Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation

Abstract

Recent laboratory findings suggest that it might be possible to promote cerebral plasticity and neurological recovery after stroke by use of exogenous pharmacological or cell-based treatments. Brain microvasculature and glial cells respond in concert to ischaemic stressors and treatment, creating an environment in which successful recovery can ensue. Neurons remote from and adjacent to the ischaemic lesion are enabled to sprout, and neural precursor cells that accumulate with cerebral microvessels in the perilesional tissue further stimulate brain plasticity and neurological recovery. These factors interact in a highly dynamic way, facilitating temporally and spatially orchestrated responses of brain networks. In view of the complexity of the systems involved, stroke treatments that stimulate and amplify these endogenous restorative mechanisms might also provoke unwanted side-effects. In experimental studies, adverse effects have been identified when neurorestorative treatments were administered to animals with severe associated illnesses, after thrombolysis with alteplase, and when therapies were initiated outside appropriate time windows. Balancing the opportunities and possible risks, we provide suggestions for the translation of restorative therapies from the laboratory to the clinic.

Figure 1. Contribution of lesion-remote plasticity to neurorestorative actions of pharmacological and cell-based therapies

(A) After ischaemia, injured axons that are part of the ipsilesional pyramidal tract degenerate. Brain tissue surrounding the infarct rim reorganises, and transcallosal fibres originating from the ipsilesional and contralesional motor cortex sprout. After treatment, the responses of transcallosal fibres are amplified. Fibres originating from the contralesional motor cortex grow out across the midline to innervate denervated target structures in the midbrain, brainstem, and spinal cord. (B) Example of corticobulbar plasticity at the level of the facial nucleus induced by the growth factor erythropoietin, which was intracerebroventricularly delivered in the subacute stroke phase, starting 3 days after ischaemia. Note the increase in fibres branching off the contralesional pyramidal tract to innervate the contralesional facial nucleus. Axonal fibre densities were assessed 7 weeks after the initiation of treatment by the anterograde tract tracer biotinylated dextran amine, which was injected into the contralesional motor cortex. (C) Representative microphotographs of fibres emanating from the pyramidal tract. Adapted from Reitmeir and colleagues, by permission of Oxford University Press. Data are mean (SD). *p<0.05 compared with non-ischaemic vehicle. †p<0.05 with ischaemic vehicle, ANOVA followed by least significant difference tests.

Figure 2. Interaction of microvascular cells with neuroblasts during post-ischaemic brain remodelling

Following ischaemia, neuroblasts (green [DCX-GFP] in upper micrograph) closely associate with cerebral microvessels (lumen stained in red [rhodamine-labelled dextran, systemically injected before animal sacrifice]; nuclei counterstained in blue [DAPI]). Via release of growth and differentiation factors, microvascular cells and neuroblasts foster neuronal survival and plasticity, and modulate glial responses and immune reactions in the brain. CD45=CD45 antigen. DAPI=4’,6-diamidino-2-phenylindole. DCX-GFP=green-fluorescent-protein-labelled doublecortin. GFAP=glial acidic fibrillary protein. Tuj-1=neuron-specific class III β-tubulin.

Figure 3. Effect of neuronal activity on brain environment, neuronal signalling, and axonal growth

Glial cells, blood vessels, and neuroblasts provide basic trophic support, having rather low selectivity for brain regions and neuronal populations. Together, they represent the stage for plasticity processes in the brain. Neuronal activity, which is temporospatially tuned and specific to the brain region and cell type, reshapes this environment, enabling temporally and spatially organised axonal growth, and promoting the proficiency and virtuosity of brain networks.