1237.2 Manipulation of the Glial Scar
Local infl ammation is an immediate consequence of neural injury and may lead to
progressive cavitation and exacerbation of the primary lesion. As injury pathology
progresses, local astrocytes activate to a reactive phenotype, exhibited by hypertro-
phy, in response to an intricate cascade of cytokine and growth factor signaling. The
reactive astrocytes then form a dense scar tissue in an effort to protect intact neural
networks from further damage [ 15 , 16 ]. Although scar tissue is primarily produced by
reactive astrocytes, the glial scar is a heterogeneous collection of many interacting cell
types, forming a complex system of dystrophic axons, reactive astrocytes, stromal
cells, activated microglia, and oligodendrocyte progenitors [ 17 – 23 ]. Leakage of blood
and serum elements into the CNS parenchyma is considered an integral event in the
formation of the glial scar. Most notably, however, astrocytes produce and deposit
chondroitin sulfate proteoglycan (CSPG) throughout the extracellular matrix (ECM)
within 24 h post-injury; high concentrations of CSPGs may persist at the injury site for
months [ 24 – 27 ]. Although literature suggests that the glial scar acts to prevent propa-
gation of the infl ammatory response to healthy tissue [ 16 , 28 – 30 ], it also serves as a
signifi cant barrier to axon regeneration [ 13 , 14 ]. As such, many groups are seeking
ways to break down or inhibit production and propagation of the glial scar. In particu-
lar, the direct administration (bolus or controlled release devices) of bacterial enzyme
chondroitinase ABC ( chABC) has shown to be effective in degrading the glial scar
and promoting axonal growth by cleaving CSPGs in animal models of SCI [ 31 – 34 ].
7.2.1 Direct Delivery of chABC
Application of chABCs has been extensively studied in experimental brain and spi-
nal cord injury models in attempts to delineate the enzyme’s infl uence on the dam-
aged CNS. chABC has traditionally been delivered to the injury site by bolus
injection, as several groups have demonstrated the effi cacy of intrathecal injections
of chABC in murine models [ 31 , 35 – 39 ]. Bradbury et al. fi rst demonstrated that
acute phase injections on alternating days up to 10 days post spinal cord injury was
suffi cient to promote CPSG degradation and functional recovery [ 31 ]. These results
were later corroborated by both Barritt et al. and Cheng et al., where acute phase
intrathecal injection of chABC post-SCI promoted CSPG degradation and subse-
quent axonal sprouting [ 37 , 38 ]. Further, Cheng et al. demonstrated the dose depen-
dence of chABC effi cacy, with high dose groups exhibiting subarachnoid
hemorrhages and death within 48 h of treatment [ 38 ]. In the brain, direct delivery via
infusion after rodent models of TBI and nigrostriatal damage demonstrate the ability
of chABC to locally degrade excessive CSPGs, thereby promoting axon regenera-
tion [ 40 , 41 ]. Moreover , bolus injection of chABC has demonstrated persistence in
a rodent model of TBI, sustaining decreased inhibitory CSPG levels out to 28 days
post injection [ 40 ]. Further, delayed chABC treatment in a rodent model of stroke
demonstrated similar benefi cial effects alongside behavioral recovery [ 31 ].
7 Regenerative Strategies for the Central Nervous System