Considerable interest has been focused on elucidating the pathogenesis of progressive cell death following stroke, and more recently on identifying the mechanisms responsible for tissue repair/recovery, in hopes of identifying relevant therapeutic targets. One potential target that has received increasing attention is the complement cascade. Despite initial data suggesting that complement-mediated cerebral injury was principally mediated through C1q, subsequent studies in deletionally mutant mice and non-human primates suggest that complete C3 blockade is critical for neuroprotection in adult animals. Unfortunately, only recently have we been able to generate specific C3 inhibitors. These tools, together with an increasing appreciation that complement, and specifically C3, play an important role in the clearance of dead/dying cells, as well in endogenous neurogenesis, lead us to hypothesize: (1) that C3 activation results in progressive tissue injury in the hours following stroke, but that ultimately its role in cell clearance and neurogenesis may exert positive effects on functional outcome, and (2) that carefully tailored, and highly specific, anti-C3 strategies will ultimately prove safer and more efficacious than non-specific strategies especially when administered together with routinely utilized anti-platelet, anti-thrombotic and fibrinolytic medications. To address these hypotheses, with the goal of developing clinically relevant therapies, experiments will: (1) investigate whether the neuroprotective effect of C3 blockade is predominantly mediated through C3a-C3a receptor, and (2) examine to what degree, and under what conditions C3-blockade alters: (a) apoptotic/necrotic cell clearance, (b) the resolution of inflammation, and (c) endogenous neurogenesis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS040409-06A2
Application #
7322593
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Jacobs, Tom P
Project Start
2000-09-30
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
6
Fiscal Year
2007
Total Cost
$363,344
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Ducruet, Andrew F; Zacharia, Brad E; Sosunov, Sergey A et al. (2012) Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke. PLoS One 7:e38664
Ducruet, Andrew F; Sosunov, Sergey A; Zacharia, Brad E et al. (2011) The Neuroprotective Effect of Genetic Mannose-binding Lectin Deficiency is not Sustained in the Sub-acute Phase of Stroke. Transl Stroke Res 2:588-599
Gigante, Paul R; Kotchetkov, Ivan S; Kellner, Christopher P et al. (2011) Polymorphisms in complement component 3 (C3F) and complement factor H (Y402H) increase the risk of postoperative neurocognitive dysfunction following carotid endarterectomy. J Neurol Neurosurg Psychiatry 82:247-53
Ducruet, Andrew F; Sosunov, Sergey A; Visovatti, Scott H et al. (2011) Paradoxical exacerbation of neuronal injury in reperfused stroke despite improved blood flow and reduced inflammation in early growth response-1 gene-deleted mice. Neurol Res 33:717-25
Akpan, Nsikan; Serrano-Saiz, Esther; Zacharia, Brad E et al. (2011) Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke. J Neurosci 31:8894-904
Kellner, Christopher P; Connolly Jr, E Sander (2010) Neuroprotective strategies for intracerebral hemorrhage: trials and translation. Stroke 41:S99-102
Hanafy, Khalid A; Morgan Stuart, R; Fernandez, Luis et al. (2010) Cerebral inflammatory response and predictors of admission clinical grade after aneurysmal subarachnoid hemorrhage. J Clin Neurosci 17:22-5
Starke, Robert M; Komotar, Ricardo J; Otten, Marc L et al. (2009) Adjuvant embolization with N-butyl cyanoacrylate in the treatment of cerebral arteriovenous malformations: outcomes, complications, and predictors of neurologic deficits. Stroke 40:2783-90
Hassid, Benjamin G; Nair, M Nathan; Ducruet, Andrew F et al. (2009) Neuronal RAGE expression modulates severity of injury following transient focal cerebral ischemia. J Clin Neurosci 16:302-6
Garrett, Matthew C; Otten, Marc L; Starke, Robert M et al. (2009) Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage. Brain Res 1298:171-7

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