Combined Treatment with Insulin-Like Growth Factor 1 and AMD3100 Improves Motor Outcome in a Murine Model of Neonatal Hypoxic-Ischemic Encephalopathy

Abstract

Stem cell transplantation is a promising intervention for neonatal hypoxic-ischemic encephalopathy (HIE); however, universal feasibility and safety have not been thoroughly evaluated. AMD3100 and insulin-like growth factor 1 (IGF1) mobilize progenitor cells into peripheral circulation. The objective of this study was to assess the short-term efficacy of inducing endogenous stem cell mobilization after injury in a model of neonatal HIE. Postnatal day 9 CD1 pups received sham surgery or unilateral carotid artery ligation and 30 min of hypoxia followed by saline, AMD3100, IGF1, or both agents. Intraperitoneal injections of 5-ethynyl-2′-deoxy­uridine (EdU) and 5-bromo-2′-deoxyuridine were used to ­label replicating progenitor cells. At P14, animals underwent rotarod testing, and the brains were sectioned for area measurements and immunofluorescence staining. Comparisons were made using one-way analysis of variance. Spearman’s rho was calculated to assess correlation between rotarod results and markers of brain injury. Pups treated with both agents had improved rotarod performance (p = 0.02) and increased EdU+ progenitor cells in the subgranular zone (SGZ) compared to injured controls (p = 0.10). An increase in active cells within the SGZ was correlated with improved rotarod performance (r = 0.84, p = 0.04). There were no differences in overall injury score or in brain area or number of activated cells in the subventricular zone between the treatment groups. Combined treatment with AMD3100 and IGF1 shows promise for decreasing brain injury and improving motor function in pups after HIE which correlated with changes in the number of active progenitor cells in the SGZ.

Biomarkers of hypoxic–ischemic encephalopathy: a systematic review

“…2 b, c). Although a single research group [ 42 ] studied the identified proteins, this is a promising target, since Insulin-like growth factor 1 (IGF-1) has already been tested as a therapeutic approach, exhibiting good outcomes in a rat HIE model [ 55 ].…”

Subacute AMD3100 Treatment Is Not Efficient in Neonatal Hypoxic-Ischemic Rats

“…Moreover, therapeutic impact on motor function was only seen when applying a combination treatment with insulin-like growth factor 1. 54 Another strategy deserving further investigation is the pharmacological combination of AMD3100 with cobalt chloride or β3 adrenergic agonists in order to increase the mobilization of mesenchymal stromal cells from BM, 55,56 a cell population with a promising protective role in HIE. 1 Thus, it may be assumed that the subacute treatment with AMD3100 alone, despite clear evidence for therapeutic benefits in other forms of adult hypoxic-ischemic brain injury, may not be ideally suited for the treatment of HIE for so far unknown reasons.…”

Monocytes in neonatal stroke and hypoxic‐ischemic encephalopathy: Pathophysiological mechanisms and therapeutic possibilities

“…The administration of AMD3100, a CXCR4 antagonist, in the subacute phase of HIE has been investigated as a possible treatment for HIE, given its ability to mobilize hematopoietic stem cells/progenitors from the bone marrow. However, this therapy provided no benefits in hypoxic‐ischemic rats and mice, and it was not shown whether AMD3100 had any impact on monocyte infiltration 99,100 …”

“…However, this therapy provided no benefits in hypoxic-ischemic rats and mice, and it was not shown whether AMD3100 had any impact on monocyte infiltration. 99,100 CD36, a type B scavenger receptor expressed in microglia/macrophages, monocytes, and other cell types, has been shown to regulate the recruitment of myelomonocytic into the CNS after NAIS. CD36 KO mice exhibited fewer classical monocytes, nonclassical monocytes, and neutrophils in the ipsilateral choroid plexus early after reperfusion, in comparison with wildtype mice.…”