Hyaluronate Nanoparticles as a Delivery System to Carry Neuroglobin to the Brain after Stroke

Abstract

Therapies against stroke can restore the blood supply but cannot prevent the ischemic damage nor stimulate the recovery of the infarcted zone. The neuroglobin protein plays an important role in the neuro-regeneration process after stroke; however, the method for its effective systemic application has not been identified yet, as neuroglobin is unable to pass through the blood-brain barrier. Previously, we developed different types of sodium hyaluronate nanoparticles, which successfully cross the blood-brain barrier after stroke. In this work, these nanoparticles have been used to carry neuroglobin through the bloodstream to the nerve cells in rats submitted to stroke. We have biosynthesized rat-recombinant neuroglobin and determined the formulation of sodium hyaluronate nanoparticles loaded with neuroglobin, as well as its size and ζ-potential, encapsulation efficiently, in vitro release, and its kinetic of liberation. The results show that the formulation achieved is highly compatible with pharmaceutical use and may act as a delivery system to transport neuroglobin within the blood. We have found that this formulation injected intravenously immediately after stroke reached the damaged cerebral parenchyma at early stages (2 h). Neuroglobin colocalizes with its nanocarriers inside the nerve cells and remains after 24 h of reperfusion. In conclusion, the systemic administration of neuroglobin linked to nanoparticles is a potential neuroprotective drug-delivery strategy after stroke episodes.

Dynamic tracing using ultra-bright labelling and multi-photon microscopy identifies endothelial uptake of poloxamer 188 coated poly(lactic-co-glycolic acid) nano-carriersin vivo

“…A major challenge of the specific detection of NPs in the fixed brain is the strong auto-fluorescence of cerebral tissue after PFA exposure deriving, among others, from, mitochondria, collagen, or lipofuscin [37]. Currently used autofluorescent quenching kits [38] are able to solve this problem just partially by removing only non-lipofuscin sources. Cerebral autofluorescence, however, is highly abundant in lipofuscin and is often particularly strong in structures of the same size and brightness as NPs.…”

“…A major challenge of the specific detection of NPs in the fixed brain is the strong auto-fluorescence of cerebral tissue after PFA exposure deriving, among others, from, mitochondria, collagen, or lipofuscin [38]. Currently autofluorescence quenching kits are reducing predominantly non-lipofuscin autofluorescence [39], however, cerebral autofluorescence is highly abundant of lipofuscin and is often particularly strong in structures of the same size and brightness as NPs. Therefore, broad emission spectrum cerebral auto-fluorescence often generates signals which very closely mimic NPs and may also generate false positive results.…”

Role of Neuroglobin in the Neuroprotective Actions of Estradiol and Estrogenic Compounds

“…Although promising, most studies using neuroglobin delivery approaches have been performed on brain ischemia in vivo and in vitro models, demonstrating the urgent need to implement these approaches for other brain diseases. More recently, the use of sodium hyaluronate to facilitate the delivery of neuroglobin following MCAO and 24 h reperfusion has been explored [72]. Although this nanocarrier successfully delivered neuroglobin to the brain, the potential biological implication of the rise of its cytosolic levels was not fully explored.…”

Marine Biocompounds for Neuroprotection—A Review

“…Moreover, this type of hydrogel has been modified with an anti-inflammatory peptide and a brain-derived neurotrophic factor, which significantly enhanced the proliferation of PC12 cells and the recovery in both neurological function and nerve tissue morphology in rat models by regulating inflammatory cytokine levels and improving axonal regeneration [128]. Additionally, HA has also proved its efficiency in stroke management, as neuroglobin-loaded sodium hyaluronate nanoparticles have been intravenously introduced in rat models and reached damaged cerebral parenchyma at early stages [129].…”