Kallikrein Cascades in Traumatic Spinal Cord Injury: In Vitro Evidence for Roles in Axonopathy and Neuron Degeneration

J Neuropathol Exp Neurol, 2013 · DOI: 10.1097/NEN.0000000000000007 · Published: November 1, 2013

Spinal Cord Injury Neurology Biochemistry

Simple Explanation

Kallikreins (KLKs) are a family of 15 secreted serine proteases with emerging roles in neurological disease. This study investigates the role of kallikreins in spinal cord injury (SCI) by examining their expression and impact on neurons. The findings suggest that certain kallikreins contribute to neurodegenerative changes after SCI, making them potential targets for neuroprotective treatments.

Study Duration

60d (murine model)

Participants

Human SCI cases (n=22), murine SCI model (n=3 per time point)

Evidence Level

In vitro and in vivo study

Key Findings

1
Temporally and spatially distinct changes in kallikrein expression were observed with partially overlapping patterns between human and murine SCI, including peak elevations (or reductions) during the acute and subacute periods.
2
A subset of kallikreins, KLK1, KLK5, KLK6, KLK7 and KLK9 were shown to be neurotoxic toward primary neurons in vitro.
3
Kallikrein immunoreactivity was also observed in association with swollen axons and retraction bulbs in the human SCI materials examined.

Research Summary

This study investigates the involvement of kallikreins (KLKs) in traumatic spinal cord injury (SCI) by examining their expression patterns in human and murine SCI models, as well as their effects on neurons in vitro. The results reveal dynamic changes in the expression of multiple kallikreins in response to SCI, with some KLKs showing neurotoxic effects in vitro. These findings suggest that kallikreins play a significant role in the pathophysiology of SCI and may serve as potential targets for the development of neuroprotective strategies.

Practical Implications

Neuroprotective Strategies

Kallikreins represent new targets for the development of neuroprotective strategies relevant to traumatic SCI and other neurological disorders.

Therapeutic Interventions

The subset of kallikreins shown to be elevated post-injury and capable of promoting neural injury in vitro (KLKs 1, 5, 6, 7 and 9) are potential targets to prevent secondary injury cascades and promote spinal cord repair and plasticity.

Understanding SCI Microenvironment

These studies define kallikreins as important regulators of the SCI microenvironment and thus understanding their role could help create an environment favorable to repair across the acute through chronic SCI continuum.

Study Limitations

1
Antibodies specific to each of the murine kallikreins studied herein are not currently available.
2
Only the direct effects of kallikreins toward neurons were examined and therefore these studies do not exclude a wider range of action in vivo, including modification of extracellular matrices or other CNS proteins and cell types that may indirectly influence neurite integrity and neuron viability.
3
The kallikrein expression patterns described in the intact and injured spinal cord do not distinguish the relative amounts of inactive pro-kallikrein compared to that which N-terminal cleavage of a 3 to 37 amino acid pro-peptide results in the release of enzymatically active protein.

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