Animal models of focal ischaemia induced by
middle cerebral artery occlusion (MCAO) provide most evidence for cellular inflammatory responses in
stroke. Permanent MCAO results in a modest neutrophil infiltration at 24 h after ischaemia, predominantly around arterial vessels at the margins of
infarction, whereas MCAO with subsequent reperfusion is associated with substantial infiltration by neutrophils throughout the entire
infarct. Several studies show that
C-reactive protein (CRP), an inflammatory marker, is associated with
stroke outcomes and future vascular events. Several drugs, especially hydroxymethylglutaryl
coenzyme A reductase inhibitors (
statins), have been demonstrated to reduce
hsCRP levels independently of their effects on plasma
cholesterol. Various
cytokines were shown to be expressed in the injured brain. Recent investigations demonstrated that mRNAs of above
cytokines were induced in the ischemic rat brain.
TNF-alpha is a pleiotropic
cytokine that mediates key roles in many physiological and pathological cellular processes including acute and chronic
inflammation, programmed cell death or apoptosis, anti-
tumor responses, and
infection. Pharmaceutical industry to search a small molecule
TNF inhibitor have taken multiple strategies. Significant protection after in vivo oral use of
SB-239063 from
brain injury and neurological deficits was observed in one study. In the same study significant protection from
brain injury and neurological deficits was also demonstrated due to i.v post-
stroke treatment with the same compound. Leukocyte-endothelial adhesion process consists of several steps, beginning with rolling of the leukocyte on the endothelial surface until it has slowed down to such a degree that it sticks to the endothelium. Treatment with a murine anti-ICAM-1 antibody (
enlimomab) has been investigated in patients with
acute ischemic stroke in the
Enlimomab Acute Stroke Trial (EAST). Unfortunately, the case fatality rate in this trial was significantly higher in the
enlimomab patient group than in the placebo group. Furthermore, experimental data have shown that focal
cerebral ischemia induces a time-dependent activation of granulocytes, lymphocytes, and macrophages. Dissipation of
ATP by CD39 reduced
P2X7 receptor stimulation and thereby suppressed baseline leukocyte alphaMbeta2-integrin expression. As alphaMbeta2-integrin blockade reversed the postischemic, inflammatory phenotype of Cd39-/- mice, these data suggest that phosphohydrolytic activity on the leukocyte surface suppresses cell-cell interactions that would otherwise promote
thrombosis or
inflammation.