Phosphoinositide 3-kinase gamma contributes to neuroinflammation in a rat model of surgical brain injury

Lei Huang, Prativa Sherchan, Yuechun Wang, Cesar Reis, Richard Lee Applegate, Jiping Tang, John H. Zhang

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Neuroinflammation plays an important role in the pathophysiology of surgical brain injury (SBI). Phosphoinositide 3-kinase gamma (PI3Kγ), predominately expressed in immune and endothelial cells, activates multiple inflammatory responses. In the present study, we investigated the role of PI3Kγ and PI3Kγ-activated phosphodiesterase 3B (PDE3B) in neuroinflammation in a rat model of SBI. One hundred and fifty-two male Sprague Dawley rats (weight 280 –350 g) were subjected to a partial right frontal lobe corticotomy model of SBI. A PI3Kγ pharmacological inhibitor (AS252424 or AS605240) was administered intraperitoneally. PI3Kγ siRNA, human recombinant active-PI3Kγ protein, or human recombinant active-PDE3B protein were administered intracerebroventricularly. Post-SBI assessments included neurobehavioral tests, brain water content, Western blot, and immunohistochemistry. Endogenous PI3Kγ levels were increased within peri-resection brain tissues after SBI, accompanied by increased brain water content and neurological functional deficits. There was a trend toward increased endogenous PDE3B phosphorylation after SBI. The selective PI3Kγ inhibitors AS252424 and AS605240 reduced brain water content surrounding corticotomy and improved neurological function after SBI. SBI increased and PI3Kγ inhibitor decreased levels of myeloperoxidase, cluster of differentiation 3, mast cell degranulation, E-selectin, and IL-1 in peri-resection brain tissues. Direct administration of human recombinant active-PI3Kγ protein and active-PDE3B protein countered the protective effect of AS252424. PI3Kγ siRNA reduced PI3Kγ levels, decreased brain water content within peri-resection brain tissues, and improved neurological function after SBI. Collectively, our findings suggest that PI3Kγ contributed to neuroinflammation after SBI. The use of selective PI3Kγ inhibitors may be a novel approach to ameliorating SBI via their anti-inflammation effects.

Original languageEnglish (US)
Pages (from-to)10390-10401
Number of pages12
JournalJournal of Neuroscience
Volume35
Issue number29
DOIs
StatePublished - Jul 22 2015
Externally publishedYes

Fingerprint

1-Phosphatidylinositol 4-Kinase
Intraoperative Complications
Brain Injuries
Type 3 Cyclic Nucleotide Phosphodiesterases
Brain
Water
Small Interfering RNA
Proteins
Cell Degranulation
E-Selectin
Frontal Lobe
Interleukin-1
Mast Cells
Peroxidase
Sprague Dawley Rats

Keywords

  • Blood–brain barrier
  • Brain edema
  • Inflammation
  • Neurosurgery
  • PDE3B
  • PI3Kγ

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Phosphoinositide 3-kinase gamma contributes to neuroinflammation in a rat model of surgical brain injury. / Huang, Lei; Sherchan, Prativa; Wang, Yuechun; Reis, Cesar; Applegate, Richard Lee; Tang, Jiping; Zhang, John H.

In: Journal of Neuroscience, Vol. 35, No. 29, 22.07.2015, p. 10390-10401.

Research output: Contribution to journalArticle

Huang, Lei ; Sherchan, Prativa ; Wang, Yuechun ; Reis, Cesar ; Applegate, Richard Lee ; Tang, Jiping ; Zhang, John H. / Phosphoinositide 3-kinase gamma contributes to neuroinflammation in a rat model of surgical brain injury. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 29. pp. 10390-10401.
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