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

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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.

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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.

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Authors and Affiliations

  1. Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No.30, Gaotanyan Street, Chongqing, 400038, People’s Republic of China

    Jun Tang, Qianwei Chen, Jing Guo, Liming Yang, Yihao Tao, Lin Li, Hongping Miao, Hua Feng, Zhi Chen & Gang Zhu

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  1. Jun Tang
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  2. Qianwei Chen
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Correspondence to Zhi Chen or Gang Zhu.

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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)

High resolution image (TIFF 8446 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)

High resolution image (TIFF 12282 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)

High resolution image (TIFF 17342 kb)

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Tang, J., Chen, Q., Guo, J. et al. Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2. Mol Neurobiol 53, 1935–1948 (2016). https://doi.org/10.1007/s12035-015-9154-x

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