Biology Reference
In-Depth Information
on the other hand, was increased between 3 and 28 days; with a threefold
increase at day 3 that decreased to about a twofold increase between 14 and
28 days. The active 52-kDa cleaved form of iPLA
2
is increased three- to
fourfold between 7 and 28 days except at day 14 when it reaches a peak
of about sixfold. sPLA
2
GIIA and iPLA
2
GVIA are widely expressed in most
cell types (astrocytes, oligodendrocytes, neurons, and microglia/
macrophages) in the injured spinal cord with some key differences. sPLA
2
GIIA is expressed mainly in astrocytes and oligodendrocytes, while iPLA
2
GVIA is expressed mainly in oligodendrocytes. cPLA
2
GIVA, on the other
hand, is expressedmainly by neurons and oligodendrocytes in the injured cord.
We dissected out the functional roles of three PLA
2
s in SCI using a panel
of small molecule inhibitors that were selective for each of the three PLA
2
s
or inhibitors that were able to partially or completely block all three. Please
see our publication of details of the selectivity and potency of these
inhibitors, and additional information on related work on these inhibitors
(
Lopez-Vales et al., 2011
). Blocking sPLA
2
GIIA with a highly selective
small amide inhibitor (GK115) yielded improved recovery of locomotor
control assessed using the BMS analysis. Treatment with this inhibitor also
led to reduced myelin loss and tissue damage, and improved serotonergic
innervation of the ventral horn. The reduction in myelin loss correlates
with the increased expression of sPLA
2
GIIA in oligodendrocytes. Other
work has also shown that injection of sPLA
2
GIII, a bee venom form of
PLA
2
into the intact spinal cord induced myelin damage and tissue loss
(
Liuetal.,2006
). Our work with a selective inhibitor (GK115) provides
direct evidence for a role for sPLA
2
GIIA in the pathology and functional
loss seen after SCI. Inhibition of sPLA
2
has also been shown to be neuro-
protective after transient global brain ischemia in gerbils (
Wang et al.,
2009
). In contrast to blocking sPLA
2
GIIA, blocking iPLA
2
GVIA with
a selective pentafluorokeone inhibitor (FKGK11) did not improve loco-
motor function except for some minimal effects in the BMS subscore at
28 days. The inhibitor treatment, however, reduced myelin loss and some
tissue loss but had no effect on survival of ventral motor neurons or on
serotonergic innervation of the ventral horns after injury. The lack of effect
on ventral horn neuron survival and reinnervation may underlie the poor
recovery of locomotor function. As blocking iPLA
2
GVIA can signifi-
cantly reduce myelin loss and tissue loss, the combined blocking of iPLA
2
GVIA and sPLA
2
GIIA might be expected to provide better recovery as
compared to blocking each alone.
