Intranasal administration of aTf protects and repairs the neonatal white matter after a cerebral hypoxic–ischemic event

Abstract

Our previous studies showed that the intracerebral injection of apotransferrin (aTf) attenuates white matter damage and accelerates the remyelination process in a neonatal rat model of cerebral hypoxia‐ischemia (HI) injury. However, the intracerebral injection of aTf might not be practical for clinical treatments. Therefore, the development of less invasive techniques capable of delivering aTf to the central nervous system would clearly aid in its effective clinical use. In this work, we have determined whether intranasal (iN) administration of human aTf provides neuroprotection to the neonatal mouse brain following a cerebral hypoxic–ischemic event. Apotransferrin was infused into the naris of neonatal mice and the HI insult was induced by right common carotid artery ligation followed by exposure to low oxygen concentration. Our results showed that aTf was successfully delivered into the neonatal HI brain and detected in the olfactory bulb, forebrain and posterior brain 30 min after inhalation. This treatment successfully reduced white matter damage, neuronal loss and astrogliosis in different brain regions and enhanced the proliferation and survival of oligodendroglial progenitor cells (OPCs) in the subventricular zone and corpus callosum (CC). Additionally, using an in vitro hypoxic model, we demonstrated that aTf prevents oligodendrocyte progenitor cell death by promoting their differentiation. In summary, these data suggest that iN administration of aTf has the potential to be used for clinical treatment to protect myelin and to induce remyelination in demyelinating hypoxic–ischemic events in the neonatal brain. © 2012 Wiley Periodicals, Inc.

Neurodevelopmental Abnormalities and Congenital Heart Disease

“…Repeated intranasal delivery of heparin-binding EGF immediately after hypoxic exposure led to reduced OL death, enhanced OL genesis, and improved behavioral recovery in mice 160 . Intranasal administration of human aTf prior to hypoxia-ischemia resulted in less WM injury and an increase in OPC survival and proliferation within the corpus callosum and subventricular zone in mice 161 . Together, these studies provide insights into the dynamic cellular and molecular mechanisms involved in WM injury and recovery imposed by chronic hypoxic exposure and hypoxia-ischemia and offer therapeutic avenues which should be explored in models of CHD-induced WM injury.…”

Glial Development: The Crossroads of Regeneration and Repair in the CNS

“…Iron deficiency causes hypomyelination and neurological abnormalities, which can be reversed by intracranial injection of apotransferrin (aTf) at early developmental stages (Badaracco et al, 2008). The use of aTf to restore physiological levels of iron transport has been explored in neonatal WMI after HI, as HI increases iron release in WM regions (Guardia Clausi et al, 2012). Intranasal administration of aTf immediately after HI promoted neuroprotection of the neonatal mouse brain by reducing WM damage, astrogliosis, and OL death.…”

Controversies in preterm brain injury

“…Intranasal delivery of drugs and growth factors has been used for different types of brain disorders and neurological conditions (Dhuria, Hanson et al 2010). A few studies have reported successful interventions in animal models of premature brain injury based on intranasal delivery of factors (Guardia Clausi, Paez et al 2012, Scafidi, Hammond et al 2014). As mentioned above, intranasal delivery of heparin binding-EGF was recently reported to ameliorate rodent preterm WMI (Scafidi, Hammond et al 2014).…”