Ultrasound-induced release of GDNF from lipid coated microbubbles injected into striatum reduces hypoxic–ischemic injury in neonatal rats

Previous studies showed that inflammation and apoptosis were involved in the pathogenesis of hypoxic–ischemic brain injury. The immature brain is particularly vulnerable to damage. Intracerebral injection of glial cell line-derived neurotrophic factor (GDNF) has been shown to reduce the injury induced by hypoxia–ischemia (HI). In this study, the neuroprotective effect of intracerebral ultrasound-induced dissolution of lipid-coated GDNF microbubbles was investigated in a neonatal rat model of hypoxic–ischemic brain injury. Hypoxic–ischemic injury was induced in 7-day-old rats in the present study. The rats with hypoxia–ischemia received intracerebral injections of GDNF-containing microbubbles (0.5 mg/kg). They then received low frequency ultrasound stimulation (20 kHz, 2 h intervals for a total of 24 h and each time lasted for 1 min) to induce release of GDNF into the right striatum. We found that low frequency ultrasound stimulation can induce lipid-coated GDNF microbubbles to release GDNF. Ultrasound-induced dissolution of lipid-coated GDNF microbubbles treatment reduced infarction volume and improved neurological outcomes in neonatal rats. In the meanwhile, the microbubbles attenuated the production of inducible nitric oxide synthase, nitric oxide and tumor necrosis factor-alpha, as well as the activation of caspase-3 in insulted side of brain in neonatal rats. These data demonstrated that ultrasound-induced dissolution of lipid-coated GDNF microbubbles treatment can provide a neuroprotective effect against hypoxia–ischemia in neonatal rats.

► We prepared ultrasound-induced dissolution of lipid-coated GDNF microbubbles.
► The microbubbles were injected into the rat brains with hypoxic–ischemic injury.
► Microbubbles reduced infarct volume and improved neurological outcomes.
► Microbubbles reduced nitric oxide production and the activation of caspase-3.
► Microbubbles treatment reduced iNOS levels and TNF-α expression.