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correlated with behavioral improvements following Epo treatment
(
120
). During stroke models Epo also significantly improved neu-
rogenesis and functional recovery by increasing cerebral BDNF
levels (
110
). Epo also enhanced oligodendrogenesis (
117
) and
recovery of neurological function after neonatal hypoxic/ischemic
brain (
113
). In the retina, Epo promoted neurite extension from
postnatal retinal ganglion cells in vitro (
128
), induced JAK2/
STAT3 phosphorylation and activated PI3K/Akt (see Fig.
1
).
Inhibition of JAK2/STAT3 abolished Epo-induced growth verify-
ing the pathway is involved in conferring regeneration-enhancing
Epo functions in the retina (
129
).
Thus the positive effects of Epo are not limited to neuropro-
tection but extend to neurogenesis and differentiation. Indeed
more research needs to be performed in this area.
Studies using Epo to combat brain disease progression have been
largely encouraging. In 2002 the Göttingen Epo stroke pilot study
demonstrated the neuroprotective effectiveness of Epo in human
stroke patients (
130
). Epo-treated patients showed significantly
better recovery than the control group regarding the clinical out-
come parameters, the evolution of infarct size, and the profile of
circulating damage markers. Disappointingly, the recent German
multicenter Epo Stroke Trial revealed an increased risk of serious
complications such as death, intracerebral hemorrhage, brain
edema, and thromboembolic events (
131
). This study emphasized
the point that when used in combination with other drugs (in this
case recombinant tissue plasminogen activator used for hemodialy-
sis) Epo may even be detrimental for patient outcome.
Epo therapy was effective in reducing progressive atrophy and
loss of gray matter in patients diagnosed with schizophrenia (
132
).
Also in healthy volunteers Epo improved cognitive and neural pro-
cessing of emotional information showing similar effects to those
of serotonergic and noradrenergic antidepressant drugs (
133
).
Together these trials suggest future clinical applications for Epo in
the treatment of psychiatric disorders characterized by cognitive
dysfunction. During the first phase I/IIa study of high dose Epo
treatment in patients with chronic progressive multiple sclerosis
significant improvement in clinical and electrophysiological motor
function as well as cognitive performance was achieved (
134
). Epo
treatment also somewhat improved outcome for patients after sub-
arachnoid hemorrhage (
135
). However, in contrast, the first ran-
domized trial of Epo in moderate traumatic brain injury patients
during the resuscitative phase showed Epo did not reduce neu-
ronal cell death compared to placebo and disappointingly injury
severity was worse in the Epo group (
136
).
Many of the clinical studies performed show promise, however
they also have a number of limitations. For example frequently the
patient numbers have been small and some of the studies not blind.
5.5 Epo in Treatment
of Brain Diseases
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