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Neuroprotection in stroke by complement inhibition and immunoglobulin therapy.
Neuroscience. 2008 Jul 12
Arumugam TV, Woodruff TM, Lathia JD, Selvaraj PK, Mattson MP, Taylor SM.
Department
of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University
Health Sciences Center, 1300 Coulter Drive, Amarillo, TX 79106, USA.
Activation
of the complement system occurs in a variety of neuroinflammatory
diseases and neurodegenerative processes of the CNS. Studies in the
last decade have demonstrated that essentially all of the activation
components and receptors of the complement system are produced by
astrocytes, microglia, and neurons.
There is also rapidly growing
evidence to indicate an active role of the complement system in
cerebral ischemic injury. In addition to direct cell damage, regional
cerebral ischemia and reperfusion (I/R) induces an inflammatory
response involving complement activation and generation of active
fragments, such as C3a and C5a anaphylatoxins, C3b, C4b, and iC3b. The
use of specific inhibitors to block complement activation or their
mediators such as C5a, can reduce local tissue injury after I/R.
Consistent with therapeutic approaches that have been successful in
models of autoimmune disorders, many of the same complement inhibition
strategies are proving effective in animal models of cerebral I/R
injury. One new form of therapy, which is less specific in its
targeting of complement than monodrug administration, is the use of
immunoglobulins. I.v. immunoglobulin (IVIG) has the potential to
inhibit multiple components of inflammation, including complement
fragments, pro-inflammatory cytokine production and leukocyte cell
adhesion. Thus, IVIG may directly protect neurons, reduce activation of
intrinsic inflammatory cells (microglia) and inhibit transendothelial
infiltration of leukocytes into the brain parenchyma following an
ischemic stroke. The striking neuroprotective actions of IVIG in animal
models of ischemic stroke suggest a potential therapeutic potential
that merits consideration for clinical trials in stroke patients.
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