30 research outputs found
New insights into the circuitry underlying levodopa-induced dyskinesia in rodent models of Parkinson's disease
No full textAbnormal involuntary movements (AIMs) or dyskinesias are probably the most debilitating side-effect elicited by levodopa pharmacotherapy of Parkinson’s disease. Development of levodopa-induced dyskinesias (LID) reflects a processes of sensitization to levodopa taking place primarily in striatum, and leading to the abnormal response to dopaminomimetics. Despite the growing knowledge about the intracellular pathways involved in the development of LID, little is known about the impact of antidyskinetic treatments on the basal ganglia circuitry. In the present thesis, we used microdialysis to investigate the neurochemical and behavioural changes exerted by different antidyskinetic treatments or approaches in basal ganglia. We first found that levodopa evoked AIMs, and simultaneously elevated GABA levels in the substantia nigra reticulata but not globus pallidus of dyskinetic mice and rats, suggesting the involvement of the striato-nigral “direct” GABAergic pathway in both species (Bido et al., J Neurochem 118, 1043-1055, 2011). Amantadine (the only antidyskinetic drug marketed for treating LID) attenuated AIMs expression and prevented the nigral GABA rise (Bido et al., J Neurochem 118:1043-55, 2011), suggesting nigral GABA as a neurochemical correlate of LID. To further investigate which pathway is involved in LID and in the antidyskinetic effect of amantadine, we took advantage from recent studies showing the specificity of Ras-guanine nucleotide-releasing factor 1 and 2 to selectively couple NR2B and NR2A NMDA receptor subunits, respectively. We showed that blockade of striatal expression of Ras-GRF1 using a lentiviral vector carrying a short hairpin RNA (LV Ras-GRF1) caused an attenuation of LID development and expression, which was accompanied by the lack of the increase in nigral GABA. However, in LV Ras-GRF1 mice the antidyskinetic effect of amantadine and its neurochemical correlates were lost, suggesting LV Ras-GRF1 might interfere with the antidyskinetic effect of amantadine by acting on the same target (possibly the NR2B receptor). Conversely, injection of a viral construct expressing a small hairpin directed against RasGRF2 caused only a not significant reduction of LID, and did not prevent the increase of nigral GABA following L-DOPA. In these mice, also the antidyskinetic effect of amantadine remained unaltered (Bido et al., in preparation).
To confirm the involvement of the direct pathway in LID, and dissect out the role of striatal and nigral dopamine D1 and D2 receptors we performed regional perfusion (striatum and substantia nigra pars reticulata) of selective D1 and D2 antagonists simultaneously with systemic L-DOPA
administration. Intrastriatal blockade of D1 receptor attenuated LID and prevented the accompanying rise of nigral GABA levels whereas blockade of D2 receptor was ineffective (Mela et al., Neurobiol Dis 45, 574-583, 2012). When perfused in the substantia nigra, both the D1 and D2 antagonists attenuated LID expression, although only the D1 antagonist prevented the GABA rise.
Overall, the data provide neurochemical evidence that LID is accompanied by activation of D1-receptor expressing striato-nigral GABAergic neurons, and that the antidyskinetic effect of amantadine partly relies on the modulation of this pathway, possibly through NR2B-subunit expressing NMDA receptors. Nonetheless, by using different antidyskinetic approaches we were able to cause only ~50% reduction of LID in face of a complete inhibition of the GABA rise in substantia nigra. This points to the existence of other important neurochemical modulators of LID, possibly also in brain structures outside the basal ganglia
Amantadine attenuates levodopa-induced dyskinesia in mice and rats preventing the accompanying rise in nigral GABA levels
No full textAmantadine is the only drug marketed for treating levodopa-induced dyskinesia. However, its impact on basal ganglia circuitry in the dyskinetic brain, particularly on the activity of striatofugal pathways, has not been evaluated. We therefore used dual probe microdialysis to investigate the effect of amantadine on behavioral and neurochemical changes in the globus pallidus and substantia nigra reticulata of 6-hydroxydopamine hemi-lesioned dyskinetic mice and rats. Levodopa evoked abnormal involuntary movements (AIMs) in dyskinetic mice, and simultaneously elevated GABA release in substantia nigra reticulata (∼3-fold) but not globus pallidus. Glutamate levels were unaffected in both areas. Amantadine (40 mg/kg, i.p.), ineffective alone, attenuated (∼50%) AIMs expression and prevented the GABA rise. Moreover, it unraveled a facilitatory effect of levodopa on pallidal glutamate levels. Levodopa also evoked AIMs expression and a GABA surge (∼2-fold) selectively in the substantia nigra of dyskinetic rats. However, different from mice, glutamate levels rose simultaneously. Amantadine, ineffective alone, attenuated (∼50%) AIMs expression preventing amino acid increase and leaving unaffected pallidal glutamate. Overall, the data provide neurochemical evidence that levodopa-induced dyskinesia is accompanied by activation of the striato-nigral pathway in both mice and rats, and that the anti-dyskinetic effect of amantadine partly relies on the modulation of this pathway. © 2011 International Society for Neurochemistry
Further evidence for an involvement of nociceptin/orphanin FQ in the pathophysiology of Parkinson’s disease: a behavioral and neurochemical study in reserpinized mice
No full textThe contribution of nociceptin/orphanin FQ (N/OFQ) to reserpine-induced parkinsonism was evaluated in mice. A battery of motor tests revealed that reserpine caused dose-dependent and long-lasting motor impairment. Endogenous N/OFQ sustained this response since N/OFQ peptide (NOP) receptor knockout (NOP-/-) mice were less susceptible to the hypokinetic action of reserpine than wild-type (NOP+/+) animals. Microdialysis revealed that reserpine elevated glutamate and reduced GABA levels in substantia nigra reticulata, and that resistance to reserpine in NOP-/- mice was accompanied by a milder increase in glutamate and lack of inhibition of GABA levels. To substantiate this genetic evidence, the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397) simultaneously reduced akinesia and nigral glutamate levels in reserpinized NOP+/+ mice, being ineffective in NOP-/- mice. Moreover, repeated J-113397 administration in reserpinized mice resulted in faster recovery of baseline motor performance which was, however, accompanied by a loss of acute antiakinetic response. The short-term beneficial effect of J-113397 was paralleled by normalization of nigral glutamate levels, whereas loss of acute response was paralleled by loss of the ability of J-113397 to inhibit glutamate levels. We conclude that endogenous N/OFQ contributes to reserpine-induced parkinsonism, and that sustained NOP receptor blockade produces short-term motor improvement accompanied by normalization of nigral glutamate release
In vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to l-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels
No full textEvidence for an involvement of striatal D1 receptors in levodopa-induced dyskinesia has been presented whereas the contribution of striatal D2 receptors remains controversial. In addition, whether D1 and D2 receptors located in the substantia nigra reticulata shape the response to levodopa remains unknown. We therefore used dual probe microdialysis to unravel the impact of striatal and nigral D1 or 02 receptor blockade on abnormal involuntary movements (AIMS) and striatal output pathways in unilaterally 6-hydroxydopamine lesioned dyskinetic rats. Regional perfusion of D1/D5 (SCH23390) and D2/D3 (raclopride) receptor antagonists was combined with systemic administration of levodopa. Levodopa-induced AIMS coincided with a prolonged surge of GABA and glutamate levels in the substantia nigra reticulata. Intrastriatal SCH23390 attenuated the levodopa-induced AIM scores (similar to 50%) and prevented the accompanying neurochemical response whereas raclopride was ineffective. When perfused in the substantia nigra, both antagonists attenuated AIM expression (similar to 21-40%). However, only intranigral SCH23390 attenuated levodopa-induced nigral GABA efflux, whereas raclopride reduced basal GABA levels without affecting the response to levodopa. In addition, intranigral raclopride elevated amino acid release in the striatum and revealed a (mild) facilitatory effect of levodopa on striatal glutamate. We conclude that both striatal and nigral D1 receptors play an important role in dyskinesia possibly via modulation of the striato-nigral direct pathway. In addition, the stimulation of nigral D2 receptors contributes to dyskinesia while modulating glutamate and GABA efflux both locally and in the striatum. (C) 2011 Elsevier Inc. All rights reserved
PKM PENGEMBANGAN PRODUK MAKANAN OLAHAN BAHAN BAKU KEDELAI PADA IRT BIDO JAYA KABUPATEN MALANG MELALUI IMPLEMENTASI TEKNOLOGI PRODUKSI TEPAT GUNA
No full textABSTRAKPermasalahan yang dimiliki oleh IRT Bido Jaya adalah kurangnya efisiensi dalam produksi karena keterbatasan produk, tampilan kemasan yang kurang sesuai standar industri makanan, manajemen usaha yang buruk karena tidak pernah melakukan riset pasar terhadap produk dan potensi produk, manajerial keuangan yang hanya berdasar kekeluargaan, menggunakan peralatan produksi yang manual. Penelitian ini bertujuan untuk memberikan solusi pengadaan alat produksi tepat guna, meningkatkan kualitas pengemasan dan manajemen usaha. Metode pelaksanaan yaitu pembelian alat dan pendampingan, workshop pendampingan dan simulasi, serta workshop dan pendampingan. Hasil dari penelitian ini berupa evaluasi tim Unikama yang didapatkan selama melakukan program kemitraan masyarakat (PKM) dapat membantu para IRT untuk bangkit kembali pasca covid dan memajukan usaha IRT di Indonesia. Saran yang disampaikan penulis bahwa perlu pendampingan dalam menggunakan aplikasi untuk media pemasaran terkait postingan foto produk dan video yang menarik minat pelanggan terutama bagi IRT yang awam terhadap penggunaan teknologi. Selain itu, perlu adanya paparan tentang strategi yang sangat matang dalam bisnis untuk mengantisipasi adanya hal yang tidak diinginkan. Kata kunci: IRT (bido jaya); teknologi produksi tepat guna; manajemen usaha; riset pasar; digital marketing ABSTRACTThe problems that IRT Bido Jaya has are the lack of efficiency in production due to limited products, the appearance of packaging that does not match industrial food standards, poor business management because it has never conducted market research on products and product potential, financial management which is only based on kinship, using equipment manual production equipment. This research aims to provide solutions for procurement of appropriate production equipment, improve the quality of packaging and business management. The method of implementation is the purchase of tools and assistance, mentoring and simulation workshops, as well as workshops and mentoring. The results of this study are in the form of an evaluation by the Unikama team obtained during the community partnership program (PKM) that can help IRTs to bounce back post-covid and advance IRT businesses in Indonesia. The suggestion conveyed by the author is that assistance is needed in using applications for media marketing related to posting product photos and videos that attract customer interest, especially for IRT who are unfamiliar with the use of technology. In addition, there needs to be an explanation of a very mature strategy in business to anticipate unwanted things. Keywords: IRT (bido jaya); appropriate production technology; business management; market research; digital marketin
Differential involvement of Ras-GRF1 and Ras-GRF2 in L-DOPA-induced dyskinesia
No full textObjective
Recent findings have shown that pharmacogenetic manipulations of the Ras-ERK pathway provide a therapeutic means to tackle l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID). First, we investigated whether a prolonged l-DOPA treatment differentially affected ERK signaling in medium spiny neurons of the direct pathway (dMSNs) and in cholinergic aspiny interneurons (ChIs) and assessed the role of Ras-GRF1 in both subpopulations. Second, using viral-assisted technology, we probed Ras-GRF1 and Ras-GRF2 as potential targets in this pathway. We investigated how selective blockade of striatal Ras-GRF1 or Ras-GRF2 expression impacted on LID (induction, maintenance, and reversion) and its neurochemical correlates.
Methods
We used both Ras-GRF1 knockout mice and lentiviral vectors (LVs) delivering short-hairpin RNA sequences (shRNAs) to obtain striatum-specific gene knockdown of Ras-GRF1 and Ras-GRF2. The consequences of these genetic manipulations were evaluated in the 6-hydroxydopamine mouse model of Parkinson's disease. Escalating doses of l-DOPA were administered and then behavioral analysis with immunohistochemical assays and in vivo microdialysis were performed.
Results
Ras-GRF1 was found essential in controlling ERK signaling in dMSNs, but its ablation did not prevent ERK activation in ChIs. Moreover, striatal injection of LV-shRNA/Ras-GRF1 attenuated dyskinesia development and ERK-dependent signaling, whereas LV-shRNA/Ras-GRF2 was without effect, ruling out the involvement of Ras-GRF2 in LID expression. Accordingly, Ras-GRF1 but not Ras-GRF2 striatal gene-knockdown reduced l-DOPA-induced GABA and glutamate release in the substantia nigra pars reticulata, a neurochemical correlate of dyskinesia. Finally, inactivation of Ras-GRF1 provided a prolonged anti-dyskinetic effect for up to 7 weeks and significantly attenuated symptoms in animals with established LID.
Interpretation
Our results suggest that Ras-GRF1 is a promising target for LID therapy based on Ras-ERK signaling inhibition in the striatum
Neuro-zika: Brain structure and functional organization of adult humans with zika virus infection and severe neurological complications
No full textSince its outbreak in the Americas in 2015, Zika virus (ZIKV) has become a major global health threat due to its potential to affect the nervous system. Although most adult cases show no or mild symptoms, some patients exhibit severe neurological complications. While these complications often present as Guillain-Barre Syndrome (GBS)-like manifestations confined to the peripheral nervous system (PNS), they extend to symptoms of the central nervous system (CNS) in a subset of severely affected patients. Yet, reports on the adult CNS have remained confined to a few single cases of structural brain changes. Further, no functional neuroimaging studies have been carried out to investigate how ZIKV affects adult human brain function. In this first case-control neuroimaging study, we investigated nine rare adult patients with ZIKV-related neurological complications of the CNS during the subacute phase (3 females, Age=35±4.46, range 30-45 years, 5±0.5 months since symptoms onset) compared to nine healthy age- and sex-matched controls. Our clinical observations comprised atypical descending and rapidly progressing PNS manifestations, and additional CNS presentations such as perceptual deficits. In light of the persistent cognitive deficits and neurological symptoms, a comprehensive and exhaustive follow up to the patients was performed. This evaluation, performed 2 years after the neurological manifestations onset included clinical assessments, behavioral questionnaires, electrophysiological studies and FLAIR images automated lesion detection. These deviations from typical GBS urgently call for a characterization of a potential impact on the brain. Neuroimaging revealed gray matter volume reductions bilaterally in motor areas (supplementary motor cortex, specifically Frontal Eye Fields) and beyond (left inferior frontal sulcus). Additionally, gray matter volume increased in right middle frontal gyrus. Functional connectivity increased in a widespread network within and across temporal lobes. Here, preliminary evidence is provided for a link between ZIKV neurological complications and changes in adult human brain structure and functional organization, comprising both motor-related regions potentially secondary to prolonged PNS weakness, and non-somatomotor regions indicative of PNS-independent alterations. The latter included the temporal lobes, particularly vulnerable in a range of neurological conditions. While future studies into the ZIKV-related neuroinflammatory mechanisms in adults are urgently needed, the current study indicates that ZIKV infection can lead to an impact on the brain.Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2021-05-01The student, Richard Bido Medina, accepted the attached license on 2019-04-16 at 15:13.The student, Richard Bido Medina, submitted this Dissertation for approval on 2019-04-16 at 15:21.This Dissertation was approved for publication on 2019-04-16 at 18:31.DSpace SAF Submission Ingestion Package generated from Vireo submission #13683 on 2019-08-22 at 15:06:51Made available in DSpace on 2019-08-23T20:35:58Z (GMT). No. of bitstreams: 2
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Multilevel Schwarz and multigrid preconditioners for the Bidomain system
No full textTwo parallel and scalable multilevel preconditioners for the Bidomain
system in computational electrocardiology are introduced and studied. The Bido-
main system, consisting of two degenerate parabolic reaction-diffusion equations
coupled with a stiff system of several ordinary differential equations, generates very
ill-conditioned discrete systems when discretized with semi-implicit methods in time
and finite elements in space. The multilevel preconditioners presented in this paper
attain the best performance to date, both in terms of convergence rate and solution
time and outperform the simpler one-level preconditioners previously introduced.
Parallel numerical results, using the PETSc library and run on Linux Clusters,
show the scalability of the proposed preconditioners and their efficiency on large-
scale simulations of a complete cardiac cycle
Reconstitution of the Human Nigro-striatal Pathway on-a-Chip Reveals OPA1-Dependent Mitochondrial Defects and Loss of Dopaminergic Synapses
No full textStem cell-derived neurons are generally obtained in mass cultures that lack both spatial organization and any meaningful connectivity. We implement a microfluidic system for long-term culture of human neurons with patterned projections and synaptic ter- minals. Co-culture of human midbrain dopaminergic and striatal medium spiny neurons on the microchip establishes an orchestrated nigro-striatal circuitry with functional dopaminergic synapses. We use this platform to dissect the mitochondrial dysfunc- tions associated with a genetic form of Parkinson’s disease (PD) with OPA1 mutations. Remarkably, we find that axons of OPA1 mutant dopaminergic neu- rons exhibit a significant reduction of mitochondrial mass. This defect causes a significant loss of dopa- minergic synapses, which worsens in long-term cultures. Therefore, PD-associated depletion of mitochondria at synapses might precede loss of neuronal connectivity and neurodegeneration. In vitro reconstitution of human circuitries by micro- fluidic technology offers a powerful system to study brain networks by establishing ordered neuronal compartments and correct synapse identity
Nanoparticulate lipidic dispersions for bromocriptine delivery: characterization and in vivo study
No full textThe physico-chemical properties and in vivo efficacies of two nanoparticulate systems delivering the antiparkinsonian drug bromocriptine (BC) were compared in the present study. Monoolein Aqueous Dispersions (MADs) and Nanostructured Lipid Carriers (NLCs) were produced and characterized. Cryogenic transmission electron microscopy (cryo-TEM) and X-ray diffraction revealed the morphology of MAD and NLC. Dimensional distribution was determined by Photon Correlation Spectroscopy (PCS) and Sedimentation Field Flow Fractionation (SdFFF). In particular, BC was shown to be encapsulated with high entrapment efficiency both in MAD and in NLC, according to SdFFF combined with HPLC. Two behavioral tests specific for akinesia (bar test) or akinesia/bradykinesia (drag test) were used to compare the effects of the different BC formulations On motor disabilities in 6-hydroxydopamine hemilesioned rats in vivo, a model of Parkinson's disease. Both free BC and BC-NLC reduced the immobility time in the bar test and enhanced the number of steps in the drag test, although the effects of encapsulated BC were longer lasting (5 h). Conversely, BC-MAD was ineffective in the bar test and improved stepping activity in the drag test to a much lower degree than those achieved with the other preparations. We conclude that MAD and NLC can encapsulate BC, although only NLC provide long-lasting therapeutic effects possibly extending BC half-life in vivo
