Effect of Inhibition of DNA Methylation Combined with Task-Specific Training on Chronic Stroke Recovery

Abstract

To develop new rehabilitation therapies for chronic stroke, this study examined the effectiveness of task-specific training (TST) and TST combined with DNA methyltransferase inhibitor in chronic stroke recovery. Eight weeks after photothrombotic stroke, 5-Aza-2′-deoxycytidine (5-Aza-dC) infusion was done on the contralesional cortex for four weeks, with and without TST. Functional recovery was assessed using the staircase test, the cylinder test, and the modified neurological severity score (mNSS). Axonal plasticity and expression of brain-derived neurotrophic factor (BDNF) were determined in the contralateral motor cortex. TST and TST combined with 5-Aza-dC significantly improved the skilled reaching ability in the staircase test and ameliorated mNSS scores and cylinder test performance. TST and TST with 5-Aza-dC significantly increased the crossing fibers from the contralesional red nucleus, reticular formation in medullar oblongata, and dorsolateral spinal cord. Mature BDNF was significantly upregulated by TST and TST combined with 5-Azd-dC. Functional recovery after chronic stroke may involve axonal plasticity and increased mature BDNF by modulating DNA methylation in the contralesional cortex. Our results suggest that combined therapy to enhance axonal plasticity based on TST and 5-Aza-dC constitutes a promising approach for promoting the recovery of function in the chronic stage of stroke.

Sequential Transcriptome Changes in the Penumbra after Ischemic Stroke

“…The primary purpose of this study was to understand the differences in gene expression that occur over time after stroke. Based on previous studies demonstrating time-specific differences after injury in the rat photothrombosis model [23], we distinguished systematically the brain after stroke at the acute (1 week post-injury), subacute (4 weeks post-injury), and chronic (8 weeks post-injury) phases. The advantage of the photothrombosis model is the ability to generate an injury with a similar size within distinct functional areas of the cortex; thus, this model is suitable for assessing the overall pattern of genetic alterations that occur after stroke [24,25].…”

“…The intact areas of ipsilateral and contralateral hemispheres were measured using ImageJ software, then the volume of intact hemisphere was calculated (intact area: × 0.04 × 20) and summed among the slices. The total infarction volume was determined: the volume of contralateral hemisphere in comparison to the volume of intact area in the ipsilateral hemisphere [23,38].…”

“…mNSS consists of a motor, sensory, reflex and balance test. Scores ranged from 0 to maximum of 14 [23]. When the rat was unable to perform the task due to neurological dysfunction, it was given one point for each task.…”

“…The experimenter then suddenly clapped and observed the response of the rat. When the rat was startled by a sudden noise, the score was zero; if not, the score was one [23].…”

The Lipid Elongation Enzyme ELOVL2 is a molecular regulator of aging in the retina

“…In particular, increased DNA methylation within the CpG island overlapping with the promoter of ELOVL2 was tightly correlated with the age of the individual 33 . We attempted to demethylate this region using 5-Aza-dc, known to inhibit the function of DNMTs also in nondividing neurons [23][24][25] . We reported that upon intravitreal injection of the compound, the DNA methylation is reduced, gene expression is upregulated, and visual function is maintained in the treated eye compared with the contralateral control.…”