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J Neuropathol Exp Neurol. 2013 Nov;72(11):1072-89. doi: 10.1097/NEN.0000000000000007.

Kallikrein cascades in traumatic spinal cord injury: in vitro evidence for roles in axonopathy and neuron degeneration.

Author information

  • 1From the Neurobiology of Disease Program (MR, JEB, IAS) and Departments of Physical Medicine and Rehabilitation (HY, NL, JW, RL, IAS) and Neurology (IAS), Mayo Medical and Graduate School, Rochester, Minnesota; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (EPD); Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida (SIB, MB); and Department of Surgery, Toronto Western Research Institute, Toronto, Ontario, Canada (MGF).

Abstract

Kallikreins (KLKs) are a family of 15 secreted serine proteases with emerging roles in neurologic diseases. To illuminate their contributions to the pathophysiology of spinal cord injury (SCI), we evaluated acute through chronic changes in the immunohistochemical appearance of 6 KLKs (KLK1, KLK5, KLK6, KLK7, KLK8, and KLK9) in postmortem human traumatic SCI cases, quantified their RNA expression levels in experimental murine SCI, and assessed the impact of recombinant forms of each enzyme toward murine cortical neurons in vitro. Temporally and spatially distinct changes in KLK expression were observed with partially overlapping patterns between human and murine SCI, including peak elevations (or reductions) during the acute and subacute periods. Kallikrein 9 showed the most marked changes and remained chronically elevated. Importantly, a subset of KLKs (KLK1, KLK5, KLK6, KLK7, and KLK9) were neurotoxic toward primary neurons in vitro. Kallikrein immunoreactivity was also observed in association with swollen axons and retraction bulbs in the human SCI cases examined. Together, these findings demonstrate that elevated levels of a significant subset of KLKs are positioned to contribute to neurodegenerative changes in cases of CNS trauma and disease and, therefore, represent new potential targets for the development of neuroprotective strategies.

PMID:
24128681
PMCID:
PMC4097185
DOI:
10.1097/NEN.0000000000000007
[PubMed - indexed for MEDLINE]
Free PMC Article
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