Reduction of infarct volume and apoptosis by grafting of encapsulated basic fibroblast growth factor—secreting cells in a model of middle cerebral artery occlusion in rats

Fujiwara, Kosuke; Date, Isao; Shingo, Tetsuro; Yoshida, Hideyuki; Kobayashi, Kazuki; Takeuchi, Akihiro; Yano, Akimasa; Tamiya, Takashi; Ohmoto, Takashi

doi:10.3171/jns.2003.99.6.1053

Cited by 28 publications

(24 citation statements)

References 47 publications

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Section: Discussionmentioning

confidence: 99%

“…bFGF is one of the most potent neurotrophic factors for the protection of neurons [1, 2, 27, 29, 38]. We previously demonstrated that grafting of encapsulated bFGF-secreting cells protected against ischemic injury after MCAO in rats by directly exerting cytoprotection through suppression of apoptosis in tandem with enhanced angiogenesis at the border of ischemic infarct [38]. Functional recovery after intravenous MSC transplantation in ischemic stroke rats also details the secretion of bFGF from MSCs, which reduces apoptosis and promotes proliferation of endogenous stem and progenitor cells within the peri-infarcted tissue [27, 29].…”

Section: Discussionmentioning

confidence: 99%

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Intra-Arterial Transplantation of Allogeneic Mesenchymal Stem Cells Mounts Neuroprotective Effects in a Transient Ischemic Stroke Model in Rats: Analyses of Therapeutic Time Window and Its Mechanisms

et al. 2015

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ObjectiveIntra-arterial stem cell transplantation exerts neuroprotective effects for ischemic stroke. However, the optimal therapeutic time window and mechanisms have not been completely understood. In this study, we investigated the relationship between the timing of intra-arterial transplantation of allogeneic mesenchymal stem cells (MSCs) in ischemic stroke model in rats and its efficacy in acute phase.MethodsAdult male Wistar rats weighing 200 to 250g received right middle cerebral artery occlusion (MCAO) for 90 minutes. MSCs (1×106cells/ 1ml PBS) were intra-arterially injected at either 1, 6, 24, or 48 hours (1, 6, 24, 48h group) after MCAO. PBS (1ml) was intra-arterially injected to control rats at 1 hour after MCAO. Behavioral test was performed immediately after reperfusion, and at 3, 7 days after MCAO using the Modified Neurological Severity Score (mNSS). Rats were euthanized at 7 days after MCAO for evaluation of infarct volumes and the migration of MSCs. In order to explore potential mechanisms of action, the upregulation of neurotrophic factor and chemotactic cytokine (bFGF, SDF-1α) induced by cell transplantation was examined in another cohort of rats that received intra-arterial transplantation at 24 hours after recanalization then euthanized at 7 days after MCAO for protein assays.ResultsBehavioral test at 3 and 7 days after transplantation revealed that stroke rats in 24h group displayed the most robust significant improvements in mNSS compared to stroke rats in all other groups (p’s<0.05). Similarly, the infarct volumes of stroke rats in 24h group were much significantly decreased compared to those in all other groups (p’s<0.05). These observed behavioral and histological effects were accompanied by MSC survival and migration, with the highest number of integrated MSCs detected in the 24h group. Moreover, bFGF and SDF-1α levels of the infarcted cortex were highly elevated in the 24h group compared to control group (p’s<0.05).ConclusionsThese results suggest that intra-arterial allogeneic transplantation of MSCs provides post-stroke functional recovery and reduction of infarct volumes in ischemic stroke model of rats. The upregulation of bFGF and SDF-1α likely played a key mechanistic role in enabling MSC to afford functional effects in stroke. MSC transplantation at 24 hours after recanalization appears to be the optimal timing for ischemic stroke model, which should guide the design of clinical trials of cell transplantation for stroke patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intra-Arterial Transplantation of Allogeneic Mesenchymal Stem Cells Mounts Neuroprotective Effects in a Transient Ischemic Stroke Model in Rats: Analyses of Therapeutic Time Window and Its Mechanisms

et al. 2015

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“…In mice with a null mutation of bFGF gene, both infarct volume and mortality rates were markedly increased after cerebral ischemia, indicating that endogenous bFGF contributes to protection against ischemic brain damage [12]. Exogenous bFGF administered before cerebral ischemia or several hours after ischemia was shown to reduce the infarction size and improve neurologic function [11,37]. However, little research has been carried out to determine the effect of anesthetics on neurotrophic factor expression.…”

Section: Discussionmentioning

confidence: 99%

Propofol Increases Expression of Basic Fibroblast Growth Factor After Transient Cerebral Ischemia in Rats

et al. 2012

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Anesthetics such as propofol can provide neuroprotective effects against cerebral ischemia. However, the underlying mechanism of this beneficial effect is not clear. Therefore, we subjected male Sprague-Dawley rats to 2 h of middle cerebral artery occlusion and investigated how post-ischemic administration of propofol affected neurologic outcome and the expression of basic fibroblast growth factor (bFGF). After 2 h of ischemia, just before reperfusion, the animals were randomly assigned to receive either propofol (20 mg•kg−1•h−1) or vehicle (10% intralipid, 2 ml•kg−1•h−1) intravenously for 4 h. Neurologic scores, infarct volume, and brain water content were measured at different time points after reperfusion. mRNA level of bFGF was measured by real-time PCR, and the protein expression level of bFGF was analyzed by immunohistochemistry and Western blot. At 6 h, 24 h, 72 h, and 7 days of reperfusion, infarct volume was significantly reduced in the propofol-treated group compared to that in the vehicle-treated group (all P<0.05). Propofol post-treatment also attenuated brain water content at 24 and 72 h and reduced neurologic deficit score at 72 h and 7 days of reperfusion (all P<0.05). Additionally, in the peri-infarct area, bFGF mRNA and protein expression were elevated at 6, 24, and 72 h of reperfusion compared to that in the vehicle-treated group (all P<0.05). These results show that post-ischemic administration of propofol provides neural protection from cerebral ischemia-reperfusion injury. This protection may be related to an early increase in the expression of bFGF.

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“…NGF and BDNF also stimulate phospholipase C (PLC)-protein kinse C (PKC) pathways, which activate survival pathways involving NF-κB and anti-apoptotic members of the Bcl-2 family [46][47][48]. Basic fibroblast growth factor (FGF-2) and VEGF acti- vate the MAP kinase pathway (ERK1/2) through PLC or ras, stimulating production of anti-apoptotic proteins, Bcl-2, cyclic AMP binding protein (CREB) and NF-κB [49,50] (Fig. 6).…”

Section: Neuroprotective Mechanismsmentioning

confidence: 99%

Gene activation and protein expression following ischaemic stroke: strategies towards neuroprotection

et al. 2005

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Current understanding of the patho-physiological events that follow acute ischaemic stroke suggests that treatment regimens could be improved by manipulation of gene transcription and protein activation, especially in the penumbra region adjacent to the infarct. An immediate reduction in excitotoxicity in response to hypoxia, as well as the subsequent inflammatory response, and beneficial control of reperfusion via collateral revascularization near the ischaemic border, together with greater control over apoptotic cell death, could improve neuronal survival and ultimately patient recovery. Highly significant differences in gene activation between animal models for stroke by middle cerebral artery occlusion, and stroke in patients, may explain why current treatment strategies based on animal models of stroke often fail. We have highlighted the complexities of cellular regulation and demonstrated a requirement for detailed studies examining cell specific protective mechanisms after stroke in humans.

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Reduction of infarct volume and apoptosis by grafting of encapsulated basic fibroblast growth factor—secreting cells in a model of middle cerebral artery occlusion in rats

Abstract: The grafting of encapsulated BHK bFGF-secreting cells protected the brain from ischemic injury. Encapsulation and grafting of genetically engineered cells such as bFGF-secreting cells is thus thought to be a useful method for protection against cerebral ischemia.

Cited by 28 publications

References 47 publications

Intra-Arterial Transplantation of Allogeneic Mesenchymal Stem Cells Mounts Neuroprotective Effects in a Transient Ischemic Stroke Model in Rats: Analyses of Therapeutic Time Window and Its Mechanisms

Intra-Arterial Transplantation of Allogeneic Mesenchymal Stem Cells Mounts Neuroprotective Effects in a Transient Ischemic Stroke Model in Rats: Analyses of Therapeutic Time Window and Its Mechanisms

Propofol Increases Expression of Basic Fibroblast Growth Factor After Transient Cerebral Ischemia in Rats

Gene activation and protein expression following ischaemic stroke: strategies towards neuroprotection

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