Publicação
Creatine protects against rotenone induced cell death of cerebellar granule neurons
| Resumo: | Parkinson´s Disease (PD) is the second most prevalent neurodegenerative brain disorder worldwide. Nevertheless, there is lack of certainty on the pathophysiology of the neurodegenerative mechanisms underlying PD. Several neurotoxins, rotenone among them, have been shown to induce parkinsonism-like brain degeneration and are widely used in cellular and animal models of PD. In spite of an extensive association of PD with dopaminergic neuron degeneration of the substantia nigra pars compacta, other brain areas like the cerebellum have been more recently implicated in the pathology of the disease. Therefore, we used a rotenone/cerebellar granule neurons (CGN) model to study not only the potential of creatine (as ergogenic compound), epicatechin and kaempferol (as antioxidant compounds) to afford neuroprotection against rotenone neurotoxicity but also to better understand the cellular mechanisms underlying this neurotoxicity. Our results revealed a strong protection by creatine against rotenone-induced CGN death, while kaempferol did not afford a significant protection and epicatechin elicited at most a very weak protection. On the contrary, kaempferol also antagonized the protective effect of creatine. These results lend support to the potential use of creatine in PD therapeutics, and alert for the avoidance of the consumption of foods or infusions with high content in kaempferol. Furthermore, we noted that rotenone triggered an energetic failure in CGN as a primary event, supported not only by the protection afforded by creatine but also by a deregulation in calcium homeostasis thought voltage operate calcium channels type L and N-Methyl-D-aspartate receptors stimulation and store-operated calcim entry inhibition, by the elevation of AMP-kinase active levels and by mitochondrial membrane depolarization. Rotenone also promoted an enhanced production of reactive oxygen species and a weak nitrosative stress, but only as a later event in the development of CGN death. In conclusion, our results support a role for creatine in affording neuroprotection against rotenone neurotoxicity, through a mechanim that prevent an energetic failure. |
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| Autores principais: | Fortalezas, Sofia Isabel Almeida |
| Assunto: | Parkinson's disease Cerebellar granule neurons Rotenone Creatine Epicatechin Kaempferol Energetic failure Teses de mestrado - 2012 |
| Ano: | 2012 |
| 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 the second most prevalent neurodegenerative brain disorder worldwide. Nevertheless, there is lack of certainty on the pathophysiology of the neurodegenerative mechanisms underlying PD. Several neurotoxins, rotenone among them, have been shown to induce parkinsonism-like brain degeneration and are widely used in cellular and animal models of PD. In spite of an extensive association of PD with dopaminergic neuron degeneration of the substantia nigra pars compacta, other brain areas like the cerebellum have been more recently implicated in the pathology of the disease. Therefore, we used a rotenone/cerebellar granule neurons (CGN) model to study not only the potential of creatine (as ergogenic compound), epicatechin and kaempferol (as antioxidant compounds) to afford neuroprotection against rotenone neurotoxicity but also to better understand the cellular mechanisms underlying this neurotoxicity. Our results revealed a strong protection by creatine against rotenone-induced CGN death, while kaempferol did not afford a significant protection and epicatechin elicited at most a very weak protection. On the contrary, kaempferol also antagonized the protective effect of creatine. These results lend support to the potential use of creatine in PD therapeutics, and alert for the avoidance of the consumption of foods or infusions with high content in kaempferol. Furthermore, we noted that rotenone triggered an energetic failure in CGN as a primary event, supported not only by the protection afforded by creatine but also by a deregulation in calcium homeostasis thought voltage operate calcium channels type L and N-Methyl-D-aspartate receptors stimulation and store-operated calcim entry inhibition, by the elevation of AMP-kinase active levels and by mitochondrial membrane depolarization. Rotenone also promoted an enhanced production of reactive oxygen species and a weak nitrosative stress, but only as a later event in the development of CGN death. In conclusion, our results support a role for creatine in affording neuroprotection against rotenone neurotoxicity, through a mechanim that prevent an energetic failure. |
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