p75ECD-Fc reverses neonatal hypoxic-ischemic encephalopathy-induced neurological deficits and inhibits apoptosis associated with Nestin
Date
2024
Authors
Xiao, Q.X.
Xue, L.L.
Tan, Y.X.
Huangfu, L.R.
Chen, L.
Zhai, C.Y.
Ma, R.F.
Al Hawwas, M.
Zhou, H.S.
Wang, T.H.
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Journal article
Citation
Biomedicine & Pharmacotherapy, 2024; 179(117338):1-17
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Abstract
A recent study has introduced a recombinant fusion protein, consisting of the extracellular domain (ECD) of p75 and the Fc fragment of human immunoglobulin IgG1 (p75ECD-Fc), as a multifaceted agent within the nervous system. This research aimed to assess the effects of p75ECD-Fc on neuronal growth and the restoration of neurological functions in rats afflicted with neonatal hypoxic-ischemic encephalopathy (NHIE). In vitro analyses revealed that 1 μM p75ECD-Fc treatment markedly increased cell viability and facilitated neurite outgrowth in neurons exposed to oxygen-glucose deprivation (OGD).
Subsequent in vivo studies determined that a dose of 78.6 μg/3 μl of p75ECD-Fc significantly mitigated brain damage and both acute and long-term neurological impairments, outperforming the therapeutic efficacy of hypothermia, as evidenced through behavioral assessments. Additionally, in vivo immunostaining showed that p75ECD-Fc administration enhanced neuronal survival and regeneration, and reduced astrocytosis and microglia activation in the cortex and hippocampus of NHIE rats. A noteworthy shift from A1 to A2 astrocyte phenotypes and from M1 to M2 microglia phenotypes was observed after p75ECD-Fc treatment.
Furthermore, a co-expression of the p75 neurotrophin receptor (p75NTR) and Nestin was identified, with an overexpression of Nestin alleviating the neurological dysfunction induced by NHIE. Mechanistically, the neuroprotective effects of p75ECD-Fc, particularly its inhibition of neuronal apoptosis post-OGD, may be attributed to Nestin. Taken together, these results highlight the neuroprotective and anti-inflammatory effects of p75ECD-Fc treatment through the modulation of glial cell phenotypes and the Nestin-mediated inhibition of neuronal apoptosis, positioning it as a viable therapeutic approach for NHIE.
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Data source: Supplementary material, https://doi.org/10.1016/j.biopha.2024.117338
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Copyright 2024 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC license (https://creativecommons.org/licenses/by-nc/4.0/)