Post-stroke remodeling processes in animal models and humans

Abstract

After cerebral ischemia, events like neural plasticity and tissue reorganization intervene in lesioned and non-lesioned areas of the brain. These processes are tightly related to functional improvement and successful rehabilitation in patients. Plastic remodeling in the brain is associated with limited spontaneous functional recovery in patients. Improvement depends on the initial deficit, size, nature and localization of the infarction, together with the sex and age of the patient, all of them affecting the favorable outcome of reorganization and repair of damaged areas. A better understanding of cerebral plasticity is pivotal to design effective therapeutic strategies. Experimental models and clinical studies have fueled the current understanding of the cellular and molecular processes responsible for plastic remodeling. In this review, we describe the known mechanisms, in patients and animal models, underlying cerebral reorganization and contributing to functional recovery after ischemic stroke. We also discuss the manipulations and therapies that can stimulate neural plasticity. We finally explore a new topic in the field of ischemic stroke pathophysiology, namely the brain-gut axis.

Keywords: Brain-gut axis; ischemia; microbiota; neuro-inflammation; recovery.

Figure 1.

Three schematic patterns of cerebral reorganization depending on lesion size or localization. Case n°1: Small brain lesions are associated with minor motor deficits, caused by injury to the primary motor cortex (M1) or corticospinal tract (CST). Cortical reorganization occurs within ipsilesional (blue) or contralesional (red) primary motor cortices. Case n°2: Medium lesions affect larger areas of the brain, thus causing moderate deficits. Reorganization relies either on perilesional direct motor tracts that may be reinforced (pink) or contralesional areas. Cortical origin of perilesional tracts possibly involved is indicated. Some pathways have been evidenced in rodents. Case n°3: Large lesions or lesions to specific brain areas, though not large in size, may cause severe deficits because of their key localization. Tracts from cortical areas that may be reinforced make relay onto motor nuclei forming alternate motor tracts that are therefore indirect. In each case, depending on severity and structural reserve, mechanisms may involve redundancy or vicariance: unmasking of existing redundant fibers, or short-distance and long-distance dendritic sprouting at cortical, sub-cortical, pontine or spinal levels, and takeover of novel functionalities by non-lesioned motor areas. Assuming that recovery depends on a large neuronal network, lesion size affects structural reserve, and being larger and larger, decreases the number of relevant potential connections, forces reorganization to take place in more distant cortical areas, thus affecting level of recovery. CST: corticospinal tract; M1: primary motor cortex; SMA: supplementary motor area; PMd: dorsal premotor cortex; PMv: ventral premotor cortex.

Figure 2.

Pathophysiological events and mechanisms of plasticity after stroke. Adaptive plasticity leading to good recovery is major during the first month post-onset. Maladaptive plasticity, when present and if untreated, may increase with time. Y-axis indicates the response, in terms of functional recovery, associated with the level of plasticity (adaptive or maladaptive) after stroke. The mechanisms underlying adaptive or maladaptive plasticity are indicated in the gray bars.

Figure 3.

Mechanisms of regeneration after stroke. During the acute and the chronic phases after stroke, angiogenesis, neuro- and gliogenesis need to be reestablished in the brain. Crucial mediators for angiogenesis are BDNF, VEGF, TGF-β, HIF and EPO. The excess of ECM has to be digested by MMPs. VEGF and BDNF also participate in neurogenesis and gliogenesis starting from neuronal and glia precursors in the neurogenic niches (i.e. the SVZ). Cell migration, differentiation and (trans)differentiation is triggered by CXCL12, Nestrin-1 and Neurod-1, in addition to VEGF and BDNF. To complete the regeneration process, factors like CK2, GAP-43, LIF, KLF7, CNTF favor axonal regrowth. Netrin-1, SHH, Sox17, Axin2, ATP and cAMP are involved in myelination. Finally, synaptogenesis is stimulated by IGF-1, TNF-α, CXCL12, CCL2, VEGF, eNOS, BDNF, FGF, CAP, MARCKS, SPRR1. Control mechanisms to avoid aberrant axonal growth that may inhibit regrowth include NogoA, Eph A4/A5, CSPG, PTEN, SOC-3. BBB: blood–brain barrier; BDNF: brain-derived neurotrophic factor; VEGF: vascular endothelial growth factor; TGF-β: transforming growth factor-beta; HIF: hypoxia-inducible factor; EPO: erythropoietin; ECM: extracellular matrix; MMPs: metalloproteinases; SVZ: subventricular zone; CXCL12: C-X-C motif chemokine ligand 12; GAP-43: growth associated protein 43; LIF: leukemia inhibitory factor; KLF7: Kruppel-like factor 7; CNTF: ciliary neurotrophic factor; SHH: sonic hedgehog signaling; ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate; IGF-1: insulin-like growth factor 1; TNF-α: tumor necrosis factor-alpha; CCL2: C-C motif chemokine ligand 2; eNOS: endothelial nitric oxide synthase; FGF: fibroblast growth factor; CAP: cortical cytoskeleton-associated protein; MARCKS: myristoylated alanine-rich C-kinase substrate; SPRR1: small proline repeat rich protein 1; CSPG: chondroitin sulfate proteoglycans; PTEN: phosphatase and tensin homolog; SOC-3: suppressor of cytokine signaling 3.

Figure 4.

Mechanisms of neuroinflammation after stroke. The first event happening is the BBB breakdown, together with neuronal injury/death and gliosis consequent to hypoxia. Gliosis includes activation of astrocytes (astrogliosis) and of microglia, with a switch from the anti-inflammatory to the pro-inflammatory phenotype. Gliosis is then characterized by the release of pro-inflammatory molecules, such as TNF-α, IL1β, IL6, CCL2, MIP-1α, MMPs, DAMPs, ROS, HMGB1. Additionally, activated astrocytes and microglia, together with fibroblasts and pericytes migrating from the meninges and the blood vessels, form a physical barrier called “glial scar” that contains inflammation. BBB rupture leads to the infiltration of immune cells, namely monocytes, leukocytes and DCs, which also release pro-inflammatory mediators (ROS, IFN-γ, NO, VCAM1, ICAM1, S1P3). The amplified inflammatory scenario causes secondary neurotoxic effects. In a later phase, Treg cells counteract CD4⁺ T-cell cytotoxic effects, initiating the protective phase. This phase is also characterized by the switch of microglia to the non-inflammatory phenotype and the release of TGF-β, which together with IL10, EPO, IGF1, IL13, IL4 favors neuroprotection. BBB: blood–brain barrier; TNF-α: tumor necrosis factor-alpha; IL1β: interleukin-1beta; IL6: interleukin-6; CCL2: C-C motif chemokine ligand 2; MIP-1α: macrophage inflammatory protein-1 alpha; MMPs: metalloproteinases; DAMPs: damage-associated molecular patterns; DCs: dendritic cells; ROS: reactive oxygen species; HMGB1: high mobility group box 1; IFN-γ: interferon gamma; NO: Nitric oxide; VCAM1: vascular cell adhesion protein 1; ICAM1: intercellular adhesion molecule 1; S1P3: sphingosine 1-phosphate receptor subtype 3; TGF-β: transforming growth factor-beta; IL10: interleukin-10; EPO: erythropoietin; IGF1: insulin-like growth factor-1; IL13: interleukin-13; IL4: interleukin-4.

Figure 5.

Schematic representation of the brain-gut axis in healthy and stroke conditions. In physiological conditions (left side), the communication between the brain and the gut occurs through the vagus nerve (part of the autonomic nervous system), the enteric nervous system and its cells (glia and neurons), the epithelium and commensal bacteria (microbiota). In this situation, the regulation of intestinal homeostasis and cerebroprotection are assured by bottom-up and top-down signaling, respectively. In stroke (middle and right side), the brain-gut communication is altered, with morphological and functional consequences in both directions. Specifically, stroke causes alteration in microbiota content and composition. This correlates with immune/inflammatory responses in the brain, through the interplay microbiota/immune system. Antibiotic treatment after stroke (post-stroke) causes impairment of the immune-mediated (T-reg) neuroprotective response in the brain and facilitates opportunistic infections. On the other hand, in mice, antibiotic treatment given before stroke induction (pre-stroke) revealed to worsen the outcome of the disease, with increased mortality and infarct volume. GABA: gamma-aminobutyric acid; Ach: acetylcholine; 5-HT: serotonin; SCFA: short-chain fatty acids.