Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone.
BACKGROUND
The effect of neurotrophic factors in enhancing stroke-induced neurogenesis in the adult subventricular zone (SVZ) is limited by their poor blood-brain barrier (BBB) permeability.Intranasal administration is a noninvasive and valid method for delivery of neuropeptides into the brain, to bypass the BBB. We investigated the effect of treatment with intranasal transforming growth factor-beta1 (TGF-beta1) on neurogenesis in the adult mouse SVZ following focal ischemia. The modified Neurological Severity Scores (NSS) test was used to evaluate neurological function, and infarct volumes were determined from hematoxylin-stained sections. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) labeling was performed at 7 days after middle cerebral artery occlusion (MCAO). Immunohistochemistry was used to detect bromodeoxyuridine (BrdU) and neuron- or glia-specific markers for identifying neurogenesis in the SVZ at 7, 14, 21, 28 days after MCAO.


RESULTS
Intranasal treatment of TGF-beta1 shows significant improvement in neurological function and reduction of infarct volume compared with control animals. TGF-beta1 treated mice had significantly less TUNEL-positive cells in the ipsilateral striatum than that in control groups. The number of BrdU-incorporated cells in the SVZ and striatum was significantly increased in the TGF-beta1 treated group compared with control animals at each time point. In addition, numbers of BrdU- labeled cells coexpressed with the migrating neuroblast marker doublecortin (DCX) and the mature neuronal marker neuronal nuclei (NeuN) were significantly increased after intranasal delivery of TGF-beta1, while only a few BrdU labeled cells co-stained with glial fibrillary acidic protein (GFAP).


CONCLUSIONS
Intranasal administration of TGF-beta1 reduces infarct volume, improves functional recovery and enhances neurogenesis in mice after stroke. Intranasal TGF-beta1 may have therapeutic potential for cerebrovascular disorders.
Ma
Minmin
M
Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, 305# East Zhongshan Road, Nanjing 21002, Jiangsu Province, PR China. mmmxkx@gmail.com
Ma
Yuping
Y
Yi
Xueming
X
Guo
Ruibing
R
Zhu
Wusheng
W
Fan
Xinying
X
Xu
Gelin
G
Frey
William H
WH
Liu
Xinfeng
X
D000281:Administration, Intranasal; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier; D002561:Cerebrovascular Disorders / Q000188:drug therapy; D003342:Corpus Striatum / Q000503:physiopathology; D000089662:Doublecortin Protein; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D020547:Lateral Ventricles / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects; D020127:Recovery of Function; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage* / Q000494:pharmacology*
C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D053773:Transforming Growth Factor beta1