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Molecular Neurobiology

, Volume 53, Issue 3, pp 1935–1948 | Cite as

Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2

  • Jun Tang
  • Qianwei Chen
  • Jing Guo
  • Liming Yang
  • Yihao Tao
  • Lin Li
  • Hongping Miao
  • Hua Feng
  • Zhi ChenEmail author
  • Gang ZhuEmail author
Article

Abstract

Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes.

Keywords

Neuroinflammation Microglia Germinal matrix hemorrhage Minocycline Cannabinoid receptor 2 

Notes

Acknowledgments

The National Science Foundation of China (NSFC, number81271281) and National “973” Project of China (2014 CB541605) supported this work. We gratefully thank Professor John H Zhang from Loma Linda University for his generous assistance regarding the model induction, and we gratefully thank Professor Guohua Xi from the University of Michigan and Liu Xin for their constructive suggestions regarding the experimental processes.

Conflict of Interest

The authors declare no competing interests.

Supplementary material

12035_2015_9154_Fig9_ESM.gif (27 kb)
Fig. S1

Effects of JWH133 and minocycline on brain edema after GMH JWH133 administration 24 h after GMH induction shared the identical effect of minocycline, which induced less brain edema compared with the GMH-induced pups that received the vehicle treatment (n = 12). The data are means ± S.D., * P < 0.05, N.S.: no significant differences were detected. (GIF 27 kb)

12035_2015_9154_MOESM1_ESM.tif (8.2 mb)
High resolution image (TIFF 8446 kb)
12035_2015_9154_Fig10_ESM.gif (98 kb)
Fig. S2

Effects of JWH133 and minocycline on lateral ventricular volume after GMH 28d following GMH, 7.0 T MRI showed the coronal section of pup’s brain after JWH133 or minocycline or the vehicle administration (A). Analysis of the lateral ventricular volume with Image J demonstrated that JWH133 and minocycline share the identical effect on decreasing the volume following GMH (B, n = 6). The data are means ± S.D., * P < 0.05 N.S.: no significant differences were detected. (GIF 98 kb)

12035_2015_9154_MOESM2_ESM.tif (12 mb)
High resolution image (TIFF 12282 kb)
12035_2015_9154_Fig11_ESM.gif (250 kb)
Fig. S3

Effects of JWH133 on P-ERK protein expression after GMH Sections were stained against Iba-1 (red) and phosphorylated p-ERK (green) antibody as described in the Material and Methods. Sham controls (A), GMH + vehi. (B), GMH+ JWH133 (C), white arrows refer to p-ERK+/Iba-1+ microglia; Vehi. = vehicle; Scale bar = 50 μm. P-ERK positive microglia were counted up in every field (D, n = 6/ each group). Western blotting was used for analysis of p-ERK protein level (E, n = 6) and quantification of relative density of bands was determined by Image J. *p < 0.05, **p < 0.01. (GIF 250 kb)

12035_2015_9154_MOESM3_ESM.tif (16.9 mb)
High resolution image (TIFF 17342 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jun Tang
    • 1
  • Qianwei Chen
    • 1
  • Jing Guo
    • 1
  • Liming Yang
    • 1
  • Yihao Tao
    • 1
  • Lin Li
    • 1
  • Hongping Miao
    • 1
  • Hua Feng
    • 1
  • Zhi Chen
    • 1
    Email author
  • Gang Zhu
    • 1
    Email author
  1. 1.Department of Neurosurgery, Southwest HospitalThird Military Medical UniversityChongqingPeople’s Republic of China

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