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1.
Brain Behav Immun ; 74: 7-27, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30217533

RESUMO

It is generally accepted that inflammation within the CNS contributes to neurodegeneration after traumatic brain injury (TBI), but it is not clear how inflammation is initiated in the absence of infection and whether this neuroinflammation is predominantly beneficial or detrimental. We have previously found that brain-enriched glycosphingolipids within neuronal lipid rafts (NLR) induced platelet degranulation and secretion of neurotransmitters and pro-inflammatory factors. In the present study, we compared TBI-induced inflammation and neurodegeneration in wild-type vs. St3gal5 deficient (ST3-/-) mice that lack major CNS-specific glycosphingolipids. After TBI, microglial activation and CNS macrophage infiltration were substantially reduced in ST3-/- animals. However, ST3-/- mice had a larger area of CNS damage with marked neuronal/axonal loss. The interaction of platelets with NLR stimulated neurite growth, increased the number of PSD95-positive dendritic spines, and intensified neuronal activity. Adoptive transfer and blocking experiments provide further that platelet-derived serotonin and platelet activating factor plays a key role in the regulation of sterile neuroinflammation, hemorrhage and neuronal plasticity after TBI.


Assuntos
Plaquetas/fisiologia , Neuroimunomodulação/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Plaquetas/metabolismo , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/fisiopatologia , Modelos Animais de Doenças , Encefalite/metabolismo , Feminino , Glicolipídeos/metabolismo , Glicolipídeos/fisiologia , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Neurônios/fisiologia , Fator de Ativação de Plaquetas/metabolismo , Fator de Ativação de Plaquetas/fisiologia , Serotonina/metabolismo
2.
Prog Neurobiol ; 188: 101783, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142857

RESUMO

The drugs currently available for treating epilepsy are only partially effective in managing this condition. Therefore, it is crucial to investigate new pathways that induce and promote epilepsy development. Previously, we found that platelets interact with neuronal glycolipids and actively secrete pro-inflammatory mediators during central nervous system (CNS) pathological conditions such as neuroinflammation and traumatic brain injury (TBI). These factors increase the permeability of the blood-brain barrier (BBB), which may create a predisposition to epileptic seizures. In this study, we demonstrated that platelets substantially enhanced epileptic seizures in a mouse model of pentylenetetrazole (PTZ) -induced seizures. We found that platelets actively secreted serotonin, contributed to increased BBB permeability, and were present in the CNS parenchyma during epileptic seizures. Furthermore, platelets directly stimulated neuronal electric activity and induced the expression of specific genes related to early neuronal response, neuroinflammation, and oxidative phosphorylation, leading to oxidative stress in neurons. The intracranial injection of physiological numbers of platelets that mimicked TBI-associated bleeding was sufficient to induce severe seizures, which resembled conventional PTZ-induced epileptic activity. These findings highlight a conceptually new role of platelets in the development of epileptic seizures, and indicate a potential new therapeutic approach targeting platelets to prevent and treat epilepsy.


Assuntos
Plaquetas/metabolismo , Encéfalo , Epilepsia , Gangliosídeos/metabolismo , Inflamação , Estresse Oxidativo/fisiologia , Convulsões , Serotonina/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Epilepsia/etiologia , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Convulsões/etiologia , Convulsões/metabolismo , Convulsões/fisiopatologia
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