Biology Reference
In-Depth Information
monitoring and anticipating for complications of secondary brain
injury and their medical and/or surgical treatment. The medical
management mainly consists of controlled ventilation, anti-edema
drugs, antibiotics, and antiseizure medications. Over the last few
decades several biochemical pathways that are crucial in the sec-
ondary injury following TBI have been described. Several mole-
cules like erythropoietin that affect these biochemical pathways
have proved to be useful in animal TBI experiments ( 3, 4 ). Though
there are no published randomized clinical trials demonstrating an
effect of Epo on outcome from TBI ( 5 ), there is indirect data in
the form of a retrospective study ( 6 ) and randomized trials in criti-
cally ill patients ( 7, 8 ), suggesting a beneficial role.
Cytokines are a family of polypeptides that regulate cell activa-
tion, proliferation, and differentiation. Under normal condition,
cytokines are present in very low concentrations in the brain, and
cytokine receptors are constitutively expressed only in low levels.
After traumatic brain injury, pro-in flammatory and anti-inflammatory
cytokines are rapidly upregulated. Pro-inflammatory cytokines,
including interleukin-1
),
and IL-6, stimulate the inflammatory response. Anti-inflammatory
cytokines, including transforming growth factor-
β
(IL-1
β
), tumor necrosis factor-
α
(TNF-
α
) and
IL-10, inhibit the expression of pro-inflammatory cytokines and
reduce inflammation. The relative balance between the harmful
and beneficial effects of cytokines depend on the injury
conditions.
Erythropoietin (Epo) is a 34-kDa hematopoietic cytokine,
synthesized predominantly by the kidney. Epo interacts with the
Epo receptor (EpoR) which is expressed both in the neural and the
nonneural tissues ( 9 ). Epo is shown to have a tissue protective ( 10 )
role through its influence on various pathways, including the JAK2
pathway, the MAPK signaling pathway, and the STAT-5 pathway
( 11-13 ). These pathways mainly have anti-inflammatory, anti-
apoptotic, anti-excitatory, and neuroprotective roles ( 14, 15 ). Epo
is also shown to increase cerebral blood flow, to maintain the integ-
rity of blood brain barrier, and to stimulate angiogenesis ( 16 ).
Studies in various experimental TBI models have demonstrated
neuroprotective effects with Epo administered after TBI ( 3, 17-23 ).
However, the potential for thromboembolic complications with
Epo have hampered its translation as a neuroprotective agent
( 24, 25 ). Clinical trials are currently ongoing with Epo in TBI
patients, but the doses being given in these trials are limited by
concern for thromboembolic events and are lower than the doses
found to be optimal in experimental TBI studies ( 26 ).
Studies with derivatives of Epo or peptides that mimic part of
the Epo molecule have clearly shown that these neuroprotective
activities of Epo can be separated from the erythropoietic effects
( 27-29 ). The receptor involved in the neuroprotective activities is
less clear. Some studies have suggested that these neuroprotective
β
(TGF-
β
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