CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Abstract

Spinal cord and brain injuries lead to complex cellular and molecular interactions within the central nervous system in an attempt to repair the initial tissue damage. Many studies have illustrated the importance of the glial cell response to injury, and the influences of inflammation and wound healing processes on the overall morbidity and permanent disability that result. The abortive attempts of neuronal regeneration after spinal cord injury are influenced by inflammatory cell activation, reactive astrogliosis and the production of both growth promoting and inhibitory extracellular molecules. Despite the historical perspective that the glial scar was a mechanical barrier to regeneration, inhibitory molecules in the forming scar and methods to overcome them have suggested molecular modification strategies to allow neuronal growth and functional regeneration. Unlike myelin associated inhibitory molecules, which remain at largely static levels before and after central nervous system trauma, inhibitory extracellular matrix molecules are dramatically upregulated during the inflammatory stages after injury providing a window of opportunity for the delivery of candidate therapeutic interventions. While high dose methylprednisolone steroid therapy alone has not proved to be the solution to this difficult clinical problem, other strategies for modulating inflammation and changing the make up of inhibitory molecules in the extracellular matrix are providing robust evidence that rehabilitation after spinal cord and brain injury has the potential to significantly change the outcome for what was once thought to be permanent disability.

Sialidase enhances recovery from spinal cord contusion injury

“…T he injured CNS is highly inhibitory for axon regeneration, severely limiting functional recovery (1). This results in part from axon regeneration inhibitors (ARIs) that accumulate at injury sites, including molecules on residual myelin [i.e., myelinassociated glycoprotein (MAG), NogoA, and oligodendrocytemyelin glycoprotein) and chondroitin sulfate proteoglycans on astrocytes in the glial scar (2)(3)(4)(5).…”

Soluble complement receptor type 1 inhibits complement system activation and improves motor function in acute spinal cord injury

“…14 Neutrophils are the main inflammatory cells in acute immune inflammatory reactions. MPO is a specific enzyme present in large quantities in azurophilic granules of neutrophils, contributing to its oxygen-dependent bactericidal activity.…”

The Role of the Brain Extracellular Matrix in Synaptic Plasticity After Brain Injuries (Review)

“…It had been shown that components of the glial scar might interact with ECM molecules [26] via numerous receptors [82][83][84], such as neurocan [85], PTPσR [86,87], CSPGs [87][88][89] etc., preventing axonal regeneration [26]. Particularly, an interaction between astrocytes and CSPGs inhibits regeneration abilities [5].…”

“…The remodeling of ECM had been demonstrated to take place after brain traumas and in the development of neurodegenerative disorders and in epilepsy. Transgenic animals lacking or having a deficient ECM structure tend to develop an epileptiform activity and characteristic changes of Mossy fibers and granule cells functioning [2,22,23], and astrogliosis [2,[24][25][26]. Additionally, ECM molecular net mechanically restricts diffusion of molecules in the extracellular space [27,28], diffusion of ions and lateral diffusion of receptors in the cell membrane [29,30].…”