Abstract
BackgroundThe 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-β1 (TGF-β1) 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.ResultsIntranasal treatment of TGF-β1 shows significant improvement in neurological function and reduction of infarct volume compared with control animals. TGF-β1 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-β1 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-β1, while only a few BrdU labeled cells co-stained with glial fibrillary acidic protein (GFAP).ConclusionIntranasal administration of TGF-β1 reduces infarct volume, improves functional recovery and enhances neurogenesis in mice after stroke. Intranasal TGF-β1 may have therapeutic potential for cerebrovascular disorders.
Highlights
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 effects of intranasal transforming growth factor-β1 (TGF-β1) on infarct volume and neurogenesis in the adult mouse SVZ following focal cerebral ischemia
All animals subjected to middle cerebral artery occlusion (MCAO) showed severe behavior deficits 1 day after ischemia, and there was a progressive improvement over time until 28 days after insult
Summary
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. 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. Usually administered by the invasive intracerebral route, have been shown to enhance neurogenesis after stroke [4]. This suggests that they have the ability to modify endogenous neural stem cells and their potential for self-repair after ischemia. Intranasal administration of growth factors provides an effective, non-invasive method for bypassing the BBB to deliver drugs to the brain along the olfactory and trigeminal neural pathways [5,6]. One recent study has demonstrated that intranasal fibroblast growth factor-2 (FGF-2) or heparin-binding epidermal growth factor-like growth factor (HB-EGF) increase neurogenesis in the normal adult mouse brain [7], but the effect of intranasal neurotrophic factors on neurogenesis in animals after stroke has not been investigated
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