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| 2. |
- Berglind, Fredrik, et al.
(författare)
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Optogenetic inhibition of chemically induced hypersynchronized bursting in mice.
- 2014
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 65, s. 133-141
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Tidskriftsartikel (refereegranskat)abstract
- Synchronized activity is common during various physiological operations but can culminate in seizures and consequently in epilepsy in pathological hyperexcitable conditions in the brain. Many types of seizures are not possible to control and impose significant disability for patients with epilepsy. Such intractable epilepsy cases are often associated with degeneration of inhibitory interneurons in the cortical areas resulting in impaired inhibitory drive onto the principal neurons. Recently emerging optogenetic technique has been proposed as an alternative approach to control such seizures but whether it may be effective in situations where inhibitory processes in the brain are compromised has not been addressed. Here we used pharmacological and optogenetic techniques to block inhibitory neurotransmission and induce epileptiform activity in vitro and in vivo. We demonstrate that NpHR-based optogenetic hyperpolarization and thereby inactivation of a principal neuronal population in the hippocampus is effectively attenuating seizure activity caused by disconnected network inhibition both in vitro and in vivo. Our data suggest that epileptiform activity in the hippocampus caused by impaired inhibition may be controlled by optogenetic silencing of principal neurons and potentially can be developed as an alternative treatment for epilepsy.
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| 3. |
- Bourdenx, Mathieu, et al.
(författare)
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Abnormal structure-specific peptide transmission and processing in a primate model of Parkinson's disease and L-DOPA-induced dyskinesia
- 2014
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 62, s. 307-312
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Tidskriftsartikel (refereegranskat)abstract
- A role for enhanced peptidergic transmission, either opioidergic or not, has been proposed for the generation of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) on the basis of in situ hybridization studies showing that striatal peptidergic precursor expression consistently correlates with LID severity. Few studies, however, have focused on the actual peptides derived from these precursors. We used mass-spectrometry to study peptide profiles in the putamen and globus pallidus (internalis and externalis) collected from 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine treated macaque monkeys, acutely or chronically treated with L-DOPA. We identified that parkinsonian and dyskinetic states are associated with an abnormal production of proenkephalin-, prodynorphin- and protachykinin-1-derived peptides in both segments of the globus pallidus. Moreover, we report that peptidergic processing is dopamine-state dependent and highly structure-specific, possibly explaining the failure of previous clinical trials attempting to rectify abnormal peptidergic transmission.
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| 5. |
- Burguillos Garcia, Miguel, et al.
(författare)
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Apoptosis-inducing factor mediates dopaminergic cell death in response to lps-induced inflammatory stimulus Evidence in Parkinson's disease patients.
- 2011
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 41, s. 177-188
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Tidskriftsartikel (refereegranskat)abstract
- We show that intranigral lipopolysaccharide (LPS) injection, which provokes specific degeneration of DA neurons, induced caspase-3 activation in the rat ventral mesencephalon, which was mostly associated with glial cells. In contrast, nigral DA neurons exhibited AIF nuclear translocation in response to LPS. A significant decrease of the Bcl-2/Bax ratio in nigral tissue after LPS injection was observed. We next developed an in vitro co-culture system with the microglial BV2 and the DA neuronal MN9D murine cell lines. The silencing of caspase-3 or AIF by small interfering RNAs exclusively in the DA MN9D cells demonstrated the key role of AIF in the LPS-induced death of DA cells. In vivo chemical inhibition of caspases and poly(ADP-ribose)polymerase-1, an upstream regulator of AIF release and calpain, proved the central role of the AIF-dependent pathway in LPS-induced nigral DA cell death. We also observed nuclear translocation of AIF in the ventral mesencephalon of Parkinson's disease subjects.
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| 8. |
- Cederfjäll, Erik, et al.
(författare)
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Key factors determining the efficacy of gene therapy for continuous DOPA delivery in the Parkinsonian brain
- 2012
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 48:2, s. 222-227
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Forskningsöversikt (refereegranskat)abstract
- L-DOPA is currently the standard treatment for alleviating the motor symptoms in Parkinson's disease. The therapeutic efficacy, however, diminishes as the disease progresses. It has been suggested that the beneficial effect of L-DOPA could be reestablished by changing the mode of administration. Indeed, continuous delivery of L-DOPA has been shown to be an effective way to circumvent many of the side effects seen with traditional oral administration, which results in an intermittent supply of the dopamine precursor to the brain. However, all currently tested continuous dopaminergic stimulation approaches rely on peripheral administration. This is not ideal since it gives rise to off target effects and is difficult to maintain long-term. Thus, there is an unmet need for an effective continuous administration method with an acceptable side effect profile. Viral-mediated gene therapy is a promising alternative paradigm that can meet this demand. Encouraging preclinical studies in animal models of Parkinson's disease showed therapeutic efficacy after expression of the genes encoding the enzymes required for biosynthesis of dopamine. Although the first phase I clinical trials using these approaches have been conducted, clear positive data in placebo controlled efficacy studies is still lacking. We are now at a critical junction and need to carefully review the preclinical data from the clinical translation perspective and identify the key factors that will determine the potential for success in gene therapy for Parkinson's disease. (C) 2011 Published by Elsevier Inc.
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| 9. |
- Correa, Fernando, et al.
(författare)
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Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: Restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β.
- 2011
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Ingår i: Neurobiology of disease. - : Elsevier BV. - 1095-953X .- 0969-9961. ; 44:1, s. 142-51
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Tidskriftsartikel (refereegranskat)abstract
- Histone deacetylase (HDAC) inhibitors have promising neuroprotective and anti-inflammatory properties although the exact mechanisms are unclear. We have earlier showed that factors from lipopolysaccharide (LPS)-activated microglia can down-regulate the astroglial nuclear factor-erythroid 2-related factor 2 (Nrf2)-inducible anti-oxidant defence. Here we have evaluated whether histone modification and activation of GSK3β are involved in these negative effects of microglia. Microglia were cultured for 24h in serum-free culture medium to achieve microglia-conditioned medium from non-activated cells (MCM(0)) or activated with 10ng/mL of LPS to produce MCM(10). Astrocyte-rich cultures treated with MCM(10) showed a time-dependent (0-72h) increase in astroglial HDAC activity that correlated with lower levels of acetylation of histones H3 and H4 and decreased levels of the transcription factor Nrf2 and γ-glutamyl cysteine ligase modulatory subunit (γGCL-M) protein levels. The HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) elevated the histone acetylation levels, restored the Nrf2-inducible anti-oxidant defence and conferred protection from oxidative stress-induced (H(2)O(2)) death in astrocyte-rich cultures exposed to MCM(10). Inhibitors of GSK3β (lithium) and p38 MAPK (SB203580) signaling pathways restored the depressed histone acetylation and Nrf2-related transcription whereas an inhibitor of Akt (Ly294002) caused a further decrease in Nrf2-related transcription. In conclusion, the study shows that well tolerated drugs such as VPA and lithium can restore an inflammatory induced depression in the Nrf2-inducible antioxidant defence, possibly via normalised histone acetylation levels.
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| 10. |
- Decressac, Mickael, et al.
(författare)
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Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons.
- 2012
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 45:3, s. 939-953
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease.
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