Hyaluronidases as Targets for the Treatment of Neurological Diseases

Hyaluronan (HA) is a glycosaminoglycan synthesized at the cell membrane that can exist in numerous states in the extracellular matrix, including in ternary complexes with proteoglycans such as aggrecan and neurocan. HA synthesis is elevated following a wide variety of insults to the central nervous system (CNS) including neuroinflammatory disease, ischemia, and various forms of dementia. Recent studies have demonstrated that, in conjunction with increased HA synthesis, the expression and activities of hyaluronidases that digest HA are also elevated in the injured CNS. While high molecular weight forms of HA have their own functions that can be disrupted by hyaluronidases, digestion products of HA generated by these hyaluronidases have their own, distinct biological activities that can impact recovery from CNS damage. Here, we review some of the conditions and diseases in which hyaluronidase activity can play a role in preventing CNS repair and discuss the potential ways that hyaluronidase inhibitors could be used as therapeutic agents.