The NCX1 calcium exchanger is implicated in delayed axotomy after peripheral nerve stretch injury.
NCX1
calpain
cytoskeleton
peripheral nerve injury
secondary axotomy
Journal
Journal of the peripheral nervous system : JPNS
ISSN: 1529-8027
Titre abrégé: J Peripher Nerv Syst
Pays: United States
ID NLM: 9704532
Informations de publication
Date de publication:
14 Oct 2024
14 Oct 2024
Historique:
received:
12
08
2024
accepted:
30
09
2024
medline:
15
10
2024
pubmed:
15
10
2024
entrez:
15
10
2024
Statut:
aheadofprint
Résumé
After peripheral nerve stretch injury, most degenerating axons are thought to become disconnected at the time of injury, referred to as primary axotomy. The possibility of secondary axotomy-a delayed and potentially reversible form of disconnection-has not been evaluated. Here, we investigated secondary axotomy in a rat model of sciatic nerve stretch injury. We also evaluated whether axon sparing and functional improvement results from pharmacological blockade of the sodium-calcium exchanger 1 (NCX1), which is widely believed to contribute to traumatic axon degeneration but was previously only investigated in vitro. We studied peripheral nerve secondary axotomy in a clinically relevant rat model of sciatic nerve rapid stretch injury with immunolabeling and fluorescence microscopy. The role of NCX1 in secondary axotomy was studied with pharmacological inhibition with SEA0400 and immunolabeling, immunoblot, and behavioral assays. We found that early after injury, many axons remained in-continuity and that degeneration of axons was delayed, consistent with the occurrence of secondary axotomy. βAPP, a marker of secondary axotomy, accumulated at regions of axon swelling and disconnection, and NCX1 was upregulated and co-localized to βAPP axonal swellings. Pharmacological blockade of NCX1 after injury reduced calpain activation, proteolytic degradation of neurofilaments, βAPP accumulation, distal axon degeneration, and improved hindlimb function. Our data demonstrate a major role for secondary axotomy in peripheral nerve stretch injury and identify NCX1 as a promising therapeutic target to reduce secondary axotomy and improve functional outcome after nerve injury.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
After peripheral nerve stretch injury, most degenerating axons are thought to become disconnected at the time of injury, referred to as primary axotomy. The possibility of secondary axotomy-a delayed and potentially reversible form of disconnection-has not been evaluated. Here, we investigated secondary axotomy in a rat model of sciatic nerve stretch injury. We also evaluated whether axon sparing and functional improvement results from pharmacological blockade of the sodium-calcium exchanger 1 (NCX1), which is widely believed to contribute to traumatic axon degeneration but was previously only investigated in vitro.
METHODS
METHODS
We studied peripheral nerve secondary axotomy in a clinically relevant rat model of sciatic nerve rapid stretch injury with immunolabeling and fluorescence microscopy. The role of NCX1 in secondary axotomy was studied with pharmacological inhibition with SEA0400 and immunolabeling, immunoblot, and behavioral assays.
RESULTS
RESULTS
We found that early after injury, many axons remained in-continuity and that degeneration of axons was delayed, consistent with the occurrence of secondary axotomy. βAPP, a marker of secondary axotomy, accumulated at regions of axon swelling and disconnection, and NCX1 was upregulated and co-localized to βAPP axonal swellings. Pharmacological blockade of NCX1 after injury reduced calpain activation, proteolytic degradation of neurofilaments, βAPP accumulation, distal axon degeneration, and improved hindlimb function.
INTERPRETATION
CONCLUSIONS
Our data demonstrate a major role for secondary axotomy in peripheral nerve stretch injury and identify NCX1 as a promising therapeutic target to reduce secondary axotomy and improve functional outcome after nerve injury.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Association of VA Surgeons
Informations de copyright
© 2024 Peripheral Nerve Society.
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