| 1. |
- Carlsson, Thomas, et al.
(författare)
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Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration.
- 2009
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 132, s. 319-335
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that serotonin neurons play an important role in the induction and maintenance of l-DOPA-induced dyskinesia in animals with lesion of the nigrostriatal dopamine system. Patients with Parkinson's disease that receive transplants of foetal ventral mesencephalic tissue, the graft cell preparation is likely to contain, in addition to dopamine neurons, serotonin neurons that will vary in number depending on the landmarks used for dissection. Here, we have studied the impact of grafted serotonin neurons-alone or mixed with dopamine neurons-on the development of l-DOPA-induced dyskinesia in rats with a partial 6-hydroxydopamine lesion of the host nigrostriatal projection. In these rats, which showed only low-level dyskinesia at the time of transplantation, serotonin grafts induced a worsening in the severity of dyskinesia that developed during continued l-DOPA treatment, while the dopamine-rich graft had the opposite, dampening effect. The detrimental effect seen in animals with serotonin neuron grafts was dramatically increased when the residual dopamine innervation in the striatum was removed by a second 6-hydroxydopamine lesion. Interestingly, rats with grafts that contained a mixture of dopamine and serotonin neurons (in approximately 2:1) showed a marked reduction in l-DOPA-induced dyskinesia over time, and the appearance of severe dyskinesia induced by the removal of the residual dopamine innervation, seen in the animals with transplants of serotonin neurons alone, was blocked. FosB expression in the striatal projection neurons, which is associated with dyskinesias, was also normalized by the dopamine-rich grafts, but not by the serotonin neuron grafts. These data indicate that as long as a sufficient portion, some 10-20%, of the dopamine innervation still remains, the increased host serotonin innervation generated by the grafted serotonin neurons will have limited effect on the development or severity of l-DOPA-induced dyskinesias. At more advanced stages of the disease, when the dopamine innervation of the putamen is reduced below this critical threshold, grafted serotonin neurons are likely to aggravate l-DOPA-induced dyskinesia in those cases where the dopamine re-innervation derived from the grafted neurons is insufficient in magnitude or do not cover the critical dyskinesia-inducing sub-regions of the grafted putamen. We conclude that it is not the absolute number of serotonin neurons in the grafts, but the relative densities of dopamine and serotonin innervations in the grafted striatum that is the critical factor in determining the long-term effect of foetal tissue graft, beneficial or detrimental, on dyskinesia in grafted Parkinson's disease patients.
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| 2. |
- Carta, Manolo, et al.
(författare)
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Involvement of the serotonin system in L-dopa-induced dyskinesias
- 2008
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Ingår i: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020. ; 14:Suppl 2, s. 8-154
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Tidskriftsartikel (refereegranskat)abstract
- The ability of L-dopa to relieve the motor impairments in Parkinson's disease patients declines over time, and side-effects, such as dyskinesias, appear--limiting the use of the drug in the advanced stage of the disease. Serotonergic neurons are able to convert L-dopa to dopamine and to store this neurotransmitter in synaptic vesicles. This peculiarity might be very important in the advanced disease, when most of the dopaminergic neurons have degenerated. Indeed, an increasing body of evidence points to dopamine released as a false neurotransmitter from the serotonin terminals as the main pre-synaptic determinant of L-dopa-induced dyskinesias in animal models of Parkinson's disease. These findings make the serotonin system an intriguing target for anti-dyskinetic therapies.
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| 3. |
- Carta, Manolo, et al.
(författare)
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Serotonin-dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesias
- 2008
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Ingår i: Progress in Brain Research. - 1875-7855. ; 172, s. 465-478
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Tidskriftsartikel (refereegranskat)abstract
- Appearance of dyskinesia is a common problem of long-term Levodopa (L-DOPA) treatment in Parkinson's disease (PD) patients and represents a major limitation for the pharmacological management of the motor symptoms in the advanced stages of disease. An increasing body of evidence points to dopamine released as a false neurotransmitter from the striatal serotonin terminals as the main pre-synaptic determinant of L-DOPA-induced dyskinesia. Here we review the animal experimental and human clinical data in support of this view, which point to the serotonin system as a promising target for anti-dyskinetic therapy in PD patients under L-DOPA medication.
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| 4. |
- Lopez, Lourdes, et al.
(författare)
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ASA : advanced secure architecture for preventing unauthorized access in personal computer platforms and BIOS
- 2007
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Ingår i: Euro American Conference on Telematics and Information Systems - Proceedings of the 2007 Euro American Conference on Telematics and Information Systems, EATIS 2007. - New York, NY, USA : ACM. - 9781595935984 ; , s. Article number a18-
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Konferensbidrag (refereegranskat)abstract
- This paper proposes an architecture for Personal Computers (PC) to avoid BIOS alteration and unauthorized access to resources. This proposal is based on results obtained from study of most popular PC platforms security mechanisms. Authentication controls which are established in PC platform in order to grant operating system booting or BIOS integrity of code mechanism incorporated to secureand avoid executing disallowed code are quite easy to break. The architecture described in the present work (Advanced Secure Architecture - ASA) increase the overall information and system security since prevents an unauthorized platform booting and it provides procedures for BIOS code authentication. On the other hand, ASA overcomes the users' authentication challenge in a corporative environment as well as it offers a very flexible way to specify the Personal Computers Corporation set that a user is allowed to access.
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| 5. |
- Munoz, Ana, et al.
(författare)
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Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia.
- 2008
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 131, s. 3380-3394
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Tidskriftsartikel (refereegranskat)abstract
- Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT(1A) and 5-HT(1B) agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT(1A) and 5-HT(1B) agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT(1A) and 5-HT(1B) agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT(1) agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT(1A) and 5-HT(1B) agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.
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| 6. |
- Munoz, Ana, et al.
(författare)
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Serotonin neuron-dependent and -independent reduction of dyskinesia by 5-HT(1A) and 5-HT(1B) receptor agonists in the rat Parkinson model.
- 2009
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 219:1, s. 298-307
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Tidskriftsartikel (refereegranskat)abstract
- 5-HT(1) receptor agonists have been shown to reduce abnormal involuntary movements (AIMs) in the rat and monkey models of l-DOPA-induced dyskinesia. Different mechanisms have been proposed to underlie this effect. Activation of pre-synaptic 5-HT(1) receptors has been suggested to inhibit dysregulated release of dopamine from the serotonin terminals, and thus, abnormal activation of striatal dopamine receptors. Activation of post-synaptic 5-HT(1) receptors expressed in non-serotonergic neurons in different brain areas, by contrast, has been shown to result in decreased glutamate and GABA release, which may also contribute to the antidyskinetic effect. To unveil the relative contribution of these mechanisms, we have investigated the effect of increasing doses of 5-HT(1A) and 5-HT(1B) receptor agonists on AIMs induced by either l-DOPA or apomorphine. In contrast to l-DOPA-induced AIMs, which were dampened already at low doses of 5-HT(1) agonists, reduction of apomorphine-induced AIMs required higher doses. Removal of the serotonin innervation suppressed l-DOPA-induced AIMs, but neither affected apomorphine-induced AIMs nor the inhibiting effect of 5-HT(1) agonists on AIMs induced by the direct dopamine agonist, suggesting that such effect is independent on activation of pre-synaptic 5-HT(1) receptors.
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