Gene-stem cell therapy for ischemic stroke

Besides blood flow restoration, neuroprotection is essential for treating strokes at an acute stage. Both neurotrophic factors (NTFs) and free radical scavengers can act as neuroprotective agents with abilities to inhibit cell death and facilitate cell survival under cerebral ischemia. For example, topical application of glial cell line-derived neurotrophic factor (GDNF) remarkably reduced infarct size and brain edema after middle cerebral artery (MCA) occlusion in rats. Reduction in the infarct size was not found to be related to a change in the cerebral blood flow (CBF), but was accompanied by marked reduction in BrdU-positive cells in the affected area after TdT-mediated dUTP-biotin nick end labeling (TUNEL) for caspses. Thus, GDNF elicited a direct protective effect against ischemic brain damage, but without improving CBF. Sendai virus vectors harboring the GDNF gene led to a remarkable reduction in infract volume without affecting regional CBF but reduced the translocation of apoptosis inducible factor (AIF) from the mitochondria to cytoplasm. Regenerative therapy involving neural stem cells which are intrinsically activated or exogenously transplanted, is an important treatment strategy. To facilitate stem cell migration, an artificial scaffold can be implanted into the injured brain for promoting ischemic brain repair. Addition of NTFs greatly enhanced an intrinsic migration or invasion of stem cells into the scaffold: this strategy could be used in the future for enhancing regenerative potential of brain cells after chronic ischemia-induced brain damage.