Pharmacological antagonism of interleukin-8 receptor CXCR2 inhibits inflammatory reactivity and is neuroprotective in an animal model of Alzheimer’s disease

Journal of Neuroinflammation

James G McLarnon¹  N Jantaratnotai²  Hyun B Choi³  T Cho³  Jae K Ryu¹ 

[1] Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, 2176 Health Science Mall, Vancouver V6T 1Z3, British Columbia, Canada;Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada

关键词: Oxidative damage;    Neuroprotection;    Microgliosis;    AD animal model;    Alzheimer’s disease (AD);    Amyloid-beta (Aβ1–42) intrahippocampal injection;    Interleukin-8 (IL-8);    SB332235;    CXCR2 antagonist;    CXCR2;   

Others  :  1227083
DOI  :  10.1186/s12974-015-0339-z

 received in 2015-01-27, accepted in 2015-06-04,  发布年份 2015

【 摘 要 】

Background

The chemokine interleukin-8 (IL-8) and its receptor CXCR2 contribute to chemotactic responses in Alzheimer’s disease (AD); however, properties of the ligand and receptor have not been characterized in animal models of disease. The primary aim of our study was to examine effects of pharmacological antagonism of CXCR2 as a strategy to inhibit receptor-mediated inflammatory reactivity and enhance neuronal viability in animals receiving intrahippocampal injection of amyloid-beta (Aβ _1–42 ).

Methods

In vivo studies used an animal model of Alzheimer’s disease incorporating injection of full-length Aβ _1–42into rat hippocampus. Immunohistochemical staining of rat brain was used to measure microgliosis, astrogliosis, neuronal viability, and oxidative stress. Western blot and Reverse Transcription PCR (RT-PCR) were used to determine levels of CXCR2 in animal tissue with the latter also used to determine expression of pro-inflammatory mediators. Immunostaining of human AD and non-demented (ND) tissue was also undertaken.

Results

We initially determined that in the human brain, AD relative to ND tissue exhibited marked increases in expression of CXCR2 with cell-specific receptor expression prominent in microglia. In Aβ _1–42 -injected rat brain, CXCR2 and IL-8 showed time-dependent increases in expression, concomitant with enhanced gliosis, relative to controls phosphate-buffered saline (PBS) or reverse peptide Aβ _42–1injection. Administration of the competitive CXCR2 antagonist SB332235 to peptide-injected rats significantly reduced expression of CXCR2 and microgliosis, with astrogliosis unchanged. Double staining studies demonstrated localization of CXCR2 and microglial immunoreactivity nearby deposits of Aβ _1–42with SB332235 effective in inhibiting receptor expression and microgliosis. The numbers of neurons in granule cell layer (GCL) were reduced in rats receiving Aβ _1–42 , compared with PBS, with administration of SB332235 to peptide-injected animals conferring neuroprotection. Oxidative stress was indicated in the animal model since both 4-hydroxynonenal (4-HNE) and hydroethidine (HEt) were markedly elevated in Aβ _1–42vs PBS-injected rat brain and diminished with SB332235 treatment.

Conclusion

Overall, the findings suggest critical roles for CXCR2-dependent inflammatory responses in an AD animal model with pharmacological modulation of the receptor effective in inhibiting inflammatory reactivity and conferring neuroprotection against oxidative damage.

【 授权许可】

   
2015 Ryu et al.

【 图 表 】

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