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Role of cytotoxic protease granzyme-b in neuronal degeneration during human stroke.

Abstract
Infiltration of leukocytes into post-ischemic cerebrum is a well-described phenomenon in stroke injury. Because CD-8(+) T-lymphocytes secrete cytotoxic proteases, including granzyme-b (Gra-b) that exacerbates post-ischemic brain damage, we investigated roles of Gra-b in human stroke. To study the role of Gra-b in stroke, ischemic and non-ischemic tissues (from post-mortem stroke patients) were analyzed using immunoblotting, co-immunoprecipitation, terminal deoxy uridine nick end labeling (TUNEL) and Annexin-V immunostaining, and in vitro neuron survival assays. Activated CG-SH cells and supernatants were used to model leukocyte-dependent injury. Non-ischemic brain tissues were used as non-pathological controls. Non-activated CG-SH cells and supernatants were used as controls for in vitro experiments. Human stroke (ischemic) samples contained significantly higher levels of Gra-b and interferon-gamma inducible protein-10 (IP-10/CXCL10) than non-ischemic controls. In stroke, poly (ADP-ribose) polymerase-1 and heat shock protein-70 were cleaved to canonical proteolytic "signature" fragments by Gra-b. Gra-b was also found to bind to Bid and caspase-3. Gra-b also co-localized with Annexin-V(+) /TUNEL(+) in degenerating neurons. Importantly, Gra-b inhibition protected both normal and ischemia-reperfused neurons against in vitro neurotoxicity mediated by activated CG-SH cells and supernatants. These results suggest that increased leukocyte infiltration and elevated Gra-b levels in the post-stroke brain can induce contact-dependent and independent post-ischemic neuronal death to aggravate stroke injury.
AuthorsGanta Vijay Chaitanya, Prabhakar Eeka, Reinhold Munker, Jonathan Steven Alexander, Phanithi Prakash Babu
JournalBrain pathology (Zurich, Switzerland) (Brain Pathol) Vol. 21 Issue 1 Pg. 16-30 (Jan 2011) ISSN: 1750-3639 [Electronic] Switzerland
PMID20825413 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2010 The Authors; Brain Pathology © 2010 International Society of Neuropathology.
Chemical References
  • CXCL10 protein, human
  • Chemokine CXCL10
  • Granzymes
  • Caspase 3
Topics
  • Adult
  • Aged
  • Analysis of Variance
  • Apoptosis
  • Blotting, Western
  • Brain (metabolism, pathology)
  • Brain Ischemia (metabolism, pathology)
  • Caspase 3 (metabolism)
  • Cell Line, Tumor
  • Cells, Cultured
  • Chemokine CXCL10 (metabolism)
  • Female
  • Granzymes (metabolism)
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Nick-End Labeling
  • Male
  • Middle Aged
  • Necrosis
  • Nerve Degeneration (metabolism, pathology)
  • Neurons (metabolism, pathology)
  • Stroke (metabolism, pathology)

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