Abstract
Acute ischemic stroke causes a high rate of deaths and permanent neurological deficits in survivors. Current interventional treatment, in the form of enzymatic thrombolysis, benefits only a small percentage of patients. Brain ischemia triggers mobilization of innate immunity, specifically the complement system and Toll-like receptors (TLRs), ultimately leading to an exaggerated inflammatory response. Here we demonstrate that intravenous immunoglobulin (IVIG), a scavenger of potentially harmful complement fragments, and C1-esterase inhibitor (C1-INH), an inhibitor of complement activation, exert a beneficial effect on the outcome of experimental brain ischemia (I) and reperfusion (R) injury induced by transient occlusion of middle cerebral artery in mice. Both IVIG and C1-INH significantly and in a dose–responsive manner reduced brain infarction size, neurological deficit and mortality when administered to male mice 30 min before ischemia or up to 6 h after the onset of reperfusion. When combined, suboptimal doses of IVIG and C1-INH potentiated each other’s neuroprotective therapeutic effects. Complement C3 and TLR2 signals were colocalized and significantly greater in brain cells adjacent to infracted brain lesions when compared to the corresponding regions of the contralateral hemisphere and to control (sham) mice. Treatment with IVIG and C1-INH effectively reduced deposition of C3b and downregulated excessive TLR2 and p-JNK1 expression at the site of I/R injury. Taken together, these results provide a rationale for potential use of IVIG and C1-INH, alone or in combination with ischemic stroke and other neurological conditions that involve inappropriately activated components of the innate immune system.
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Acknowledgements
The authors wish to thank Dr. Mohamed R. Mughal for animal management and Drs. Ruiquian Wan, Eitan Okun and Dong Liu for their technical assistance. Supported, in part, by the Investigator Initiated Research grant from CSL Behring to Biovisions, Inc, and by the Intramural Research Program of the National Institute on Aging.
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12017_2017_8474_MOESM1_ESM.jpg
IVIG, C1-INH and their combination exert neuroprotection 6 hours after the onset of ischemia. Mice were treated with IVIG at 1 g/kg (N=11), C1-INH at 300 U/kg (N=8) or the combination (N=10) 6 hours after the beginning of ischemia; the infarction area (A) and neurological deficit score (B) were determined at 72 h post-ischemia; *P < 0.001. Data are mean ± SEM (JPEG 31 kb)
12017_2017_8474_MOESM2_ESM.jpg
IVIG, C1-INH and their combination protect old and female mice from I/R-triggered brain injury. (A) 13–14 month-old male mice were subjected to I/R injury (N=8) and I/R injury plus IVIG at 1 g/kg (N=8), I/R + C1-INH at 300 U/kg (N=9) and I/R plus the combination of suboptimal doses of both (N=8) 6 hours after ischemia; *P < 0.001, compared with I/R only; #P < 0.01, combined compared with IVIG and C1-INH. (B) Neurological deficit score evaluated in the same groups of mice as in (A) 72 h post-ischemia; *P < 0.01, compared with I/R only; **P < 0.001, combined compared with I/R only; #P < 0.01, combined compared with IVIG and C1-INH. (C) Infarction area in non-treated female mice (N=9), infused with IVIG at 1 g/kg (N = 8), C1-INH at 300 U/Kg (N=9) and the combination (N=8) 6 hours post-ischemia; *P < 0.05, compared with I/R only. (D) Neurological deficit score in the same mice as in (C) at 72 h post-ischemia; *P < 0.01, compared with I/R only. Data are mean ± SEM (JPEG 51 kb)
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Chen, X., Arumugam, T.V., Cheng, YL. et al. Combination Therapy with Low-Dose IVIG and a C1-esterase Inhibitor Ameliorates Brain Damage and Functional Deficits in Experimental Ischemic Stroke. Neuromol Med 20, 63–72 (2018). https://doi.org/10.1007/s12017-017-8474-6
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DOI: https://doi.org/10.1007/s12017-017-8474-6