- Chrysin protects against behavioral, cognitive and neurochemical alterations in a 6-hydroxydopamine model of Parkinson's disease. [Journal Article]
- NLNeurosci Lett 2019 May 20
- Parkinson's disease (PD) is an age-related neurodegenerative disorder that severely affects quality of life of patients and their families. The flavonoid chrysin (5,7-dihydroxylflavone) is a naturall…
Parkinson's disease (PD) is an age-related neurodegenerative disorder that severely affects quality of life of patients and their families. The flavonoid chrysin (5,7-dihydroxylflavone) is a naturally occurring flavone with several pharmacological activities, including anti-inflammatory and anti-oxidative. We investigated the effects of a 28-day chrysin treatment (10 mg/kg/day, i.g.) on a model of PD induced by 6-OHDA in aged (20-month old) mice. We found a protective effect of chrysin on behavioral and cognitive alterations (rotational behavior, passive avoidance and Barnes maze tests), nitric oxide synthesis (NOx), lipid peroxidation (HNE), glutathione levels (GSH), reactive species levels (RS), neuroinflammation (interleukin-1 beta - IL-1β and tumor necrosis factor alpha - TNF-α), Na+, K+-ATPase and nicotinamide adenine dinucleotide phosphate oxidase activity (NADPH oxidase) activities. In addition, chrysin protected against changes in striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. In conclusion, chrysin improved several behavioral, cognitive and neurochemical parameters in a relevant preclinical model of PD in aged mice.
- Multi-modal imaging with specialized sequences improves accuracy of the automated subcortical grey matter segmentation. [Journal Article]
- MRMagn Reson Imaging 2019 May 20
- The basal ganglia and limbic system, particularly the thalamus, putamen, internal and external globus pallidus, substantia nigra, and sub-thalamic nucleus, comprise a clinically relevant signal netwo…
The basal ganglia and limbic system, particularly the thalamus, putamen, internal and external globus pallidus, substantia nigra, and sub-thalamic nucleus, comprise a clinically relevant signal network for Parkinson's disease. In order to manually trace these structures, a combination of high-resolution and specialized sequences at 7 T are used, but it is not feasible to routinely scan clinical patients in those scanners. Targeted imaging sequences at 3 T have been presented to enhance contrast in a select group of these structures. In this work, we show that a series of atlases generated at 7 T can be used to accurately segment these structures at 3 T using a combination of standard and optimized imaging sequences, though no one approach provided the best result across all structures. In the thalamus and putamen, a median Dice Similarity Coefficient (DSC) over 0.88 and a mean surface distance <1.0 mm were achieved using a combination of T1 and an optimized inversion recovery imaging sequences. In the internal and external globus pallidus a DSC over 0.75 and a mean surface distance <1.2 mm were achieved using a combination of T1 and inversion recovery imaging sequences. In the substantia nigra and sub-thalamic nucleus a DSC of over 0.6 and a mean surface distance of <1.0 mm were achieved using the inversion recovery imaging sequence. On average, using T1 and optimized inversion recovery together significantly improved segmentation results than over individual modality (p < 0.05 Wilcoxon sign-rank test).
- Apelin-13 attenuates motor impairments and prevents the changes in synaptic plasticity- related molecules in the striatum of Parkinsonism rats. [Journal Article]
- PPeptides 2019 May 20
- The striatum plays a critical role in motor control and also learning and memory of motor skills. It has been reported that striatal synaptic components are significantly decreased in dopaminergic-de…
The striatum plays a critical role in motor control and also learning and memory of motor skills. It has been reported that striatal synaptic components are significantly decreased in dopaminergic-denervated striatum. In this study the effects of apelin-13 were investigated on motor disorders and striatal synaptosomal expression of PSD-95, neurexin1, neuroligin, metabotropic glutamate receptor (mGlu R1) and dopaminergic receptors (DR1 and DR2) in rat parkinsonism experimental model. 6-hydroxydopamine (6-OHDA) was injected into the substantia nigra. Apelin-13 (1, 2 and 3 µg/rat) was administered into the substantia nigra one week after the 6-OHDA injection. Accelerating rotarod, beam-balance, beam-walking and bar tests were performed one month after the apelin injection. Immunohistochemistry staining of dopaminergic neurons was performed. The levels of synaptic proteins were determined by immunoblotting. 6-OHDA-treated animals showed a significant impairment in motor-skill tasks and a dramatically change in the expression levels of mentioned proteins. Apelin-13 (3 µg/rat) significantly attenuates the motor impairments and prevents the changes in striatal synaptic elements in 6-OHDA-treated animals. In addition, it could rescue the dopaminergic neurons of the substantia nigra. The data will potentially extend the possible benefic aspect of apelin in neurodegenerative disorders.
- Metformin reverses the schizophrenia-like behaviors induced by MK-801 in rats. [Journal Article]
- BRBrain Res 2019 May 20
- Schizophrenia is known to be a complex and disabling psychiatric disorder. Dopamine receptor antagonists have a significant therapeutic effect in improving the positive symptoms that are associated w…
Schizophrenia is known to be a complex and disabling psychiatric disorder. Dopamine receptor antagonists have a significant therapeutic effect in improving the positive symptoms that are associated with the illness. Therefore, dopamine receptor antagonists are commonly used in the treatment of schizophrenia; however, they do not achieve satisfactory results in improving negative symptoms and cognitive impairment. Metformin, widely known as an antidiabetic drug, has been found to enhance spatial memory formation and improve anxiety-like behaviors in rodents. Metformin's neuroprotective effect has been well documented in several neurological disorders including Alzheimer's disease, Parkinson's disease, strokes, Huntington's disease, and seizures. In the present study, we used a rat model to explore the effect of metformin on schizophrenia-like behaviors induced by MK-801 (dizocilpine), an N-methyl-D-aspartate (NMDA) receptor antagonist. We found that the pre-pulse inhibition (PPI) deficit caused by MK-801 could be alleviated by metformin. The hyperlocomotion in the open field test induced by chronic treatment of MK-801 was reversed by administration of metformin. Metformin has no effect on the baseline level of anxiety in normal naive rats, while metformin could relieve the anxiety-like behaviors in MK-801-treatment rats, though this effect is not reaching a significant level. Additionally, metformin could significantly ameliorate working memory impairments induced by MK-801. Moreover, the increased level of phosphorylation of Akt and GSK3β in the frontal cortex induced by MK-801 was normalized by metformin. In conclusion, our results demonstrate that metformin improved schizophrenia-like symptoms in rats, and is therefore a potential agent for the treatment of schizophrenia.
- STAT1 drives M1 microglia activation and neuroinflammation under hypoxia. [Journal Article]
- ABArch Biochem Biophys 2019 May 20
- Microglia are resident immune cells that act as the first active defence in the central nervous system. These cells constantly monitor the tissue microenvironment and rapidly react in response to hyp…
Microglia are resident immune cells that act as the first active defence in the central nervous system. These cells constantly monitor the tissue microenvironment and rapidly react in response to hypoxia, infection and injuries. Hypoxia in the brain has been detected in several neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. Hypoxic conditions activate microglia cells towards M1 phenotype resulting in oxidative stress and the release of pro-inflammatory cytokines. Recently, we have demonstrated that oxidative stress induces S-glutathionylation of the STAT1 and hyper-activates its signaling in microglia BV2 cells pointing out the importance of this transcription factor in neuroinflammation. In this paper we analyse the cellular mechanisms that drive M1 microglia activation in BV2 cells in response to hypoxia correlating it to STAT1 activation. The analysis of the molecular mechanism of STAT1 signaling reveals that hypoxia generates oxidative stress and induces both phosphorylation and S-glutathionylation of STAT1 that are responsible of its aberrant activation. The silencing of STAT1 protein expression counteracts hypoxia-M1 microglia phenotype suggesting the strong link between hypoxia-STAT1 and STAT1-microglia activation.
- Metabolomics-driven identification of adenosine deaminase as therapeutic target in a mouse model of Parkinson's disease. [Journal Article]
- JNJ Neurochem 2019 May 23
- Neuroinflammation is one of the driving forces of progressive neurodegeneration in Parkinson's disease (PD). The metabolomics approach has been proved highly useful in identifying potential therapeut…
Neuroinflammation is one of the driving forces of progressive neurodegeneration in Parkinson's disease (PD). The metabolomics approach has been proved highly useful in identifying potential therapeutic targets. Here, to identify inflammation-relevant treatment targets for PD, mass spectrometry-based untargeted metabolomics was applied to characterize metabolic changes in the striatum of mice with double-hit PD induced by lipopolysaccharide (LPS) plus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Seven days after the final MPTP administration, metabolites from the purine metabolism pathway, including adenosine, 1-methyladenosine, adenine, inosine, hypoxanthine, xanthine, xanthosine and guanosine, were found to be significantly dysregulated. The metabolite-protein interaction network and changes in the concentration ratio of these metabolites indicated that adenosine and adenosine deaminase (ADA; EC 184.108.40.206) were the most promising therapeutic targets and adenosine augmentation might be a rational approach to slow PD progression. These findings were then verified in a subacute MPTP-induced PD mouse model treated with ADA inhibition alone or in conjunction with antagonism of adenosine A2A receptors (A2 A R). Behavioral, biochemical and immunohistochemical analysis demonstrated that ADA inhibition significantly ameliorated the MPTP-mediated motor disabilities, dopamine depletion and dopaminergic cell death. Significantly enhanced neuroprotective effects were further observed when the ADA inhibitor was utilized in conjunction with an A2 A R antagonist. Together, our study indicated for the first time that ADA inhibitors protected against neurodegeneration induced by the neurotoxin MPTP, and ADA inhibitors in combination with A2 A R antagonists showed additive antiparkinsonian effects. This article is protected by copyright. All rights reserved.
- Repetitive Finger Movement and Dexterity Tasks in People With Parkinson's Disease. [Journal Article]
- AJAm J Occup Ther 2019 May/Jun; 73(3):7303205090p1-7303205090p8
- CONCLUSIONS: Changes in movement amplitude and movement rate may influence fine-motor dexterity tasks differently. Thus, it is important to consider the quantitative assessment of both movement rate and movement amplitude because they may indicate differential clinical applications in the treatment of people with PD.
- Drug treatment strategies for depression in Parkinson disease. [Journal Article]
- EOExpert Opin Pharmacother 2019 May 23; :1-13
- Introduction: Depression is a common non-motor symptom in Parkinson disease (PD), occurring in approximately 20% of patients with PD. While depression can occur anytime in the disease process, it pre…
Introduction: Depression is a common non-motor symptom in Parkinson disease (PD), occurring in approximately 20% of patients with PD. While depression can occur anytime in the disease process, it predates PD diagnosis in about 30% of patients. Between 20% and 60% of depressed patients with PD are either without recognition or treatment of their depression. Areas covered: The pathophysiology of depression in PD is unclear. There are several structural changes seen in depressed patients with PD that are also seen in patients with depression. In addition, the neurotransmitters dopamine, serotonin, and norepinephrine are all depleted in PD. This article covers the pharmacological treatment of depression in PD; this involves standard antidepressant treatment such as selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. As with depression not associated with PD, most treatment is partially successful. Non-pharmacological approaches are also touched upon. Expert opinion: Most antidepressant therapy shows partial efficacy in patients with PD. However, there is a need for better study design as well as more comparative studies for the treatment of depression in PD. Biomarkers will help identify patients with PD and depression earlier in the future.
- Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice. [Journal Article]
- JIJCI Insight 2019 May 23; 5
- Parkinson's is primarily a non-familial, age-related disorder caused by α-synuclein accumulation and the progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc). G protein-co…
Parkinson's is primarily a non-familial, age-related disorder caused by α-synuclein accumulation and the progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc). G protein-coupled receptor (GPCR)-cAMP signaling has been linked to a reduction in human Parkinson's incidence and α-synuclein expression. Neuronal cAMP levels are controlled by GPCRs coupled to Gs or Gi/o, which increase or decrease cAMP, respectively. Regulator of G protein signaling 6 (RGS6) powerfully inhibits Gi/o signaling. Therefore, we hypothesized that RGS6 suppresses D2 autoreceptor- Gi/o signaling in SNc dopamine neurons promoting neuronal survival and reducing α-synuclein expression. Here we provide novel evidence that RGS6 critically suppresses late-age-onset SNc dopamine neuron loss and α-synuclein accumulation. RGS6 is restrictively expressed in human SNc dopamine neurons and, despite their loss in Parkinson's, all surviving neurons express RGS6. RGS6-/- mice exhibit hyperactive D2 autoreceptors with reduced cAMP signaling in SNc dopamine neurons. Importantly, RGS6-/- mice recapitulate key sporadic Parkinson's hallmarks, including: SNc dopamine neuron loss, reduced nigrostriatal dopamine, motor deficits, and α-synuclein accumulation. To our knowledge, Rgs6 is the only gene whose loss phenocopies these features of human Parkinson's. Therefore, RGS6 is a key regulator of D2R-Gi/o signaling in SNc dopamine neurons, protecting against Parkinson's neurodegeneration and α-synuclein accumulation.
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- DNAJC proteins and pathways to parkinsonism. [Review]
- FJFEBS J 2019 May 23
- The DNAJC protein family is a subclass of heat shock proteins that has attracted recent attention due to the identification of mutations that are linked with parkinsonism, a feature of Parkinson's di…
The DNAJC protein family is a subclass of heat shock proteins that has attracted recent attention due to the identification of mutations that are linked with parkinsonism, a feature of Parkinson's disease and other neurological disorders. In this review we discuss the current genetic and functional evidence of the association of these DNAJC proteins with disease and how mutations in these proteins may contribute to disease pathogenesis. Whereas DNAJC6 (Auxilin), DNAJC12 and DNAJC5 (CSPα) exhibit strong genetic association with disease, DNAJC26 (GAK), DNAJC13 (RME-8) and DNAJC10 (Erdj5) require additional evidence to definitively link reported variants to parkinsonism. Remarkably, multiple DNAJC proteins (Auxilin, GAK, RME-8, CSPα) functionally converge on pathways of synaptic trafficking and clathrin dynamics, highlighting an important role of those pathways in the pathogenesis of parkinsonism. Further research is required to define the mechanisms through which these mutations contribute to disease etiology. This article is protected by copyright. All rights reserved.