Publicação
Neuroprotective effects of TUDCA in Parkinson’s disease: dissecting the anti-oxidant and anti-inflammatory effects of this bile acid in the mouse cerebral cortex
| Resumo: | Parkinson’s disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Although the main cause of this disorder remains elusive, neurodegeneration has been associated with different mechanisms of cell damage including oxidative stress, mitochondrial dysfunction and neuroinflammation. Despite SNpc being considered the primary affected region in PD, the neuropathological features may not solely be confined to the nigro-striatal axis. It is conceivable that other brain regions are also affected, namely the cerebral cortex, being the neurologic insult to this brain region still not completely unraveled. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent for PD treatment and relevant the pursuit of its mechanism of action in this disease. In this thesis we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. Moreover, we intended to dissect the anti-oxidant and neuroprotective effects of TUDCA in this brain region. In addition, we proposed to investigate the anti-inflammatory mechanisms triggered by this bile acid, in the cerebral cortex and in microglia cells, namely its ability to modulate Annexin-1 (ANXA1) expression and secretion. Our results revealed that in mice cortex TUDCA: i) increases the expression of nuclear factor erythroid 2 related factor 2 antioxidant downstream targets, namely Glutathione peroxidase 1 and Heme oxygenase 1 enzymes, upon MPTP exposure; ii) up-regulates parkin expression and AMP-activated protein kinase activation, and prevents MPTP-induced ATP depletion; and iii) decreases inflammatory makers of astrogliosis and microgliosis, and up-regulates the expression of the anti-inflammatory protein ANXA1. Additionally, results from cellular models corroborate TUDCA modulation of ANXA1 synthesis and secretion and point to the possibility of this protein being a direct target of this bile acid. Together, these results reinforce the potential benefits of using TUDCA as a therapeutic strategy in the treatment of PD. |
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| Autores principais: | Mendes, Mariana de Oliveira |
| Assunto: | ANXA1 Mitochondrial Dysfunction MPTP Neuroinflammation TUDCA Teses de mestrado - 2017 |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Parkinson’s disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Although the main cause of this disorder remains elusive, neurodegeneration has been associated with different mechanisms of cell damage including oxidative stress, mitochondrial dysfunction and neuroinflammation. Despite SNpc being considered the primary affected region in PD, the neuropathological features may not solely be confined to the nigro-striatal axis. It is conceivable that other brain regions are also affected, namely the cerebral cortex, being the neurologic insult to this brain region still not completely unraveled. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent for PD treatment and relevant the pursuit of its mechanism of action in this disease. In this thesis we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. Moreover, we intended to dissect the anti-oxidant and neuroprotective effects of TUDCA in this brain region. In addition, we proposed to investigate the anti-inflammatory mechanisms triggered by this bile acid, in the cerebral cortex and in microglia cells, namely its ability to modulate Annexin-1 (ANXA1) expression and secretion. Our results revealed that in mice cortex TUDCA: i) increases the expression of nuclear factor erythroid 2 related factor 2 antioxidant downstream targets, namely Glutathione peroxidase 1 and Heme oxygenase 1 enzymes, upon MPTP exposure; ii) up-regulates parkin expression and AMP-activated protein kinase activation, and prevents MPTP-induced ATP depletion; and iii) decreases inflammatory makers of astrogliosis and microgliosis, and up-regulates the expression of the anti-inflammatory protein ANXA1. Additionally, results from cellular models corroborate TUDCA modulation of ANXA1 synthesis and secretion and point to the possibility of this protein being a direct target of this bile acid. Together, these results reinforce the potential benefits of using TUDCA as a therapeutic strategy in the treatment of PD. |
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