Publicação
Neuroprotective strategies for transient focal cerebral ischemia : an experimental model
| Resumo: | Object: The aim of this research was to explore the effects of single pretreatment dose of potential neuroprotective drugs in a focal cerebral ischemia-reperfusion (I-R) model. Methods: After the setting up and establisment of the selected animal model, forty-two Wistar male adult rats were subjected to right middle cerebral artery (MCA) intraluminal occlusion for 60 minutes, under continuously cortical perfusion monitoring. Rats were randomly divided into three groups: control (saline), recombinant human erythropoietin (rhEPO, 1.000 IU/kg)-treated and 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD- 8, 5 mg/kg) -treated. Saline or drugs were administered 10 minutes before the onset of ischemia. At 24-hour reperfusion, animals were examined for neurological deficits, blood samples were collected and animals euthanized. The following parameters were blindly evaluated: brain infarct volume, ipsilateral hemispheric edema, neuron specific enolase (NSE) plasma levels, parenchyma histology, Fluoro-Jade positive neurons, p-Akt and total Akt expression, and p-Akt-positive nuclei. Results: Data demonstrated that for rhEPO-treated group severity of neurological deficits (p<0.001), brain edema (p<0.001), and NSE plasma levels (p<0.001) were significantly reduced when compared to control group. Infarct volume and counting number of degenerating neurons in the interest area were similar between these groups, however, perivascular edema was less marked following treatment. No variations on the expression or localization of p-Akt were seen. TDZD-8-treated group compared to control group had: reduced infarct volume (p<0.001) and hemispheric edema (p<0.001), diminished number of dying neurons (p<0.001), decreased serum rise of NSE (p<0.001), and improved neurological performance (p<0.001). Fewer signs of perivascular edema and increased p-Akt nucleus translocation (p<0.05) were found. Conclusions: Results suggest that TDZD-8 has neuroprotective effects due to a complex and mixed synergic interaction between direct neuronal GSK-3β inhibition and Akt modulation, but further research is required before this drug may become clinically available. Additionally, it is presented first evidence that prophylactic rhEPO administration at the considered dose, which has its safety profile well-described in humans, reduced brain edema xi and preserved the neuronal pool of the penumbra area following I-R-injury. These benefits appear to be the result of an indirect effect in brain swelling as a consequence of diminished blood-brain barrier disruption and not due to a direct rhEPO neuronal action in the infarct area. Erythropoietin is a potential therapy to prevent neuronal injury induced by intraoperative transient artery occlusion. A translational study is supported and a summary protocol for a putative clinical trial is proposed. |
|---|---|
| Autores principais: | Ratilal, Bernardo Oliveira, 1975- |
| Assunto: | Aneurisma intracraniano Isquemia encefálica Eritropoetina Traumatismo por reperfusão Fármacos neuroprotectores Teses de doutoramento - 2015 |
| Ano: | 2015 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| _version_ | 1866809693070950400 |
|---|---|
| author | Ratilal, Bernardo Oliveira, 1975- |
| author_facet | Ratilal, Bernardo Oliveira, 1975- |
| author_role | author |
| contributor_name_str_mv | Sampaio, Cristina, 1963- Antunes, João Lobo, 1944- Filipe, Helder Dias Mota, 1965- Repositório Científico de Acesso Aberto da ULisboa |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Ratilal, Bernardo Oliveira, 1975-\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Sampaio, Cristina, 1963- Antunes, João Lobo, 1944- Filipe, Helder Dias Mota, 1965- Repositório Científico de Acesso Aberto da ULisboa |
| datacite.creators.creator.creatorName.fl_str_mv | Ratilal, Bernardo Oliveira, 1975- |
| datacite.date.Accepted.fl_str_mv | 2015-01-01T00:00:00Z |
| datacite.date.available.fl_str_mv | 2015-06-12T17:50:26Z |
| datacite.date.embargoed.fl_str_mv | 2015-06-12T17:50:26Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.fl_str_mv | Aneurisma intracraniano Isquemia encefálica Eritropoetina Traumatismo por reperfusão Fármacos neuroprotectores Teses de doutoramento - 2015 |
| datacite.titles.title.fl_str_mv | Neuroprotective strategies for transient focal cerebral ischemia : an experimental model |
| dc.contributor.none.fl_str_mv | Sampaio, Cristina, 1963- Antunes, João Lobo, 1944- Filipe, Helder Dias Mota, 1965- Repositório Científico de Acesso Aberto da ULisboa |
| dc.creator.none.fl_str_mv | Ratilal, Bernardo Oliveira, 1975- |
| dc.date.Accepted.fl_str_mv | 2015-01-01T00:00:00Z |
| dc.date.available.fl_str_mv | 2015-06-12T17:50:26Z |
| dc.date.embargoed.fl_str_mv | 2015-06-12T17:50:26Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10451/18264 |
| dc.language.none.fl_str_mv | eng |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.fl_str_mv | Aneurisma intracraniano Isquemia encefálica Eritropoetina Traumatismo por reperfusão Fármacos neuroprotectores Teses de doutoramento - 2015 |
| dc.title.fl_str_mv | Neuroprotective strategies for transient focal cerebral ischemia : an experimental model |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_db06 |
| description | Object: The aim of this research was to explore the effects of single pretreatment dose of potential neuroprotective drugs in a focal cerebral ischemia-reperfusion (I-R) model. Methods: After the setting up and establisment of the selected animal model, forty-two Wistar male adult rats were subjected to right middle cerebral artery (MCA) intraluminal occlusion for 60 minutes, under continuously cortical perfusion monitoring. Rats were randomly divided into three groups: control (saline), recombinant human erythropoietin (rhEPO, 1.000 IU/kg)-treated and 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD- 8, 5 mg/kg) -treated. Saline or drugs were administered 10 minutes before the onset of ischemia. At 24-hour reperfusion, animals were examined for neurological deficits, blood samples were collected and animals euthanized. The following parameters were blindly evaluated: brain infarct volume, ipsilateral hemispheric edema, neuron specific enolase (NSE) plasma levels, parenchyma histology, Fluoro-Jade positive neurons, p-Akt and total Akt expression, and p-Akt-positive nuclei. Results: Data demonstrated that for rhEPO-treated group severity of neurological deficits (p<0.001), brain edema (p<0.001), and NSE plasma levels (p<0.001) were significantly reduced when compared to control group. Infarct volume and counting number of degenerating neurons in the interest area were similar between these groups, however, perivascular edema was less marked following treatment. No variations on the expression or localization of p-Akt were seen. TDZD-8-treated group compared to control group had: reduced infarct volume (p<0.001) and hemispheric edema (p<0.001), diminished number of dying neurons (p<0.001), decreased serum rise of NSE (p<0.001), and improved neurological performance (p<0.001). Fewer signs of perivascular edema and increased p-Akt nucleus translocation (p<0.05) were found. Conclusions: Results suggest that TDZD-8 has neuroprotective effects due to a complex and mixed synergic interaction between direct neuronal GSK-3β inhibition and Akt modulation, but further research is required before this drug may become clinically available. Additionally, it is presented first evidence that prophylactic rhEPO administration at the considered dose, which has its safety profile well-described in humans, reduced brain edema xi and preserved the neuronal pool of the penumbra area following I-R-injury. These benefits appear to be the result of an indirect effect in brain swelling as a consequence of diminished blood-brain barrier disruption and not due to a direct rhEPO neuronal action in the infarct area. Erythropoietin is a potential therapy to prevent neuronal injury induced by intraoperative transient artery occlusion. A translational study is supported and a summary protocol for a putative clinical trial is proposed. |
| dirty | 0 |
| eu_rights_str_mv | openAccess |
| format | doctoralThesis |
| fulltext.url.fl_str_mv | https://repositorio.ulisboa.pt/bitstreams/d62fc007-1923-4171-b3a4-74efead6e846/download |
| id | ul_719e22fb00892a5d4d0deee1b8758721 |
| identifier.url.fl_str_mv | http://hdl.handle.net/10451/18264 |
| instacron_str | ul |
| institution | Universidade de Lisboa |
| instname_str | Universidade de Lisboa |
| language | eng |
| network_acronym_str | ul |
| network_name_str | Repositório da Universidade de Lisboa |
| oai_identifier_str | oai:repositorio.ulisboa.pt:10451/18264 |
| organization_str_mv | urn:organizationAcronym:ul |
| person_str_mv | Ratilal, Bernardo Oliveira, 1975- |
| publishDate | 2015 |
| reponame_str | Repositório da Universidade de Lisboa |
| repository_id_str | urn:repositoryAcronym:ul |
| service_str_mv | urn:repositoryAcronym:ul |
| spelling | engporObject: The aim of this research was to explore the effects of single pretreatment dose of potential neuroprotective drugs in a focal cerebral ischemia-reperfusion (I-R) model. Methods: After the setting up and establisment of the selected animal model, forty-two Wistar male adult rats were subjected to right middle cerebral artery (MCA) intraluminal occlusion for 60 minutes, under continuously cortical perfusion monitoring. Rats were randomly divided into three groups: control (saline), recombinant human erythropoietin (rhEPO, 1.000 IU/kg)-treated and 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD- 8, 5 mg/kg) -treated. Saline or drugs were administered 10 minutes before the onset of ischemia. At 24-hour reperfusion, animals were examined for neurological deficits, blood samples were collected and animals euthanized. The following parameters were blindly evaluated: brain infarct volume, ipsilateral hemispheric edema, neuron specific enolase (NSE) plasma levels, parenchyma histology, Fluoro-Jade positive neurons, p-Akt and total Akt expression, and p-Akt-positive nuclei. Results: Data demonstrated that for rhEPO-treated group severity of neurological deficits (p<0.001), brain edema (p<0.001), and NSE plasma levels (p<0.001) were significantly reduced when compared to control group. Infarct volume and counting number of degenerating neurons in the interest area were similar between these groups, however, perivascular edema was less marked following treatment. No variations on the expression or localization of p-Akt were seen. TDZD-8-treated group compared to control group had: reduced infarct volume (p<0.001) and hemispheric edema (p<0.001), diminished number of dying neurons (p<0.001), decreased serum rise of NSE (p<0.001), and improved neurological performance (p<0.001). Fewer signs of perivascular edema and increased p-Akt nucleus translocation (p<0.05) were found. Conclusions: Results suggest that TDZD-8 has neuroprotective effects due to a complex and mixed synergic interaction between direct neuronal GSK-3β inhibition and Akt modulation, but further research is required before this drug may become clinically available. Additionally, it is presented first evidence that prophylactic rhEPO administration at the considered dose, which has its safety profile well-described in humans, reduced brain edema xi and preserved the neuronal pool of the penumbra area following I-R-injury. These benefits appear to be the result of an indirect effect in brain swelling as a consequence of diminished blood-brain barrier disruption and not due to a direct rhEPO neuronal action in the infarct area. Erythropoietin is a potential therapy to prevent neuronal injury induced by intraoperative transient artery occlusion. A translational study is supported and a summary protocol for a putative clinical trial is proposed.application/pdfporNeuroprotective strategies for transient focal cerebral ischemia : an experimental modelRatilal, Bernardo Oliveira, 1975-Sampaio, Cristina, 1963-Antunes, João Lobo, 1944-Filipe, Helder Dias Mota, 1965-HostingInstitutionOrganizationalRepositório Científico de Acesso Aberto da ULisboae-mailmailto:repositorio@reitoria.ulisboa.ptrepositorio@reitoria.ulisboa.ptURNurn:tid:1013051252015-06-12T17:50:26Z201520142015-01-01T00:00:00ZHandlehttp://hdl.handle.net/10451/18264http://purl.org/coar/access_right/c_abf2open accessAneurisma intracranianoIsquemia encefálicaEritropoetinaTraumatismo por reperfusãoFármacos neuroprotectoresTeses de doutoramento - 201568365920 bytesliteraturehttp://purl.org/coar/resource_type/c_db06doctoral thesishttp://purl.org/coar/access_right/c_abf2application/pdffulltexthttps://repositorio.ulisboa.pt/bitstreams/d62fc007-1923-4171-b3a4-74efead6e846/download |
| spellingShingle | Neuroprotective strategies for transient focal cerebral ischemia : an experimental model Ratilal, Bernardo Oliveira, 1975- Aneurisma intracraniano Isquemia encefálica Eritropoetina Traumatismo por reperfusão Fármacos neuroprotectores Teses de doutoramento - 2015 |
| status | SINGLETON |
| subject.fl_str_mv | Aneurisma intracraniano Isquemia encefálica Eritropoetina Traumatismo por reperfusão Fármacos neuroprotectores Teses de doutoramento - 2015 |
| title | Neuroprotective strategies for transient focal cerebral ischemia : an experimental model |
| title_full | Neuroprotective strategies for transient focal cerebral ischemia : an experimental model |
| title_fullStr | Neuroprotective strategies for transient focal cerebral ischemia : an experimental model |
| title_full_unstemmed | Neuroprotective strategies for transient focal cerebral ischemia : an experimental model |
| title_short | Neuroprotective strategies for transient focal cerebral ischemia : an experimental model |
| title_sort | Neuroprotective strategies for transient focal cerebral ischemia : an experimental model |
| topic | Aneurisma intracraniano Isquemia encefálica Eritropoetina Traumatismo por reperfusão Fármacos neuroprotectores Teses de doutoramento - 2015 |
| topic_facet | Aneurisma intracraniano Isquemia encefálica Eritropoetina Traumatismo por reperfusão Fármacos neuroprotectores Teses de doutoramento - 2015 |
| url | http://hdl.handle.net/10451/18264 |
| visible | 1 |