Biology Reference
In-Depth Information
To our surprise, blocking cPLA
2
GIVA with a highly selective
2-oxoamide inhibitor (AX059) resulted in worsening of all functional and
histological outcome measures. Locomotor function assessed with the
BMS analysis, tissue sparing, and ventral motor neuron survival were all sig-
nificantly worse in mice treated with the cPLA
2
GVIA inhibitor (
Lopez-
Vales et al., 2011
). This was an unexpected result as cPLA
2
GIVA has been
reported to be detrimental in other models of neurological disorders such as
cerebral ischemia (
Bonventre et al., 1997
) and EAE (
Kalyvas et al., 2009
). In
brain ischemia/reperfusion injury, cPLA
2
was thought to contribute to
blood-brain barrier disruption through the p38 MAPK pathway (
Nito
et al., 2008
). In the EAE study, we reported that the same inhibitor
(AX059) used in SCI had beneficial effects. We therefore assessed the effects
of spinal cord contusion in cPLA
2
GIVA null mice, which also showed sig-
nificant worsening of various outcome measures after SCI as was seen with
the inhibitor treatment. cPLA
2
GIVA is expressed in ventral motor neurons
in the normal uninjured spinal cord; our findings therefore suggest that loss
of this expression may be detrimental to the survival of these neurons. This
may have to do with its role in membrane turnover related to synaptic vesicle
release from the large motor neurons projecting to neuromuscular junctions.
cPLA
2
has also been reported to play a role in survival of neurons in hippo-
campal slice cultures and in preventing calcium-mediated cell death of other
nonneural cell types (
Casas et al., 2006; Forlenza, Mendes, Marie, & Gattaz,
2007; Oikawa et al., 2005
). The importance of cPLA
2
was further confirmed
using a pan-PLA
2
inhibitor (FKGK2) that blocked all three PLA
2
s to about
90%. Treatment with this inhibitor after SCI also led to worsening of all
outcome measures assessed. These findings suggest that the beneficial
effects of blocking sPLA
2
GIIA and iPLA
2
GVIA can be lost if cPLA
2
is
inhibited. Interestingly, a weak pan-PLA
2
inhibitor that partially blocked
all three inhibitors to about 50% level (cPLA
2
by 62%, iPLA
2
by 45%,
and sPLA
2
by 52%) was the most effective in promoting locomotor
recovery and reducing histopathology, including about a threefold
increase in serotonergic innervation. We showed that this effect appears
to be mediated by upregulation of cPLA
2
, COX-2, and prostaglandin E
synthetic pathway via the EP1 receptor, suggesting potential cross talk
between various PLA
2
s as has been reported in other models (
Murakami
& Kudo, 2001; Offer et al., 2005
).
These findings show that different members of the PLA
2
superfamily can
have either beneficial or detrimental effects in SCI (
Table 5.2
). Interestingly,
we found that the same inhibitors had different effects in EAE, a model of
