parkinson's disease (PD) are the dopamin neurons loss caused by neuroinflammation responses. C alycosin, an isoflavone phytoestrogen isolated from Astragalus membranaceus, has multiple pharmacological activities, such as anti-inflammation, anti-tumor, and neuroprotective effects. However, it is unknown whether calycosin can mitigate PD symptoms. This study aims to explore whether calycosin can alleviate PD symptoms and the underlying mechanisms. PD was induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection, and calycosin was given intracerebroventricularly to these mice. A cell model of nerve inflammation was established by BV2 microglia cells injected with lipopolysaccharide (LPS). The motor states were evaluated by stepping, whisker, and cylinder experiments. The states of dopaminergic neurons and microglia were detected by immunostainning of tyrosine hydroxylase and cluster of differentiation molecule 11b (CD11b). The expression levels of inflammatory factors were detected by qPCR. Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were investigated by western blot. We found that calycosin treatment mitigated the behavioral dysfunctions and inflammatory responses in MPTP-induced PD mice. The TLR/NF-κB and MAPK pathways in MPTP-induced PD mice were inhibited by calycosin treatment, which was coincident with experiments in LPS-induced BV2 cells. Above all, calycosin mitigates PD symptoms through TLR/NF-κB and MAPK pathways in mice and cell lines.

Manganese exposure exacerbates progressive motor deficits and neurodegeneration in the MitoPark mouse model of Parkinson's disease: Relevance to gene and environment interactions in metal neurotoxicity.

Parkinson's disease (PD) is now recognized as a neurodegenerative condition caused by a complex interplay of genetic and environmental influences. Chronic manganese (Mn) exposure has been implicated in the development of PD. Since mitochondrial dysfunction is associated with PD pathology as well as Mn neurotoxicity, we investigated whether Mn exposure augments mitochondrial dysfunction and neurodegeneration in the nigrostriatal dopaminergic system using a newly available mitochondrially defective transgenic mouse model of PD, the MitoPark mouse. This unique PD model recapitulates key features of the disease including progressive neurobehavioral changes and neuronal degeneration. We exposed MitoPark mice to a low dose of Mn (10mg/kg, p.o.) daily for 4 weeks starting at age 8 wks and then determined the behavioral, neurochemical and histological changes. Mn exposure accelerated the rate of progression of motor deficits in MitoPark mice when compared to the untreated MitoPark group. Mn also worsened olfactory function in this model. Most importantly, Mn exposure intensified the depletion of striatal dopamine and nigral TH neuronal loss in MitoPark mice. The neurodegenerative changes were accompanied by enhanced oxidative damage in the striatum and substantia nigra (SN) of MitoPark mice treated with Mn. Furthermore, Mn-treated MitoPark mice had significantly more oligomeric protein and IBA-1-immunoreactive microglia cells, suggesting Mn augments neuroinflammatory processes in the nigrostriatal pathway. To further confirm the direct effect of Mn on impaired mitochondrial function, we also generated a mitochondrially defective dopaminergic cell model by knocking out the TFAM transcription factor by using a CRISPR-Cas9 gene-editing method. Seahorse mitochondrial bioenergetic analysis revealed that Mn decreases mitochondrial basal and ATP-linked respiration in the TFAM KO cells. Collectively, our results reveal that Mn can augment mitochondrial dysfunction to exacerbate nigrostriatal neurodegeneration and PD-related behavioral symptoms. Our study also demonstrates that the MitoPark mouse is an excellent model to study the gene-environment interactions associated with mitochondrial defects in the nigral dopaminergic system as well as to evaluate the contribution of potential environmental toxicant interactions in a slowly progressive model of Parkinsonism.

Photoactivation of ERK/CREB/VMAT2 pathway attenuates MPP+-induced neuronal injury in a cellular model of Parkinson's disease.

The vesicular monoamine transporter 2 (VMAT2) pumps dopamine from cytoplasm into synaptic vesicles for subsequent release, and the deficits of VMAT2 has been implicated in the dopaminergic neuronal cell loss which is considered as a typical pathological feature of Parkinson's disease (PD). Low-power laser irradiation (LPLI), a potent noninvasive physiotherapy approach, is capable of penetrating into nerve tissue to exert beneficial effects such as promoting nerve regeneration and ATP production. In the present study, we demonstrated that LPLI protects against MPP+-induced neurotoxicity via upregulation of VMAT2 in SH-SY5Y human dopaminergic neuroblastoma cells. The photoactivation of ERK phosphorylated cAMP-response element binding protein (CREB) at Ser133, and thus increased the ability of CREB binding to the promoter region of VMAT2, leading to elevated VMAT2 expression, which contributes to dopamine release and cell survival. Taken together, for the first time to our knowledge, the results showed that LPLI attenuates MPP+-induced neurotoxicity through activation of ERK/CREB/VMAT2 pathway, suggesting that the manipulation of VMAT2 by LPLI may provide a potential therapeutic strategy for PD.

A moderate metal-binding hydrazone meets the criteria for a bioinorganic approach towards Parkinson's disease: Therapeutic potential, blood-brain barrier crossing evaluation and preliminary toxicological studies.

Alzheimer's and Parkinson's diseases share similar amyloidogenic mechanisms, in which metal ions might play an important role. In this last neuropathy, misfolding and aggregation of α-synuclein (α-Syn) are crucial pathological events. A moderate metal-binding compound, namely, 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone (INHHQ), which was previously reported as a potential 'Metal-Protein Attenuating Compound' for Alzheimer's treatment, is well-tolerated by healthy Wistar rats and does not alter their major organ weights, as well as the tissues' reduced glutathione and biometal levels, at a concentration of 200mgkg-1. INHHQ definitively crosses the blood-brain barrier and can be detected in the brain of rats so late as 24h after intraperitoneal administration. After 48h, brain clearance is complete. INHHQ is able to disrupt, in vitro, anomalous copper-α-Syn interactions, through a mechanism probably involving metal ions sequestering. This compound is non-toxic to H4 (human neuroglioma) cells and partially inhibits intracellular α-Syn oligomerization. INHHQ, thus, shows definite potential as a therapeutic agent against Parkinson's as well.

Neuroprotective Effects of a Standardized Flavonoid Extract from Safflower against a Rotenone-Induced Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a major age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra par compacta (SNpc). Rotenone is a neurotoxin that is routinely used to model PD to aid in understanding the mechanisms of neuronal death. Safflower (Carthamus tinctorius. L.) has long been used to treat cerebrovascular diseases in China. This plant contains flavonoids, which have been reported to be effective in models of neurodegenerative disease. We previously reported that kaempferol derivatives from safflower could bind DJ-1, a protein associated with PD, and that a flavonoid extract from safflower exhibited neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD. In this study, a standardized safflower flavonoid extract (SAFE) was isolated from safflower and found to primarily contain flavonoids. The aim of the current study was to confirm the neuroprotective effects of SAFE in rotenone-induced Parkinson rats. The results showed that SAFE treatment increased body weight and improved rearing behavior and grip strength. SAFE (35 or 70 mg/kg/day) treatment reversed the decreased protein expression of tyrosine hydroxylase, dopamine transporter and DJ-1 and increased the levels of dopamine and its metabolite. In contrast, acetylcholine levels were decreased. SAFE treatment also led to partial inhibition of PD-associated changes in extracellular space diffusion parameters. These changes were detected using a magnetic resonance imaging (MRI) tracer-based method, which provides novel information regarding neuronal loss and astrocyte activation. Thus, our results indicate that SAFE represents a potential therapeutic herbal treatment for PD.