Intranasal delivery of transforming growth factor-beta 1 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-beta 1 (TGF-beta 1) 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-beta 1 shows significant improvement in neurological function and reduction of infarct volume compared with control animals. TGF-beta 1 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-beta 1 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-beta 1, while only a few BrdU labeled cells co-stained with glial fibrillary acidic protein (GFAP). Conclusion: Intranasal administration of TGF-beta 1 reduces infarct volume, improves functional recovery and enhances neurogenesis in mice after stroke. Intranasal TGF-beta 1 may have therapeutic potential for cerebrovascular disorders.