Noggin improves ischemic brain tissue repair and promotes alternative activation of microglia in mice.
We previously reported that bone morphogenetic proteins (BMPs) and their endogenous antagonist noggin are expressed in the brain weeks after an ischemic insult. Here, to define their roles in ischemic brain tissue repair and remodeling, we infused recombinant BMP7 or noggin into the ipsilateral ventricle of mice for 2weeks starting 2weeks after transient middle cerebral artery occlusion (MCAO). Four weeks after MCAO, we measured ischemic brain volume, functional recovery, and molecules related to neurogenesis and angiogenesis such as synaptophysin, GAP-43, and VEGF. Noggin-treated mice but not BMP7-treated mice showed preserved ipsilateral brain volume and reduced neurological deficits compared with artificial cerebrospinal fluids (aCSF)-treated mice. Noggin treatment also decreased glial scar thickness, increased levels of GAP-43 and VEGF protein, and increased the number of Iba1-positive activated microglia in the ipsilateral brain. Furthermore, noggin treatment decreased M1 markers (IL-1β, TNF-α, IL-12, CCL2 and CD86) and increased M2 markers (IL-1ra, IL-10, arginase 1, CD206 and Ym1) of activated microglia, suggesting a shift from M1 to M2 phenotypes. These results suggest that noggin improves functional recovery from ischemic stroke and enhances alternatively activated microglia, thereby promoting tissue repair and remodeling.
Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Jin A
JA
Shin
Department of Radiology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Soo Mee
SM
Lim
Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Sae Im
SI
Jeong
Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Jihee Lee
JL
Kang
Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea. Electronic address: empark@ewha.ac.kr.
Eun-Mi
EM
Park
D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology; D002352:Carrier Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D000099176:Noggin Protein
D055419:Bone Morphogenetic Protein 7; D002352:Carrier Proteins; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D000099176:Noggin Protein; C525820:bmp7 protein, mouse
BMPs; Brain atrophy; Functional recovery; Glial scar; Ischemic stroke; M2 phenotype; Microglia; Neurorestorative therapy; Noggin; Repair process