Intracerebral Delivery of rhFGF20 via Heparin-Poloxamer Hydrogel Promotes Neurological Recovery in Ischemic Stroke

BACKGROUND: Ischemic stroke poses a significant threat to human health. FGF (fibroblast growth factor) 20 is involved in the repair of central nervous system diseases, but it has the shortcomings of short half-life and inability to penetrate the blood-brain barrier. Therefore, to overcome the drawbacks of rhFGF20 (recombinant human FGF20) and explore its role in ischemic stroke, the effects of intracerebral administration of rhFGF20 by heparin-poloxamer hydrogel (HP-rhFGF20 [heparin-poloxamer hydrogel-encapsulated rhFGF20]) in a rat stroke model were the focus of this study. METHODS: A rat model of middle cerebral artery occlusion/reperfusion and oxygen-glucose deprivation-reoxygenation models were established to mimic ischemic stroke in vivo and in vitro, respectively. Endogenous FGF20 levels were measured in patients, ischemic rats, and oxygen-glucose deprivation-reoxygenation-injured neurons. To assess the therapeutic potential, rhFGF20 was administered intracerebrally via heparin-poloxamer hydrogel implants (1 mg/mL, 20 μL) on day 5 poststroke. 2,3,5-Triphenyltetrazolium chloride staining, neurobehavioral tests (including the mNSS test [modified Neuro-Severity Score], the corner test, the rotarod test, the cylinder test, and the Morris water maze test), and Nissl staining were performed to evaluate neurological recovery. Immunofluorescence and Western blotting were conducted to assess the brain repair processes (neurogenesis, neuronal remodeling, and angiogenesis). RESULTS: High expression of FGF20 was detected in the serum of patients with ischemic stroke, the cortex of ischemic rats, and oxygen-glucose deprivation-reoxygenation-injured neurons. Heparin-poloxamer increased the stability and bioavailability of rhFGF20. HP-rhFGF20 attenuated neurobehavioral deficits and infarct volume in ischemic stroke rats. HP-rhFGF20 inhibited neuronal cell death, microglial activation, and glial scar formation on day 7 post-implantation. Moreover, HP-rhFGF20 promoted the proliferation, migration, and differentiation of neural stem cells and improved neuronal plasticity and angiogenesis in ischemic stroke rats. CONCLUSIONS: HP-rhFGF20 promoted functional recovery in ischemic stroke rats by enhancing neurogenesis and angiogenesis. The combination of growth factors and biomaterials provides a promising therapeutic strategy for central nervous system diseases. REGISTRATION: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR2100051104.