Novel Therapeutic Strategy to Treat Brain Ischemia

Abstract

Background-Although cerebral occlusive disease leads to cerebral ischemic events, an effective treatment has not yet been established. An ideal therapeutic approach to treat ischemia might have both aspects of enhancement of collateral formation and prevention of neuronal death. Hepatocyte growth factor (HGF) is a potent angiogenic factor that also acts as a neurotrophic factor. Thus, in this study, we examined the therapeutic effects of HGF on brain injury in a rat permanent middle cerebral artery occlusion model. Methods and Results-Gene transfer into the brain was performed by injection of human HGF gene with hemagglutinating virus of Japan-envelope vector into the cerebrospinal fluid via the cisterna magna. Overexpression of the HGF gene resulted in a significant decrease in the infarcted brain area as assessed by triphenyltetrazolium chloride staining, whereas rats transfected with control vector exhibited a wide area of brain death after 24 hours of ischemia. Consistently, the decrease in neurological deficit was significantly attenuated in rats transfected with the HGF gene at 24 hours after the ischemic event. Stimulation of angiogenesis was also detected in rats transfected with the HGF gene compared with controls. Of importance, no cerebral edema or destruction of the blood-brain barrier was observed in rats transfected with the HGF gene. Conclusions-Overall, the present study demonstrated that overexpression of the HGF gene attenuated brain ischemic injury in a rat model, without cerebral edema, through angiogenic and neuroprotective actions. In particular, the reduction of brain injury by HGF may provide a new therapeutic option to treat cerebrovascular disease.

Novel Therapeutic Strategy for Stroke in Rats by Bone Marrow Stromal Cells and ex vivo HGF Gene Transfer with HSV-1 Vector

“…Both of them showed significant improvement of neurological deficits compared with MSC-only cell therapy. We got the same result as that Shimamura et al (2004) had reported, that HGF had the therapeutic efficiency of reducing the infarction volume after transient MCAO. We also found on day 14 that the MSC-only treated group could significantly reduce the infarction volume under the superacute treatment compared with the PBS-treated group, but not under the acute treatment.…”

“…So far, to reduce the disability resulting from stroke, some studies have focused on the development of neuroprotective agents such as brainderived neurotrophic factor, the fibroblast growth factor that effectively prevents delayed neuronal death after transient brain ischemia (Kurozumi et al, 2004;Watanabe et al, 2004). Recently, overexpression of HGF that can improve the neurological sequalae by neuroprotection, reduce the infarct volume, and the likelihood of brain edema after stroke was reported (Miyazawa et al, 1998;Tsuzuki et al, 2000;Hayashi et al, 2001;Shimamura et al, 2004). It suggested that HGF should be one of the most potent growth factors for treating brain ischemia.…”

“…Subsequently, several functions have been ascribed to HGF, including antiapoptosis, angiogenesis, motogenesis, morphogenesis, hematopoiesis, tissue regeneration in a variety of organs, and the enhancement of neurite outgrowth (Matsumoto and Nakamura, 1997;Hayashi et al, 2001;Sun et al, 2002a, b;Jin et al, 2003). It has also been reported that HGF administration could inhibit the BBB destruction, decrease brain edema, and provide a neuroprotective effect after brain ischemia (Miyazawa et al, 1998;Hayashi et al, 2001;Shimamura et al, 2004).…”

Ischemic Cerebral Tissue Response to Subventricular Zone Cell Transplantation Measured by Iterative Self-Organizing Data Analysis Technique Algorithm

“…Restored perfusion in the expanded ischemic border area ( Figure 4F) appeared to be connected with the promotion of collateral flow, which enhances the recovery of blood flow in ischemia-affected tissue ( Figure 6A). The restored perfusion may prevent continuing cell death and promote neural plasticity in a neuroprotective microenvironment, since neurons are highly sensitive to hypoxia-ischemia (Shimamura et al, 2004). Finally, early elimination of edema in the lesion boundary area, which was associated with significant reduction of relaxation times (Figures 5B and 5C in pseudo-normal area), may also contribute to the rescue of tissue from ongoing damage.…”

Postischemic Gene Transfer of Soluble Flt-1 Protects against Brain Ischemia with Marked Attenuation of Blood—Brain Barrier Permeability

“…Briefly, Evans blue dye (Sigma-Aldrich Inc., St Louis, MO, USA, 2% in saline, 3 mL/kg) was injected via the femoral vein under pentobarbital anesthesia (65 mg/kg, intraperitoneally) 1 day after ischemic insult (Shimamura et al, 2004). One hour after the injection, the rats were anesthetized with pentobarbital (overdose, intraperitoneally) and perfused transcardially with physiologic saline.…”