Delayed treatment with chondroitinase ABC promotes sensorimotor recovery and plasticity after stroke in aged rats

Abstract

Stroke is the dominant cause of sensorimotor disability that primarily affects the elderly. We now show that neuroplasticity and functional recovery after stroke is constrained by inhibitory chondroitin sulphates. In two blinded, randomized preclinical trials, degradation of chondroitin sulphate using chondroitinase ABC reactivated neuroplasticity and promoted sensorimotor recovery after stroke in elderly rats. Three days after stroke, chondroitinase ABC was microinjected into the cervical spinal cord to induce localized plasticity of forelimb sensorimotor spinal circuitry. Chondroitinase ABC effectively removed chondroitin sulphate from the extracellular matrix and perineuronal nets. Three different tests of sensorimotor function showed that chondroitinase ABC promoted recovery of forelimb function. Anterograde and retrograde tracing showed that chondroitinase ABC also induced sprouting of the contralesional corticospinal tract in the aged treated hemicord. Chondroitinase ABC did not neuroprotect the peri-infarct region. We show for the first time delayed chondroitinase ABC treatment promotes neuroanatomical and functional recovery after focal ischaemic stroke in an elderly nervous system.

Exercise and Environmental Enrichment as Enablers of Task-Specific Neuroplasticity and Stroke Recovery

“…Exposing animals to poststroke EE and exercise decreases the expression of PNNs and Nogo A in perilesional tissue [60,61], potentially contributing to the observed functional recovery. Similarly, treating poststroke animals with anti-Nogo A antibody or PNN-digesting chondroitinase ABC is associated with enhanced axonal plasticity and enhanced recovery [62,63]. Together, these findings suggest that exercise and EE contribute to the induction of a permissive environment for structural remodeling of neural networks by decreasing the involvement of growth inhibitory molecules.…”

Hippocampal Extracellular Matrix Levels and Stochasticity in Synaptic Protein Expression Increase with Age and Are Associated with Age-dependent Cognitive Decline

“…Yamada and Jinno, for instance, reported age-dependent alterations in hippocampal ECM localization and composition in subjects up to one year of age (49). In addition, reducing cortical ECM levels in aged rats reactivates plasticity, both in sensorimotor cortex (50) and in visual cortex (51). Finally, increased expression of ECM proteins, in particular heparin sulfate proteoglycans, is associated with Alzheimer disease pathology (reviewed in Ref.…”

“…Here, we made use of iTRAQ 1 technology and high-coverage mass spectrometry to study the effects of aging on the proteomic composition of mouse hippocampal synaptosomes. We investigated the synaptic proteomes of individual mice at 20,40,50,60,70,80,90, and 100 weeks of age. Our findings show that both specific changes and increased variance in synaptic protein expression are associated with age-related cognitive decline.…”

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

“…Rehabilitation may enhance functional integration and wiring of newly generated or transplanted neurons (Winstein et al, 2016). Targeting the desired neural pathways with specific rehabilitative tasks simultaneously with delivered cells or drugs may stimulate the reestablishment of appropriate functional connections and discourage the formation of aberrant ones; this was demonstrated with the use of ChABC to produce task-specific recovery (Soleman et al, 2012). Furthermore, recovery of fine motor skills appears to be dependent on receiving the proper type of training; animals that received training in gross locomotor skills performed worse in fine motor tasks than those which received no treatment (García-Alías et al, 2009).…”