Deferoxamine Prevents Neonatal Posthemorrhagic Hydrocephalus Through Choroid Plexus-Mediated Iron Clearance

Ramagiri, Sruthi; Pan, Shelei; DeFreitas, Dakota; Yang, Peter; Raval, Dhvanii K.; Wozniak, David F.; Esakky, Prabagaran; Strahle, Jennifer

doi:10.1007/s12975-022-01092-7

Cited by 8 publications

(6 citation statements)

References 54 publications

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“…Although in a prior study conducted by Zhou et al [39], estimating BR concentration in blood (using an optical resolution PA microscopy system) was used for diagnosing jaundice, to the best of our knowledge, linear array based PAI has been used for the first time to determine the relative concentrations of BR, BV and HB, which can be used for analyzing the hemorrhage progression and age. The PAIbased measurements of BV and BR in tissues and fluids can potentially be used to determine the intracranial hemorrhage "age" in forensic medicine [40], quantitatively evaluate the hemorrhage resorption or detect a rebleeding, and assess responses to novel surgical and non-surgical treatments [41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Bilirubin–biliverdin concentration measurement using photoacoustic spectroscopic analysis for determining hemorrhage age

Manwar

Gelovani

Avanaki

2023

Journal of Biophotonics

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Section: Discussionmentioning

confidence: 99%

Bilirubin–biliverdin concentration measurement using photoacoustic spectroscopic analysis for determining hemorrhage age

Manwar

Gelovani

Avanaki

2023

Journal of Biophotonics

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“…Rodents recovered from anesthesia and were returned to their cage with the dam for 72 h before CSF tracer injection at P7. Rats injected with hemoglobin developed ventriculomegaly by the time of tracer injection at P7 [ 15 – 17 ].…”

Section: Methodsmentioning

confidence: 99%

Postnatal meningeal CSF transport is primarily mediated by the arachnoid and pia maters and is not altered after intraventricular hemorrhage-posthemorrhagic hydrocephalus

Pan,

Koleske,

Koller

et al. 2024

Fluids Barriers CNS

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Background CSF has long been accepted to circulate throughout the subarachnoid space, which lies between the arachnoid and pia maters of the meninges. How the CSF interacts with the cellular components of the developing postnatal meninges including the dura, arachnoid, and pia of both the meninges at the surface of the brain and the intracranial meninges, prior to its eventual efflux from the cranium and spine, is less understood. Here, we characterize small and large CSF solute distribution patterns along the intracranial and surface meninges in neonatal rodents and compare our findings to meningeal CSF solute distribution in a rodent model of intraventricular hemorrhage-posthemorrhagic hydrocephalus. We also examine CSF solute interactions with the tela choroidea and its pial invaginations into the choroid plexuses of the lateral, third, and fourth ventricles. Methods 1.9-nm gold nanoparticles, 15-nm gold nanoparticles, or 3 kDa Red Dextran Tetramethylrhodamine constituted in aCSF were infused into the right lateral ventricle of P7 rats to track CSF circulation. 10 min post-1.9-nm gold nanoparticle and Red Dextran Tetramethylrhodamine injection and 4 h post-15-nm gold nanoparticle injection, animals were sacrificed and brains harvested for histologic analysis to identify CSF tracer localization in the cranial and spine meninges and choroid plexus. Spinal dura and leptomeninges (arachnoid and pia) wholemounts were also evaluated. Results There was significantly less CSF tracer distribution in the dura compared to the arachnoid and pia maters in neonatal rodents. Both small and large CSF tracers were transported intracranially to the arachnoid and pia mater of the perimesencephalic cisterns and tela choroidea, but not the falx cerebri. CSF tracers followed a similar distribution pattern in the spinal meninges. In the choroid plexus, there was large CSF tracer distribution in the apical surface of epithelial cells, and small CSF tracer along the basolateral surface. There were no significant differences in tracer intensity in the intracranial meninges of control vs. intraventricular hemorrhage-posthemorrhagic hydrocephalus (PHH) rodents, indicating preserved meningeal transport in the setting of PHH. Conclusions Differential CSF tracer handling by the meninges suggests that there are distinct roles for CSF handling between the arachnoid-pia and dura maters in the developing brain. Similarly, differences in apical vs. luminal choroid plexus CSF handling may provide insight into particle-size dependent CSF transport at the CSF-choroid plexus border.

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“…Other proposed mechanisms of PHH development implicate the complement cascade (457, 458); aquaporins 1, 4, and 5 upregulation (437,459,460); CSF pathway obstruction by blood breakdown products, blood clots, debris, or fibrosis secondary to inflammation (12, 461-463); and dysfunction of the blood-brain and blood-CSF barriers (464). Altogether, these proposed mechanisms fall under two (466).…”

Section: The Role Of Iron In the Pathogenesis Of Post-hemorrhagic Hyd...mentioning

confidence: 99%

“…In conjunction with previous studies which demonstrated associations between smaller hippocampal size and worse cognitive and motor outcomes in humans (467,468), these results together suggest that iron overload and toxicity after IVH may lead to hippocampal neuronal degeneration, which in turn leads to impaired neuromotor developmental outcomes. Furthermore, to directly relate intraventricular blood breakdown product levels with behavioral outcomes, intraventricular hemoglobin injection in rodents has been directly associated with an impaired acoustic startle response (437), a behavioral impairment which was prevented when rodents were treated with intraventricular deferoxamine at the time of IVH (437). Future studies should investigate the precise mechanisms by which iron and blood breakdown product exposure may lead to hippocampal neuron toxicity (ie.…”

Section: The Role Of Iron In the Pathogenesis Of Post-hemorrhagic Hyd...mentioning

confidence: 99%

“…In line with the hypothesis that iron plays a role in PHH pathogenesis, recent pre-clinical studies have investigated iron chelators as a possible treatment to prevent PHH after adult and neonatal IVH (101,104,(437)(438)(439)(440)475). DFX is an iron chelator that sequesters free iron and has been used in the clinical setting to treat hemochromatosis (476,477), thalassemia (478-480), and other ironoverload syndromes.…”

Section: Therapeutic Directions For Neurological Sequelae After Gmh-i...mentioning

confidence: 99%

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Iron homeostasis and post-hemorrhagic hydrocephalus: a review

Pan,

Hale,

Lemieux

et al. 2024

Front. Neurol.

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Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH.

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Deferoxamine Prevents Neonatal Posthemorrhagic Hydrocephalus Through Choroid Plexus-Mediated Iron Clearance

Cited by 8 publications

References 54 publications

Bilirubin–biliverdin concentration measurement using photoacoustic spectroscopic analysis for determining hemorrhage age

Bilirubin–biliverdin concentration measurement using photoacoustic spectroscopic analysis for determining hemorrhage age

Postnatal meningeal CSF transport is primarily mediated by the arachnoid and pia maters and is not altered after intraventricular hemorrhage-posthemorrhagic hydrocephalus

Iron homeostasis and post-hemorrhagic hydrocephalus: a review

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