Table 2.
Mechanism | Effects | Reference(s) |
---|---|---|
Endothelial glycocalyx (EG) | ||
EG heparan sulfate (HS) degradation by multiple mechanisms (see Table 1) | Increased blood-brain barrier (BBB) permeability evidenced by increased edema and leukocyte infiltration of brain interstitium | (7, 31–37, 40) |
Neuroinflammation | ||
HPSE overexpression | Attenuates endotoxin-induced neuroinflammation | (42) |
Activation of TLR pathway by HSPGs and biglycan | Stimulates microglial activation and their production of proinflammatory cytokines TNFα and IL-1β in culture and rodent subarachnoid hemorrhage (SAH) | (11, 50, 56, 57) |
Binding of LAR and CD44 by CSPGs | Facilitates microglial activation and upregulates their expression of MMPs in vitro | (55, 108) |
HS activation of TGF-β | Induces microglial activation and increased CSPG production by activated microglia and astrocytes in vitro | (52, 53, 109) |
Glial scar | ||
Binding of LAR and RPTPσ by CSPGs | Facilitates inhibition of axon growth through several common signaling pathways including Rho/ROCK, mTOR and Erk, as well as distinct effects through cofilin and PKC. Disruption ofcytoskeletal assembly and autophagic flux near growth cones are a few of the downstream effects that inhibit axon regrowth | (69, 70, 108) |
Binding of NgR1 and NgR3 by CSPGs | Inhibits axon outgrowth presumably by enhancing myelin-associated inhibitor activity through Rho/ROCK mechanisms | (70) |
Binding of RPTPσ to HSPGs | Competes with CSPGs for the binding domain and promotes axon extension by oligomerizing RPTPσ and inhibiting its downstream effects | (70, 86) |
Antagonism of TGF-β by decorin | Decreases fibrosis, CSPG expression and promotes neural regeneration both in culture and across in vivo models of TBI, SCI, and SAH | (57, 90, 91) |
CNS, central nervous system; CSPG, chondroitin sulfate proteoglycan; HSPG, heparan sulfate proteoglycan; LAR, leukocyte common antigen-related phosphatase; MMP, matrix-metalloproteinase; mTOR, mammalian target of rapamycin; SCI, spinal cord injury; TBI, traumatic brain injury; TLR, Toll-like receptor.