The endogenous calpain inhibitor calpastatin attenuates axon degeneration in murine Guillain-Barré syndrome

J Peripher Nerv Syst, 2023 · DOI: 10.1111/jns.12520 · Published: January 1, 2023

Simple Explanation

This research investigates a potential therapy for Guillain-Barré syndrome (GBS) by targeting axon degeneration, a key factor in poor clinical outcomes. The study focuses on calpains, intra-axonal proteases that contribute to axon damage. Transgenic mice overexpressing calpastatin, an endogenous calpain inhibitor, were used to assess the impact of axonally-restricted calpain inhibition on nerve integrity in GBS models. The study found that calpain inhibition can protect axonal integrity in a GBS paradigm, potentially accelerating recovery. This supports further development of calpain inhibitors for clinical studies.

Study Duration

Not specified

Participants

hCAST, GalNAc-T−/−-Tg(neuronal), and hCAST x Neuronal transgenic mice

Evidence Level

Level 2: Experimental study using animal model

Key Findings

1
Endogenous hCAST expression protects axonal and nodal integrity in an acute ex vivo injury model, as evidenced by the attenuation of neurofilament breakdown.
2
In an acute in vivo injury model, endogenous hCAST expression protects axonal and nodal integrity, although respiratory function remains initially impaired.
3
Calpain inhibition promotes functional recovery in a sub-acute model of injury, suggesting that early structural improvements can lead to faster functional restoration.

Research Summary

This study investigates the neuroprotective potential of axonal calpain inhibition in Guillain-Barré syndrome (GBS) using transgenic mice overexpressing the endogenous calpain inhibitor calpastatin (hCAST). The results demonstrate that hCAST expression protects distal nerve structural integrity both ex and in vivo, as shown by attenuation of neurofilament breakdown and improved occupancy of key nodal proteins. While acute respiratory function remained impaired initially, hCAST expression accelerated recovery in an extended in vivo model, reinforcing the potential of calpain inhibitors as a therapeutic strategy for GBS.

Practical Implications

Therapeutic Potential

Calpain inhibition represents a promising therapeutic strategy for GBS by protecting axonal integrity and promoting earlier functional recovery.

Clinical Translation

These findings justify the development of further animal and human clinical studies using exogenous calpain inhibitors to target axon degeneration in GBS.

Biomarker Utilization

Serum neurofilament light chain (NF-L) levels can serve as a useful biomarker to assess axon injury and treatment efficacy in GBS models and potentially in clinical settings.

Study Limitations

1
The dose of calpastatin in the transgenic model is fixed, which may limit the extent of calpain inhibition and structural protection.
2
Incomplete structural protection observed in the acute model suggests that other cytotoxic mediators or physiological changes may also contribute to nerve dysfunction.
3
The study focuses on a specific AMAN model, and further research is needed to assess the applicability of calpain inhibition to other variants of GBS.

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