Induction of Neuronal PI3Kγ Contributes to Endoplasmic Reticulum Stress and Long-Term Functional Impairment in a Murine Model of Traumatic Brain Injury.
Neurotherapeutics
; 16(4): 1320-1334, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31187475
ABSTRACT
Phosphoinositide 3-kinase γ (PI3Kγ) expressed in immune cells is linked to neuroinflammation in several neurological diseases. However, the expression and role of PI3Kγ in preclinical traumatic brain injury (TBI) have not been investigated. In WT mice, we found that TBI induced rapid and extensive expression of PI3Kγ in neurons within the perilesional cortex and the ipsilateral hippocampal subfields (CA1, CA3), which peaked between 1 and 3 days and declined significantly 7 days after TBI. Intriguingly, the induction of neuronal PI3Kγ in these subregions of the brain spatiotemporally coincided with both the TBI-induced activation of the neuronal ER stress pathway (p-eIF2α, ATF4, and CHOP) and neuronal cell death (marked by TUNEL-positive neurons) 3 days after TBI. Further, we show that the absence of PI3Kγ in knockout mice profoundly reduced the TBI-induced activation of the ER stress pathway and neuronal cell death. White matter disruption is a better predictor of long-term clinical outcomes than focal lesion size. We show that PI3Kγ deficiency not only reduced brain tissue loss but also alleviated white matter injury (determined by axonal injury and demyelination) up to 28 days after TBI. Importantly, PI3Kγ-knockout mice exhibited greater functional recovery including forepaw use, sensorimotor balance and coordination, and spatial learning and memory up to 28 days after TBI. These results unveil a previously unappreciated role for neuronal PI3Kγ in the regulation of ER stress associated with neuronal cell death, white matter damage, and long-term functional impairment after TBI.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Encéfalo
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Classe Ib de Fosfatidilinositol 3-Quinase
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Estresse do Retículo Endoplasmático
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Lesões Encefálicas Traumáticas
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Transtornos da Memória
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Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Neurotherapeutics
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos