TY - JOUR
T1 - Kallikrein cascades in traumatic spinal cord injury
T2 - in vitro evidence for roles in axonopathy and neuron degeneration.
AU - Radulovic, Maja
AU - Yoon, Hyesook
AU - Larson, Nadya
AU - Wu, Jianmin
AU - Linbo, Rachel
AU - Burda, Joshua E.
AU - Diamandis, Eleftherios P.
AU - Blaber, Sachiko I.
AU - Blaber, Michael
AU - Fehlings, Michael G.
AU - Scarisbrick, Isobel A.
PY - 2013/11
Y1 - 2013/11
N2 - 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.
AB - 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.
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U2 - 10.1097/NEN.0000000000000007
DO - 10.1097/NEN.0000000000000007
M3 - Article
C2 - 24128681
AN - SCOPUS:84891653211
SN - 0022-3069
VL - 72
SP - 1072
EP - 1089
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 11
ER -