Neurodegeneration and glial morphological changes are both prevented by TRPM2 inhibition during the progression of a Parkinson's disease mouse model.

Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuron death and neuroinflammation. Emerging evidence points to the involvement of the transient receptor potential melastatin 2 (TRPM2) channel in neuron death and glial activation in several neurodegenerative diseases. However, the involvement of TRPM2 in PD and specifically its relation to the neuroinflammation aspect of the disease remains poorly understood. Here, we hypothesized that AG490, a TRPM2 inhibitor, can be used as a treatment in a mouse model of PD. Mice underwent stereotaxic surgery for 6-hydroxydopamine (6-OHDA) administration in the right striatum. Motor behavioral tests (apomorphine, cylinder, and rotarod) were performed on day 3 post-injection to confirm the PD model induction. AG490 was then daily injected i.p. between days 3 to 6 after surgery. On day 6, motor behavior was assessed again. Substantia nigra (SNc) and striatum (CPu) were collected for immunohistochemistry, immunoblotting, and RT-qPCR analysis on day 7. Our results revealed that AG490 post-treatment reduced motor behavior impairment and nigrostriatal neurodegeneration. In addition, the compound prevented TRPM2 upregulation and changes of the Akt/GSK-3ß/caspase-3 signaling pathway. The TRPM2 inhibition also avoids the glial morphology changes observed in the PD group. Remarkably, the morphometrical analysis revealed that the ameboid-shaped microglia, found in 6-OHDA-injected animals, were no longer present in the AG490-treated group. These results indicate that AG490 treatment can reduce dopaminergic neuronal death and suppress neuroinflammation in a PD mouse model. Inhibition of TRPM2 by AG490 could then represent a potential therapeutical strategy to be evaluated for PD treatment.

Antioxidant responses driven by Hesperetin and Hesperidin counteract Parkinson's disease-like phenotypes in Drosophila melanogaster.

The study investigated the protective effects of Hesperetin (HSP) and Hesperidin (HSD) on 1 methyl, 4 phenyl, 1,2,3,6 tetrahydropyridine hydrochloride (MPTP)-induced Parkinsonism in Drosophila melanogaster (D. melanogaster). After a lifespan study to select exposure time and concentrations, flies were co-exposed to MPTP (0.4 mg/g diet), Hesperetin (0.2 and 0.4 mg/g diet), and Hesperidin (0.1 and 0.4 mg/g) for 7 days. In addition to in vivo parameters, we assayed some markers of oxidative stress and antioxidant status (lipid peroxidation, protein carbonylation, thiol content, hydrogen peroxide, and nitrate/nitrite levels, mRNA expression of Keap-1 (Kelch-like ECH associated protein 1), /Nrf2 (Nuclear factor erythroid 2 related factor 2), catalase, and glutathione-S-transferase (GST) activities), and cholinergic (acetyl cholinesterase activity (AChE) and dopaminergic signaling content and the mRNA expression of tyrosine hydroxylase (TH), monoamine oxidase (MAO-like) activity). In addition to increasing the lifespan of flies, we found that both flavonoids counteracted the adverse effects of MPTP on survival, offspring emergence, and climbing ability of flies. Both flavonoids also reduced the oxidative damage on lipids and proteins and reestablished the basal levels of pro-oxidant species and activities of antioxidant enzymes in MPTP-exposed flies. These responses were accompanied by the normalization of the mRNA expression of Keap1/Nrf2 disrupted in flies exposed to MPTP. MPTP exposure also elicited changes in mRNA expression and content of TH as well as in MAO and AChE activity, which were reversed by HST and HSD. By efficiently hindering the oxidative stress in MPTP-exposed flies, our findings support the promising role of Hesperetin and Hesperidin as adjuvant therapy to manage Parkinsonism induced by chemicals such as MPTP.

Preventative effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives (N-functional group loading) on MPTP-induced parkinsonism in mice.

1,2,3,4-tetrahydroisoquinoline (TIQ) is endogenously present in the human brain, and some of its derivatives are thought to contribute to the induction of Parkinson's disease (PD)-like signs in rodents and primates. In contrast, the endogenous TIQ derivative 1-methyl-TIQ (1-MeTIQ) is reported to be neuroprotective. In the present study, we compared the effects of artificially modified 1-MeTIQ derivatives (loading an N-propyl, N-propenyl, N-propargyl, or N-butynyl group) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like signs in mice. In a behavioral study, MPTP-induced bradykinesia was significantly decreased by all compounds. However, only 1-Me-N-propargyl-TIQ showed an inhibitory effect by blocking the MPTP-induced reduction in striatal dopamine content and the number of nigral tyrosine hydroxylase-positive cells. Western blot analysis showed that 1-Me-N-propargyl-TIQ and 1-Me-N-butynyl-TIQ potently prevented the MPTP-induced decrease in dopamine transporter expression, whereas 1-MeTIQ and 1-Me-N-propyl-TIQ did not. These results suggest that although loading an N-propargyl group on 1-MeTIQ clearly enhanced neuroprotective effects, other N-functional groups showed distinct pharmacological properties characteristic of their functional groups. Thus, the number of bonds and length of the N-functional group may contribute to the observed differences in effect.

Dopamine D3 receptor ligand suppresses the expression of levodopa-induced dyskinesia in nonhuman primate model of parkinson's disease.

Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.

Fecal Microbiota Transplantation Exerts a Protective Role in MPTP-Induced Parkinson's Disease via the TLR4/PI3K/AKT/NF-κB Pathway Stimulated by α-Synuclein.

Gut microbiota is closely related to the Parkinson's disease (PD) pathogenesis. Additionally, aggregation of α-synuclein (α-syn) is central to PD pathogenesis. Here we identified the further mechanisms of gut microbiota in PD. A mouse model with PD was established via injection of MPTP. Normal or MPTP-induced PD like animals were treated with FMT from healthy normal mice. Pole test and traction test were performed to examine the effects of FMT on motor function of PD mice. Fecal SCFAs were assessed by gas chromatography-mass spectrometry. The α-syn level in the substantia nigra pars compacta (SN) of mice was measured using western blot. Dopaminergic neurons and microglial activation in the SN were analyzed by immunohistochemistry (IHC) and immunofluorescence (IF) staining. FMT alleviated physical impairment, decreased fecal SCFAs in a mouse model of PD. Additionally, FMT decreased the expression of α-syn, as well as inhibited the activation of microglia in the SN, and blocked the TLR4/PI3K/AKT/NF-κB signaling in the SN and striatum. FMT could protect mice against PD via suppressing α-syn expression and inactivating the TLR4/PI3K/AKT/NF-κB signaling.

Antioxidant Effect of Hydroxytyrosol, Hydroxytyrosol Acetate and Nitrohydroxytyrosol in a Rat MPP+ Model of Parkinson's Disease.

3,4-Dihydroxyphenyl ethanol, known as hydroxytyrosol (HTy), is a phenylpropanoid found in diverse vegetable species. Several studies have demonstrated that HTy is a potent antioxidant. Thus, our study is aimed to evaluate the antioxidant effect of HTy and its derivatives, hydroxytyrosol acetate (HTyA) and nitrohydroxytyrosol (HTyN), in a model of oxidative stress induced by 1-methyl-4-phenylpyridinium (MPP+) in rats. Rats were administered intravenously (i.v.) in the tail with 1 mL saline solution or polyphenol compound (1.5 mg/kg) 5 min before intrastriatal infusion of 10 µg MPP+/8 µL. We found that rats injured with MPP+, pretreatment with HTy, HTyA or HTyN significantly decreased ipsilateral turns. This result was consistent with a significant preservation of striatal dopamine levels and decreased lipid fluorescence products (LFP), a marker of oxidative stress. Brain GSH/GSSG ratio, from rats pretreated with HTy or HTyN showed a significant preservation of that marker, decreased as a consequence of MPP+-induced oxidative damage. These results show an antioxidant effect of HTy, HTyA and HTyN in the MPP+ model of Parkinson's disease in the rat.

SKP-SCs transplantation alleviates 6-OHDA-induced dopaminergic neuronal injury by modulating autophagy.

Parkinson's disease is a common neurodegenerative disease. Cell transplantation is a promising therapeutic option for improving the survival and function of dopaminergic neurons, but the mechanisms underlying the interaction between the transplanted cells and the recipient neurons remain to be studied. In this study, we investigated the effects of skin precursor cell-derived Schwann cells (SKP-SCs) directly cocultured with 6-OHDA-injured dopaminergic neurons in vitro and of SKP-SCs transplanted into the brains of 6-OHDA-induced PD mice in vivo. In vitro and in vivo studies revealed that SKP-SCs could reduce the damage to dopaminergic neurons by enhancing self-autophagy and modulating neuronal autophagy. Thus, the present study provides the first evidence that cell transplantation mitigates 6-OHDA-induced damage to dopaminergic neurons by enhancing self-autophagy, suggesting that earlier transplantation of Schwann cells might help alleviate the loss of dopaminergic neurons.

SIRT1 Protects Dopaminergic Neurons in Parkinson's Disease Models via PGC-1α-Mediated Mitochondrial Biogenesis.

SIRT1 is a deacetylase with multiple physiological functions by targeting histones and non-histone proteins. It has been shown that SIRT1 activation is involved in neuroprotection in Parkinson's disease (PD) models. In the present study, we provided direct evidences showing the neuroprotective roles of SIRT1 in dopaminergic neurons. Our data showed that increased expression of SIRT1 plays beneficial roles against MPP+ insults in SH-SY5Y cells and primary dopaminergic neurons, including increased cell viability, reduced LDH release, improved the mitochondrial membrane potential (MMP), and attenuated cell apoptosis. On the contrary, knockdown of SIRT1 further aggravated cell injuries induced by MPP+. Moreover, mutated SIRT1 without deacetylase activity (SIRT1 H363Y) failed to protect dopaminergic neurons from MPP+ injuries. Mechanistically, SIRT1 improved PGC-1α expression and mitochondrial biogenesis. Knockdown of PGC-1α almost completely abolished the neuroprotective roles of SIRT1 in SH-SY5Y cells. Collectively, our data indicate that SIRT1 has neuroprotective roles in dopaminergic neurons, which is dependent upon PGC-1α-mediated mitochondrial biogenesis. These findings suggest that SIRT1 may hold great therapeutic potentials for treating dopaminergic neuron loss associated disorders such as PD.

Inhibition of NLRP3 inflammasome by glibenclamide attenuated dopaminergic neurodegeneration and motor deficits in paraquat and maneb-induced mouse Parkinson's disease model.

Pesticides exposure can lead to damage of dopaminergic neurons, which are associated with increased risk of Parkinson's disease (PD). However, the etiology of PD remains poorly understood and no therapeutic strategy is available. Previous studies suggested the involvement of NLRP3 inflammasome in the onset of PD. This study was designed to investigate whether glibenclamide, an inhibitor of NLRP3 inflammasome, could offer a reliable protective strategy for PD in a mouse PD model induced by paraquat and maneb. We found that glibenclamide exerted potent neuroprotection against paraquat and maneb-induced upregulation of α-synuclein, dopaminergic neurodegeneration and motor impairment in brain of mice. Mechanistically, glibenclamide treatment blocked NLRP3 inflammasome activation evidenced by reduced expressions of NLRP3, activated caspase-1 and mature interleukin-1ß in glibenclamide co-treated mice compared with those in paraquat and maneb group mice. Furthermore, glibenclamide treatment mitigated paraquat and maneb-induced microglial M1 proinflammatory response and nuclear factor-κB activation in mice. Finally, the increased superoxide production, lipid peroxidation, protein levels of NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) induced by paraquat and maneb were all attenuated by glibenclamide. Overall, our findings demonstrated that glibenclamide protected dopaminergic neurons in a mouse PD model induced by combined exposures of paraquat and maneb through suppression of NLRP3 inflammasome activation, microglial M1 polarization and oxidative stress.

Nanoemulsion Improves the Neuroprotective Effects of Curcumin in an Experimental Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction. Recent studies have shown that curcumin (CUR) has neuroprotective effects in PD experimental models. However, its efficacy is limited due to low water solubility, bioavailability, and access to the central nervous system. In this study, we compared the effects of new curcumin-loaded nanoemulsions (NC) and free CUR in an experimental model of PD. Adult Swiss mice received NC or CUR (25 and 50 mg/kg) or vehicle orally for 30 days. Starting on the eighth day, they were administered rotenone (1 mg/kg) intraperitoneally until the 30th day. At the end of the treatment, motor assessment was evaluated by open field, pole test, and beam walking tests. Oxidative stress markers and mitochondrial complex I activity were measured in the brain tissue. Both NC and CUR treatment significantly improved motor impairment, reduced lipoperoxidation, modified antioxidant defenses, and prevented inhibition of complex I. However, NC was more effective in preventing motor impairment and inhibition of complex I when compared to CUR in the free form. In conclusion, our results suggest that NC effectively enhances the neuroprotective potential of CUR and is a promising nanomedical application for PD.

IDO-1 inhibition protects against neuroinflammation, oxidative stress and mitochondrial dysfunction in 6-OHDA induced murine model of Parkinson's disease.

Parkinson's disease (PD), a common neurodegenerative motor disorder characterized by striatal dopaminergic neuronal loss and localized neuroinflammation in the midbrain region. Activation of microglia is associated with various inflammatory mediators and Kynurenine pathway (KP) being one of the major regulator of immune response, is involved in the neuroinflammatory and neurotoxic cascade in PD. In the current study, 1-Methyltryptophan (1-MT), an Indolamine-2,3-dioxygenase-1 (IDO-1) inhibitor was tested at different doses (2.5 mg/kg, 5 mg/kg and 10 mg/kg) for its effect on behavioral parameters, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, neurotransmitter levels, biochemical and behavioral alterations in unilateral 6-OHDA (3 µg/µL) murine model of PD. The results showed improved locomotion in open field test and motor coordination in rota-rod, reduced oxidative stress, neuroinflammatory markers (TNF-α, IFN-γ, IL-6), mitochondrial dysfunction and neuronal apoptosis (caspase-3). Also, restoration of neurotransmitter levels (dopamine and homovanillic acid) in the striatum and increased striatal BDNF levels were observed. Overall findings suggest that 1-MT could be a potential candidate for further studies to explore its possibility as an alternative in the pharmacotherapy of PD.

Neuroprotection of Exendin-4 by Enhanced Autophagy in a Parkinsonian Rat Model of α-Synucleinopathy.

Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 µg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson's disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson's disease.

Polygonatum sibiricum Polysaccharides Protect against MPP-Induced Neurotoxicity via the Akt/mTOR and Nrf2 Pathways.

Polygonatum sibiricum, a well-known life-prolonging tonic in Chinese medicine, has been widely used for nourishing nerves in the orient, but the underlying molecular mechanisms remain unclear. In this study, we found that P. sibiricum polysaccharides (PSP) ameliorated 1-methyl-4-phenyl-1,2.3,6-tetrahydropyridine- (MPTP-) induced locomotor activity deficiency and dopaminergic neuronal loss in an in vivo Parkinson's disease (PD) mouse model. Additionally, PSP pretreatment inhibited N-methyl-4-phenylpyridine (MPP+) induced the production of reactive oxygen species, increasing the ratio of reduced glutathione/oxidized glutathione. In vitro experiments showed that PSP promoted the proliferation of N2a cells in a dose-dependent manner, while exhibiting effects against oxidative stress and neuronal apoptosis elicited by MPP+. These effects were found to be associated with the activation of Akt/mTOR-mediated p70S6K and 4E-BP1 signaling pathways, as well as nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (Gclc), and glutamate-cysteine ligase modulatory subunit (Gclm), resulting in antiapoptotic and antioxidative effects. Meanwhile, PSP exhibited no chronic toxicity in C57BJ/6 mice. Together, our results suggest that PSP can serve as a promising therapeutic candidate with neuroprotective properties in preventing PD.

Cystic fibrosis transmembrane conductance regulator-associated ligand protects dopaminergic neurons by differentially regulating metabotropic glutamate receptor 5 in the progression of neurotoxin 6-hydroxydopamine-induced Parkinson's disease model.

Due to limitations in early diagnosis and treatments of Parkinson's disease (PD), it is necessary to explore the neuropathological changes that occur early in PD progression and to design neuroprotective therapies to prevent or delay the ongoing degeneration process. Metabotropic glutamate receptor 5 (mGlu5) has shown both diagnostic and therapeutic potential in preclinical studies on PD. Clinical trials using mGlu5 negative allosteric modulators to treat PD have, however, raised limitations about the neuroprotective role of mGlu5. It is likely that mGlu5 has different regulatory roles in different stages of PD. Here, we investigated a protective role of cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) in the progression of PD by differential regulation of mGlu5 expression and activity to protect against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. Following treatment with 6-OHDA, mGlu5 and CAL expressions were elevated in the early stage and reduced in the late stage, both in vitro and in vivo. Activation of mGlu5 in the early stage by (RS)-2-chloro-5-hydroxyphenylglycine, or blocking mGlu5 in the late stage by 2-methyl-6-(phenylethynyl) pyridine, increased cell survival and inhibited apoptosis, but these effects were significantly weakened by knockdown of CAL. CAL alleviated 6-OHDA-induced neurotoxicity by regulating mGlu5-mediated signaling pathways, thereby maintaining the physiological function of mGlu5 in different disease stages. In PD rat model, CAL deficiency aggravated 6-OHDA toxicity on dopaminergic neurons and increased motor dysfunction because of lack of regulation of mGlu5 activity. These data reveal a potential mechanism by which CAL specifically regulates the opposite activity of mGlu5 in progression of PD to protect against neurotoxicity, suggesting that CAL is a favorable endogenous target for the treatment of PD.

The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson's disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway.

Recent studies implicate the defects or altered expression of the orphan nuclear receptor Nurr1 gene in the substantia nigra in Parkinson's disease pathogenesis. In an attempt to corroborate the treatment-modifying disease that would replicate the effect of Nurr1, it has been found that amodiaquine and Nurr1 had the same chemical scaffolding, indicating a crucial structure-activity relationship. Interestingly, amodiaquine stimulate the transcriptional function of Nurr1 by physical interaction with its ligand-binding domain (LBD). However, the signaling route by which Nurr1 is activated by amodiaquine to cause the protective effect remains to be elucidated. We first demonstrated that amodiaquine treatment ameliorated behavioural deficits in 6-OHDA Parkinson's disease mouse model, and it promoted dopaminergic neurons protection signified by Tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA; Tyrosine hydroxylase (TH) protein expression level and the immunoreactivity in the substantia nigra compacta. Subsequently, we used inhibitors to ascertain the effect of amodiaquine on Akt and P38 Mapk as crucial signaling pathways for neuroprotection. Wortmannin (Akt Inhibitor) induced a significant reduction of Akt mRNA; however, there was no statistical difference between the amodiaquine-treated group and the control group suggesting that amodiaquine may not be the active stimulant of Akt. Western blot analysis confirmed that the phosphorylated Akt decreased significantly in the amodiaquine group compared to the control group. In the same vein, we found that amodiaquine substantially increased the level of phosphorylated P38 Mapk. When P38 Mapk inhibited by SB203580 (P38-Mapk Inhibitor), the total P38 Mapk but not the phosphorylated P38 Mapk decreased significantly, while tyrosine hydroxylase significantly increased. These results collectively suggest that amodiaquine can augment tyrosine hydroxylase expression via phosphorylated P38 Mapk while negatively regulating the phosphorylated Akt in protein expression.

Febuxostat Inhibits MPP+-Induced Inflammatory Response Through Inhibiting the JNK/NF-κB Pathway in Astrocytes.

Parkinson's disease (PD) is a severe neurodegenerative disease lacking effective clinical therapies. It is reported that astrocyte-associated neuroinflammation and oxidative stress are involved in the pathological mechanism of PD. In the present study, we aimed to investigate the protective effect of febuxostat against 1 methyl 4 phenyl pyridine (MPP+)-induced injury on primary astrocytes to highlight the potential therapeutic property of febuxostat in PD.MPP+ was used to induce an in vitro PD model in primary rat astrocytes. The levels of ROS and intracellularly reduced GSH were determined using DCFH-DA assay and a commercial GSH kit, respectively. MTT and LDH release assays were utilized to evaluate the cell viability of astrocytes. The expressions of IL-8, IL-1ß, TNF-α, MMP-2, and MMP-9 in the astrocytes were detected using qRT-PCR and ELISA assays. QRT-PCR and Western blot analysis were used to determine the expression levels of GFAP in astrocytes. The expression of p-JNK and nuclear levels of NF-κB p65 were evaluated using Western blot analysis. The transcriptional activity of NF-κB was measured using the luciferase activity assay.Firstly, the elevated levels of ROS and decreased levels of intracellularly reduced GSH in primary astrocytes induced by MPP+ were significantly ameliorated by febuxostat. Secondly, treatment with febuxostat rescued MPP+-induced reduction in cell viability and increased LDH release. Thirdly, febuxostat alleviated MPP+-induced inflammatory responses in astrocytes by reducing the expressions of IL-8, IL-1ß, TNF-α, GFAP, MMP-2, and MMP-9. Importantly, we found that febuxostat mitigated activation of the JNK/NF-κB signaling pathway by inhibiting the phosphorylation of JNK and nuclear translocation of NF-κB p65.Febuxostat attenuated MPP+-induced inflammatory response by suppressing the JNK/NF-κB signaling pathway in astrocytes.

Emergency Room Visit Prevention for Older Patients with Parkinsonism in a Geriatric Clinic.

BACKGROUND: Older persons with parkinsonism (PWP) are at high risk for hospitalization and adverse outcomes. Few effective strategies exist to prevent Emergency Department (ED) visits and hospitalization. The interdisciplinary Geriatrics Clinic for Parkinson's ("our clinic") was founded to address the complexity of parkinsonism in older patients, supported by a pharmacist-led telephone intervention (TI) service. Our primary objective was to study whether TI could avert ED visits in older PWP. METHODS: Using a prospective, observational cohort, we collected data from all calls in 2016, including who initiated and reasons for the calls, patient demographics, number of comorbidities and medications, diagnoses, duration of disease, and intervention provided. Calls with intention to visit ED were classified as "crisis calls". Outcome of whether patients visited ED was collected within 1 week, and user satisfaction by anonymous survey within 3 weeks. RESULTS: We received 337 calls concerning 114 patients, of which 82 (24%) were "crisis calls". Eighty-one percent of calls were initiated by caregivers. Ninety-three percent of "crisis calls" resolved without ED visit after TI. The main reasons for "crisis calls" were non-motor symptoms (NMS) (39%), adverse drug effects (ADE) (29%), and motor symptoms (18%). Ninety-seven percent of callers were satisfied with the TI. CONCLUSION: Pharmacist-led TI in a Geriatrics Clinic for Parkinson's was effective in preventing ED visits in a population of older PWP, with high user satisfaction. Most calls were initiated by caregivers. Main reasons for crisis calls were NMS and ADE. These factors should be considered in care planning for older PWP.

Protection induced by estradiol benzoate in the MPP+ rat model of Parkinson's disease is associated with the regulation of the inflammatory cytokine profile in the nigro striatum.

Previously, we have demonstrated that ß-estradiol-3-benzoate (EB) has a protective effect on the neurodegenerative experimental model of Parkinson's disease. The protective effect is through the induction of the expression of paraoxonase-2 (PON2) in the striatum. PON2 has proven to have antioxidant and anti-inflammatory activity, this protein has a beneficial effect in MPP+ model in rats decreasing the lipid peroxidation and the oxidative stress. Furthermore, the molecular effect and the pathway by which EB induces protection were not further pursued. This study shows the regulation by EB of the anti-inflammatory effect through the modulation of cytokines, antioxidant enzymes and PON2 in the rat striatum. Rats were gonadectomized and 30 days after were randomly assigned into four experimental groups; only vehicles (Control group); EB treatment (EB group); MPP+ injury (M group); EB plus MPP+ injured (EB/M group). EB treatment consisted of 100 µg of the drug administered every 48 h for 11 days. Results showed that EB (group EB/M) treatment decrease significantly (40%) the number of ipsilateral turns respect to the M group and prevents significantly the dopamine (DA) decreased induced by MPP+ (~75%). This results are correlate with a significant decrease in the level of lipid peroxidation (60%) of the EB/M group respect to the M group. The EB treatment showed protection against neurotoxicity induced with MPP+, this could be due to EB capacity to prevent the increase in the expression level of proinflammatory cytokines TNF-α, IL-1 and IL-6 induced by MPP+. While, TGF-ß1 and TGF-ß3 expression was reduced in the rats treated only with MPP+, in the rats of EB/M group the expression of both cytokines was increased. EB protective effect against MPP+ neurotoxicity is related to antioxidant effect of PON2, pro-inflammatory cytokines and GSHR but not to SOD2, catalase, GPX1 or GPX4.

Ameliorative effects of flavonoids and polyketides on the rotenone induced Drosophila model of Parkinson's disease.

Parkinson's disease (PD) is a movement disorder associated with the progressive loss of dopaminergic neurons (DA). PD treatment remains unsatisfactory as the current synthetic drugs in clinical use relies on managing only motor symptoms. This study investigated antioxidant potentials of selected compounds namely, 5,6,7,4'-tetramethoxyflavone (1), 6-hydroxy-2,3,4,4'-tetramethoxychalcone (2), 6-methoxyhamiltone A (3), diosquinone (4) and toussantine D (5) against rotenone (6) induced PD in Drosophila melanogaster. Toxicity of these compounds was conducted by monitoring flies' survival for seven days and determining the lethal concentrations (LC50). Whereas compound 1 had LC50 value of 91.3 µM within three days, compounds 2, 3, 4, and 5 had LC50 values of 87.2, 58.0, 64.0 and > 1000 µM, respectively on the seventh day of the experiment. We exposed flies (1-4 days old) to 500 µM rotenone and co-treated with different doses of the test compounds in the diet for seven days at final concentrations of 11.0, 43.6 and 87.2 µM for compounds 2 and 3. The concentrations used for compound 4 were 8.0, 32.0 and 64.0 µM, while 250, 500 and 1000 µM were used for compound 5. Rotenone fed flies showed impaired climbing ability compared to control flies, the phenotype that was rescued by the treatment of tested phytochemicals. Rotenone toxicity also increased malondialdehyde levels assayed by lipid peroxidation in the brain tissues relative to control flies. This effect was reduced in flies exposed to rotenone and co-treated with the phytochemicals. Moreover, expression levels of mRNA of antioxidant enzymes; superoxide dismutase and catalase were elevated in flies exposed to rotenone and normalized in flies that were co-treated with tested compounds. Besides compound 1, this study provides overall evidence that the tested flavonoids and polyketides ameliorated the rotenone provoked neurotoxicity in D. melanogaster by battling the induced oxidative stress in brain cells including DA neurons and hence rescue the locomotor behaviour deficits.

Preparation and Neuroprotective Activity of Glucuronomannan Oligosaccharides in an MPTP-Induced Parkinson's Model.

Parkinson's disease (PD), characterized by dopaminergic neuron degeneration in the substantia nigra and dopamine depletion in the striatum, affects up to 1% of the global population over 50 years of age. Our previous study found that a heteropolysaccharide from Saccharina japonica exhibits neuroprotective effects through antioxidative stress. In view of its high molecular weight and complex structure, we degraded the polysaccharide and subsequently obtained four oligosaccharides. In this study, we aimed to further detect the neuroprotective mechanism of the oligosaccharides. We applied MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to induce PD, and glucuronomannan oligosaccharides (GMn) was subsequently administered. Results showed that GMn ameliorated behavioral deficits in Parkinsonism mice. Furthermore, we observed that glucuronomannan oligosaccharides contributed to down-regulating the apoptotic signaling pathway through enhancing the expression of tyrosine hydroxylase (TH) in dopaminergic neurons. These results suggest that glucuronomannan oligosaccharides protect dopaminergic neurons from apoptosis in PD mice.