Biology Reference
In-Depth Information
shown that MMP-9, which is produced by macrophages, blood vessels, and
astrocytes, mediates breakdown of the blood-spinal cord barrier, resulting in
an increased inflammatory response and scar formation after SCI (
Noble,
Donovan, Igarashi, Goussev, & Werb, 2002
); MMP-9
/
mice show
improved histological and locomotor outcomes after SCI (
Noble et al.,
2002
). In contrast, MMP-2 activity reduces glial scar formation and chon-
droitin sulfate proteoglycan (CSPG) deposition (
Hsu et al., 2006
); recovery
after SCI is worse in MMP-2 null mice as compared to wild-type mice (
Hsu
et al., 2006
). The changes we observed in cytotoxic and beneficial mediators
in MK2 knockout mice after SCI were correlated with reduced secondary
damage assessed at 28 day after SCI. These include several histological mea-
sures such as reduced ventral horn neuron loss, reduced myelin loss, and
increased serotonergic innervation of the ventral horn. In addition, there
is a 40% reduction in 3-nitrotyrosine. Our work therefore suggests that
MK2 plays multiple roles in different cell types that contribute to inflamma-
tion and secondary tissue damage after SCI. This work also suggests that
selective pharmacological inhibitors of MK2, would be useful to treat spinal
cord injury.
4.2.
/KCa3.1
This intermediate conductance Ca
2
þ
-activated K
þ
channel also known as
IK1, KCa3.1, or SK4 (
KCNN4
for the gene) is expressed inmany types of non-
excitable cells (T cells, red blood cells, and microglia) (
Gardos, 1958; Kaushal
et al., 2007; Khanna, Chang, Joiner, Kaczmarek, & Schlichter, 1999
). Small
increases in intracellular Ca
2
þ
(
K
d
KCNN4
300 nM) opens the channel leading to
K
þ
efflux and subsequent increases in Ca
2
þ
influx that can regulate a wide
variety of Ca
2
þ
mediated changes. Microglia
in vitro
express KCa3.1 and
experiments using a selective inhibitor (triarylmethane-34 [TRAM-34])
showed that it mediates LPS-induced increase in iNOS, NO and
peroxynitrite production, and neurotoxicity (
Kaushal et al., 2007
). Blocking
KCa3.1 channels
in vitro
with TRAM-34 inhibits p38 MAPK activation
(
Kaushal et al., 2007
). Further, intraocular injection of TRAM-34 reduced
retinal ganglion cell loss after optic nerve transection (
Kaushal et al., 2007
).
Other work has also shown that TRAM-34 reduces clinical disability and
proinflammatory cytokine production in experimental autoimmune
encephalomyelitis (EAE;
Reichetal.,2005
). KCa3.1 channel blockers were
also reported to reduce brain edema, intracranial pressure, and infarct
volume in animal model of acute subdural hematoma (
Mauler et al., 2004
),
