http://jcb.sagepub.com/content/early/2016/11/17/0271678X16679170.abstract
- Jenna L Leclerc1,2
- Juan Santiago-Moreno1
- Alex Dang1
- Andrew S Lampert1
- Pedro E Cruz2
- Awilda M Rosario2
- Todd E Golde2
- Sylvain Doré1,2,3⇑
- 1Department of Anesthesiology, University of Florida, Gainesville, FL, USA
- 2Department of Neuroscience, McKnight Brain Institute, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA
- 3Departments of Neurology, Psychology, Psychiatry, and Pharmaceutics, University of Florida, Gainesville, FL, USA
- Sylvain Doré, College of Medicine, University of Florida, 1275 Center Dr, PO 100159, Gainesville, FL 32610, USA. Email: sdore@ufl.edu
Abstract
Following intracerebral hemorrhage (ICH),
extracellular heme precipitates secondary brain injury, which results in
irreversible
brain damage and enduring neurological deficits.
Hemopexin (Hpx) is an endogenous protein responsible for scavenging
heme,
thereby modulating its intrinsic
proxidant/proinflammatory properties. Although Hpx is present in the
brain, the endogenous
levels are insufficient to combat the massive heme
overload following ICH. We hypothesized that increasing brain Hpx levels
would improve ICH outcomes. Unique recombinant
adeno-associated viral vectors were designed to specifically overexpress
Hpx
within the mouse brain. Western blotting, ELISA,
and immunohistochemistry of brain homogenates/sections, CSF, and serum
were
performed. As compared to controls, Hpx mice have
increased Hpx protein levels in all three types of biospecimens
evaluated,
which results in 45.6 ± 6.9% smaller lesions and
improved functional recovery after ICH (n=14–19/group, p < 0.05).
Local mechanistic analyses show significantly less tissue injury,
trends toward smaller hematoma volumes, unchanged
heme oxygenase 1 and iron levels, and significantly
increased microgliosis and decreased astrogliosis and lipid
peroxidation.
Peripheral levels of heme-related markers indicate a
positive modulation of iron-binding capacity. These findings reveal
that
high local Hpx levels improve ICH outcomes, likely
through both central and peripheral clearance mechanisms, and establish
the potential for therapeutically administering
clinical-grade Hpx for ICH.
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