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activities are mediated through an Epo and CD131 heteroreceptor
(
30
). Other studies have observed cytoprotection with Epo deriva-
tives even in the absence of the CD131 receptor (
31
), and found
that EpoR is necessary for neuroprotection (
29
).
Various chemical alterations that eliminate the erythropoietic
activity of Epo, by either shortening the circulating half-time or
by eliminating the ability of the derivative to interact with
EpoR, have been developed (
32
). This has led to engineering
of some non-erythropoietic derivatives of Epo like non-sialic Epo
(asialoEpo), low sialic Epo (Neuro-Epo), and carbamylated Epo
(CEpo). Erythropoietic activities of Epo require sustained blood
levels. AsialoEpo reacts with EpoR but has a very short half-life in
the circulation and does not significantly increase hematocrit
although neuroprotective properties in a variety of central nervous
system injury models are maintained (
33
). Neuro-Epo has been given
intranasally to enhance the neuroprotective activity of the derivative
(
34, 35
). CEpo, in contrast, does not interact with EpoR but is still
neuroprotective in models of experimental TBI (
23, 36-38
).
Epo-mimetic peptides with neuroprotective activities have also
been developed. Helix B surface peptide (HBSP) is a linear peptide
containing the amino acids from the aqueous face of helix B (amino
acids 58-85) of Epo (
28
). HBSP does not bind to EpoR, but is
thought to activate a separate neuroprotective receptor (
10
).
A modification of the N-terminal Q to pyroglutamate (U) for stabi-
lization, results in an 11-aminoacid peptide called pyroglutamate
Helix-B surface peptide (pHBSP) that has the cytoprotective effects
with no stimulation of erythropoiesis (
39, 40
). Improved cerebral
blood flow and better recovery of neurological function (reduced
contusion volume and better performance in motor tasks) have been
observed with administration of pHBSP following mild cortical
impact injury complicated by hemorrhagic hypotension in rats (
41
).
Epotris, a 20 amino acid peptide corresponding to the C
-helix
region (amino acid residues 92-111) of Epo, also has been shown
to have neuroprotective properties without stimulating erythropoi-
esis (
29
). Epotris binds to the Epo receptor, and the neuroprotec-
tive activities are blocked when the EpoR is absent (
29
).
Studying the neuroprotective effects of these compounds
requires a standardized model of experimental TBI. Human TBI is
heterogeneous and complex. There are different types of TBI
models that are described in literature, each of which has some
features of human TBI. Fluid percussion injury, weight drop accel-
eration-deceleration injury, blast injury, and controlled cortical
impact (CCI) are among the most commonly used experimental
models (
42
). The CCI model mimics many aspects of human TBI,
including concussion, contusion, and axonal injury (
43
).
Rodent TBI experiments are broadly classified into acute and
chronic activities. In an acute experiment (non-survival procedure),
after TBI and drug administration, the cerebral physiological and
α
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