Plasticity beyond peri-infarct cortex: Spinal up regulation of structural plasticity, neurotrophins, and inflammatory cytokines during recovery from cortical stroke

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Plasticity beyond peri-infarct cortex: Spinal up regulation of structural plasticity, neurotrophins, and inflammatory cytokines during recovery from cortical stroke

• Bernice Sist^{a, d,} ,
• Karim Fouad^{a, b,} ,
• Ian R. Winship^{a, c, d, ,}

• ^a Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G 2R3
• ^b Faculty of Rehabilitative Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2R3
• ^c Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada T6G 2R3
• ^d Neurochemical Research Unit, University of Alberta, Edmonton, Alberta, Canada T6G 2R3

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Highlights

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Cortical stroke induces heightened expression of GAP-43 in the spinal cord

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Plasticity in the spinal cord after cortical stroke has a finite temporal window

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TNF-α, IL-6, and NT-3 protein levels in spinal cord correlate with GAP-43 levels

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BDNF increases transiently in spinal cord prior to heightened GAP-43 expression

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Abstract

Stroke induces pathophysiological and adaptive processes in regions proximal and distal to the infarct. Recent studies suggest that plasticity at the level of the spinal cord may contribute to sensorimotor recovery after cortical stroke. Here, we compare the time course of heightened structural plasticity in the spinal cord against the temporal profile of cortical plasticity and spontaneous behavioural recovery. To examine the relation between trophic and inflammatory effectors and spinal structural plasticity, spinal expression of brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured. Growth-associated protein 43 (GAP-43), measured at 3, 7, 14, or 28 days after photothrombotic stroke of the forelimb sensorimotor cortex (FL-SMC) to provide an index of periods of heightened structural plasticity, varied as a function of lesion size and time after stroke in the cortical hemispheres and the spinal cord. Notably, GAP-43 levels in the cervical spinal cord were significantly increased after FL-SMC lesion, but the temporal window of elevated structural plasticity was more finite in spinal cord relative to ipsilesional cortical expression (returning to baseline levels by 28 post-stroke). Peak GAP-43 expression in spinal cord occurred during periods of accelerated spontaneous recovery, as measured on the Montoya Staircase reaching task, and returned to baseline as recovery plateaued. Interestingly, spinal GAP-43 levels were significantly correlated with spinal levels of the inflammatory cytokines TNF-α and IL-6 as well as the neurotrophin NT-3, while a transient increase in BDNF levels preceded elevated GAP-43 expression. These data identify a significant but time-limited window of heightened structural plasticity in the spinal cord following stroke that correlates with spontaneous recovery and the spinal expression of inflammatory cytokines and neurotrophic factors.

Abbreviations

• IC, ipsilesional cortex;
• CC, contralesional cortex;
• CSC, cervical spinal cord;
• LSC, lumbar spinal cord;
• FL-SMC, forelimb sensorimotor cortex;
• GAP-43, growth associated protein-43;
• TNF-α, tumor necrosis factor - alpha;
• IL-6, interleukin 6;
• BDNF, brain derived neurotrophic factor;
• NT-3, neurotrophin-3

Keywords

• Ischemia;
• Sensorimotor cortex;
• Plasticity;
• Spinal cord;
• Inflammation;
• Neurotrophins;
• GAP-43;
• TNF-alpha;
• IL-6;
• BDNF;
• NT-3