Biology Reference
In-Depth Information
CXCL8), a potent neutrophil-attracting chemokine, has been detected in the CSF of
both adults and children following severe TBI
[54,114]
, and is associated with BBB
dysfunction and increased mortality. Likewise, the murine IL-8 analogues MIP-2
(CXCL2) and KC (CXCL1) are induced in CNS tissue following experimental brain
injury
[115-117]
.
Another key chemoattractant in neuroinflammatory responses is monocyte chemoat-
tractant protein-1 (MCP-1, also known as CCL2). The exuberant monocyte-rich response
characteristic of trauma to the CNS may be attributed to this chemokine, which plays
a nonredundant role specifically in the recruitment of blood-borne monocytes from the
periphery, as well as in the activation and migration of resident microglia to the lesion
site. An elevation of MCP-1 in the injured brain has been demonstrated by our group,
with protein concentrations peaking as early as 4 hours in models of closed head injury
and diffuse axonal injury
[40,42]
. Astrocytes and endothelial cells are the primary
sources of this chemokine soon after injury
[118,119]
, indicating that chemokine syn-
thesis constitutes an important aspect of the early reactive astroglial response. Once
recruited, macrophages and activated microglia are also able to secrete MCP-1, sug-
gesting an autocrine loop of activation that may perpetuate the ongoing cell migration.
We have recently demonstrated that MCP-1 gene-deficient mice exhibit reduced neu-
ronal loss, macrophage infiltration, and astrocyte activation, and improved neurological
function following closed head injury
[42]
, suggesting that macrophages recruited in
response to MCP-1 play a primarily detrimental role following TBI.
10.7 Anti-Inflammatory Intervention after TBI
10.7.1 The Role of Erythropoietin as a Neuroprotectant
in Humans and Animal Models
The targeting of single end products of neurotoxic pathways failed to confer neuro-
protection or improve outcomes after TBI. Alternative options in clinical trials may
rely on the administration of drugs with multiple modes of action. One such promis-
ing therapeutic is erythropoietin (EPO), a 30 kDa molecule to which has been attrib-
uted immunomodulatory and neuroprotective properties in CNS pathology
[120,121]
.
EPO is synthetized by neurons and astrocytes; its receptor is expressed constitutively
by neurons and endothelial cells and is up-regulated following brain hypoxia and
injury
[122]
. Studies in injury models of the CNS have demonstrated neuroprotec-
tive and neuroregenerative functions of EPO via reduction of apoptosis, inflamma-
tion, oxidative stress, and excitotoxicity, and have also revealed its ability to decrease
lesion volume, reduce brain accumulation of leukocytes, and improve motor and
cognitive function
[123,124]
. EPO rapidly crosses the BBB following intravenous
administration in humans and mice
[125-127]
, and its beneficial neurological effects
have been proven in patients with stroke, schizophrenia, and multiple sclerosis
[120,127,128]
. Recently, there has been a remarkable increase in the number studies
demonstrating the neuroprotective role of EPO in animal models of neurological dis-
eases
[121]
. In TBI, most groups have investigated the role of EPO after focal injury
