ß-Caryophyllene exerts protective antioxidant effects through the activation of NQO1 in the MPTP model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, caused by the selective death of dopaminergic neurons in the substantia nigra pars compacta. ß-caryophyllene (BCP) is a phytocannabinoid with several pharmacological properties, producing anti-inflammatory and antihypertensive effects. In addition, BCP protects dopaminergic neurons from neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), yet it remains unclear if this effect is due to its antioxidant activity. To assess whether this is the case, the effect of BCP on the expression and activity of NAD(P)H quinone oxidoreductase (NQO1) was evaluated in mice after the administration of MPTP. Male C57BL/6 J mice were divided into four groups, the first of which received saline solution i.p. in equivalent volume and served as a control group. The second group received MPTP. The second group received MPTP hydrochloride (5 mg/kg, i.p.) daily for seven consecutive days. The third group received BCP (10 mg/kg) for seven days, administered orally and finally, the fourth group received MPTP as described above and BCP for 7 days from the fourth day of MPTP administration. The results showed that BCP inhibits oxidative stress-induced cell death of dopaminergic neurons exposed to MPTP at the same time as it enhances the expression and enzymatic activity of NQO1. Also, the BCP treatment ameliorated motor dysfunction and protected the dopaminergic cells of the SNpc from damage induced by MPTP. Hence, BCP appears to achieve at least some of its antioxidant effects by augmenting NQO1 activity, which protects cells from MPTP toxicity. Accordingly, this phytocannabinoid may represent a promising pharmacological option to safeguard dopaminergic neurons and prevent the progression of PD.

Neuronal degeneration and oxidative stress in the SNc of 6-OHDA intoxicated rats; improving role of silymarin long-term treatment.

Progressive loss in dopaminergic neurons (DA) of substantia nigra pars compacta (SNc) leads to Parkinson's disease with a hypothesis of oxidative stress generation. The present study was conducted to determine the long-term efficacy of silymarin (SM) post-treatment on 6-OHDA-induced oxidative stress in the SNc of male rats. Male Wistar rats were received 6-OHDA (8 µg/rat) into SNc. After 3 weeks, as recovery period, the animals were treated with i.p. injection of SM at different doses of 100, 200, or 300 mg/kg for 15 days. At the end of the treatment, motor function, neuronal cell count, antioxidant enzymes, and lipid peroxidation and tyrosine hydroxylase (TH) activities were evaluated in the ventral midbrain tissue. The 6-OHDA significantly decreased (p ≤ 0.05) motor function, antioxidant enzyme activity, GSH level, and GSH/GSSG ratio and caused an augmentation in GSSG and lipid peroxidation level. The 6-OHDA also reduced the population of neurons and TH expression. The SM repaired the 6-OHDA-induced motor impairment, antioxidant enzyme suppression, and TH down-regulation. All three doses of SM could restore the MDA level to the normal range in the 6-OHDA-lesioned rats and could reversed the effect of 6-OHDA on GSH, GSSG level, and GSH/GSSG ratio. The SM treatment significantly and dose-dependently increased (p ≤ 0.001) the total number of surviving neurons in the SNc. Silymarin chronic treatment restored the brain's antioxidant capacity and salvaged neurons from oxidative stress-induced neurodegeneration. The SM could also improve motor function in parkinsonian animals by increasing TH expression. These results recommend that application of SM over initial clinical stages may depict a hopeful approach versus PD. However, more research is needed to confirm this issue.

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.

Cinnamon and its Metabolite Protect the Nigrostriatum in a Mouse Model of Parkinson's Disease Via Astrocytic GDNF.

Glial cell line-derived neurotrophic factor (GDNF) has potent neurotrophic effects and is known to promote the dopaminergic (DA) neuronal survival in cellular and animal models of Parkinson's disease (PD). However, long-term ectopic GDNF delivery is associated with long lasting adverse side effects in PD patients. Therefore, finding safer and effective ways to elevate endogenous GDNF levels is an active area of research. This study underlines the importance of sodium benzoate (NaB), a metabolite of commonly-used spice cinnamon, a food-additive and an FDA-approved drug against hyperammonemia, in stimulating GDNF in primary mouse and human astrocytes. Presence of cAMP response element (CRE) in the Gdnf gene promoter, recruitment of CREB to the Gdnf promoter by NaB and abrogation of NaB-mediated GDNF expression by siRNA knockdown of CREB suggest that NaB induces the transcription of Gdnf via CREB. Finally, oral administration of NaB and cinnamon itself increased the level of GDNF in vivo in the substantia nigra pars compacta (SNpc) of normal as well as MPTP-intoxicated mice. Accordingly, cinnamon and NaB treatment protected tyrosine hydroxylase positive neurons in the SNpc and fibers in the striatum, normalized striatal neurotransmitters, and improved locomotor activities in MPTP-intoxicated Gfapcre mice, but not GdnfΔastro mice lacking GDNF in astrocytes. These findings highlight the importance of astroglial GDNF in cinnamon- and NaB-mediated protection of the nigrostriatum in MPTP mouse model of PD and suggest possible therapeutic potential of cinnamon and NaB in PD patients. Graphical abstract Cinnamon metabolite sodium benzoate (NaB) activates cAMP-response element-binding (CREB) via protein kinase A (PKA) in astrocytes. Activated CREB then binds to cAMP-response element (CRE) present in GDNF gene promoter to stimulate the transcription of GDNF in astrocytes. This astrocytic GDNF leads to nigral trophism and protects dopaminergic neurons from MPTP insult.

FTY720 Inhibits MPP+-Induced Microglial Activation by Affecting NLRP3 Inflammasome Activation.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons and excessive microglial activation in the substantia nigra pars compacta (SNpc). In the present study, we aimed to demonstrate the therapeutic effectiveness of the potent sphingosine-1-phosphate receptor antagonist fingolimod (FTY720) in an animal model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and to identify the potential mechanisms underlying these therapeutic effects. C57BL/6J mice were orally administered FTY720 before subcutaneous injection of MPTP. Open-field and rotarod tests were performed to determine the therapeutic effect of FTY720. The damage to dopaminergic neurons and the production of monoamine neurotransmitters were assessed using immunohistochemistry, high-performance liquid chromatography, and flow cytometry. Immunofluorescence (CD68- positive) and enzyme-linked immunosorbent assay were used to analyze the activation of microglia, and the levels of activated signaling molecules were measured using Western blotting. Our findings indicated that FTY720 significantly attenuated MPTP-induced behavioral deficits, reduced the loss of dopaminergic neurons, and increased dopamine release. FTY720 directly inhibited MPTP-induced microglial activation in the SNpc, suppressed the production of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α in BV-2 microglial cells treated with 1-methyl-4-phenylpyridinium (MPP+), and subsequently decreased apoptosis in SH-SY5Y neuroblastoma cells. Moreover, in MPP+-treated BV-2 cells and primary microglia, FTY720 treatment significantly attenuated the increases in the phosphorylation of PI3K/AKT/GSK-3ß, reduced ROS generation and p65 activation, and also inhibited the activation of NLRP3 inflammasome and caspase-1. In conclusion, FTY720 may reduce PD progression by inhibiting NLRP3 inflammasome activation via its effects on ROS generation and p65 activation in microglia. These findings provide novel insights into the mechanisms underlying the therapeutic effects of FTY720, suggesting its potential as a novel therapeutic strategy against PD. Graphical Abstract FTY720 may reduce ROS production by inhibiting the PI3K/AKT/GSK-3ß signaling pathway, while at the same time reducing p65 phosphorylation, thus decreasing NLRP3 inflammasome activation through these two pathways, ultimately reducing microglia activation-induced neuronal damage.

Neuroprotective effect of curcumin-I in copper-induced dopaminergic neurotoxicity in rats: A possible link with Parkinson's disease.

Numerous findings indicate an involvement of heavy metals in the neuropathology of several neurodegenerative disorders, especially Parkinson's disease (PD). Previous studies have demonstrated that Copper (Cu) exhibits a potent neurotoxic effect on dopaminergic neurons and triggers profound neurobehavioral alterations. Curcumin is a major component of Curcuma longa rhizomes and a powerful medicinal plant that exerts many pharmacological effects. However, the neuroprotective action of curcumin on Cu-induced dopaminergic neurotoxicity is yet to be investigated. The aim of the present study was to evaluate the impact of acute Cu-intoxication (10mg/kg B.W. i.p) for 3days on the dopaminergic system and locomotor performance as well as the possible therapeutic efficacy of curcumin I (30mg/kg B.W.). Intoxicated rats showed a significant loss of Tyrosine Hydroxylase (TH) expression within substantia nigra pars compacta (SNc), ventral tegmental area (VTA) and the striatal outputs. This was correlated with a clear decrease in locomotor performance. Critically, curcumin-I co-treatment reversed these changes and showed a noticeable protective effect; both TH expression and locomotor performance was reinstated in intoxicated rats. These results demonstrate altered dopaminergic innervations following Cu intoxication and a new therapeutic potential of curcumin against Cu-induced dopaminergic neurotransmission failure. Curcumin may therefore prevent heavy metal related Parkinsonism.

Protective effects of a herbal extract combination of Bupleurum falcatum, Paeonia suffruticosa, and Angelica dahurica against MPTP-induced neurotoxicity via regulation of nuclear receptor-related 1 protein.

Parkinson's disease (PD) is one of the progressive neurodegenerative diseases of whose condition is characterized by dopaminergic neuronal cell loss and dysfunction in the substantia nigra pars compacta (SNpc) and the striatum. Recent studies have demonstrated that the nuclear receptor-related 1 protein (Nurr1) is critical of dopaminergic phenotype induction in mesencephalic dopaminergic neurons. Further, Nurr1 engages in synthesizing and storing dopamine through regulating levels of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). The aim of this study was to investigate the protective effects of a herbal extract combination, consisting of Bupleurum falcatum, Paeonia suffruticosa, and Angelica dahurica (MABH), on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like symptoms and to elucidate possible mechanisms of action focusing on Nurr1. In a subacute mouse model of MPTP-induced PD, MABH treatment resulted in recovery from movement impairments. MABH prevented dopamine depletion and protected against dopaminergic neuronal degradation induced by MPTP. Additionally, MABH increased Nurr1 expression in the SNpc of mice. To evaluate the effects of MABH on Nurr1 expression, we measured the protein levels of Nurr1 and its regulating factors using Western blot analysis in PC12 cells. MABH treatment induced the phosphorylation of extracellular signal-regulated kinase protein via increasing the protein expression levels of Nurr1 and ultimately the levels of TH, VMAT2, and DAT. These results indicate that MABH has protective effects on dopaminergic neurons in a mouse model of PD by regulating Nurr1.

Amelioration of apoptotic events in the skeletal muscle of intra-nigrally rotenone-infused Parkinsonian rats by Morinda citrifolia--up-regulation of Bcl-2 and blockage of cytochrome c release.

Parkinson's disease is a progressive neurodegenerative movement disorder with the cardinal symptoms of bradykinesia, resting tremor, rigidity, and postural instability, which lead to abnormal movements and lack of activity, which in turn cause muscular damage. Even though studies have been carried out to elucidate the causative factors that lead to muscular damage in Parkinson's disease, apoptotic events that occur in the skeletal muscle and a therapeutical approach to culminate the muscular damage have not been extensively studied. Thus, this study evaluates the impact of rotenone-induced SNPc lesions on skeletal muscle apoptosis and the efficacy of an ethyl acetate extract of Morinda citrifolia in safeguarding the myocytes. Biochemical assays along with apoptotic markers studied by immunoblot and reverse transcription-polymerase chain reaction in the current study revealed that the supplementation of Morinda citrifolia significantly reverted alterations in both biochemical and histological parameters in rotenone-infused PD rats. Treatment with Morinda citrifolia also reduced the expression of pro-apoptotic proteins Bax, caspase-3 and caspase-9 and blocked the release of cytochrome c from mitochondria induced by rotenone. In addition, it augmented the expression of Bcl2 both transcriptionally and translationally. Thus, this preliminary study paves a way to show that the antioxidant and anti-apoptotic activities of Morinda citrifolia can be exploited to alleviate skeletal muscle damage induced by Parkinsonism.

Ursolic acid attenuates oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in MPTP-induced Parkinsonian mouse model.

Parkinson's disease (PD) is characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc) region of brain. Oxidative stress and inflammation plays important role in the neurodegeneration and development of PD. Ursolic Acid (UA: 3ß-hydroxy-urs-12-en-28-oic acid) is a natural pentacyclic triterpenoid found in various medicinal plants. Its anti-inflammatory and antioxidant activity is a well-established fact. In this paper, the neuroprotective efficiency of UA in MPTP induced PD mouse model has been explored. For this purpose, we divided 30 mice into 5 different groups; first was control, second was MPTP-treated, third, fourth and fifth were different doses of UA viz., 5 mg/kg, 25 mg/kg, and 50 mg/kg body weight (wt) respectively, along with MPTP. After 21 days of treatment, different behavioral parameters and biochemical assays were conducted. Tyrosine hydroxylase (TH) immunostaining of SN dopaminergic neurons as well as HPLC quantification of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) were also performed. Our results proved that, UA improves behavioral deficits, restored altered dopamine level and protect dopaminergic neurons in the MPTP intoxicated mouse. Among three different doses, 25 mg/kg body wt was the most effective dose for the PD. This work reveals the potential of UA as a promising drug candidate for PD treatment.