Epidermal Growth Factor and Erythropoietin Infusion Accelerate Functional Recovery in Combination With Rehabilitation

Abstract

Sixty-seven male Sprague-Dawley rats were matched for poststroke grasping/retrieving performance on the staircase test and randomized into 4 groups: rehabilitation+EGF/erythropoietin (n=13), rehabilitation+artificial cerebrospinal fluid (aCSF; n=12), no rehabilitation+EGF/erythropoietin (n=12), and no rehabilitation+aCSF (n=13). All procedures were approved by the Memorial University Animal Care Committee and comply with regulations set by the Canadian Council of Animal Care (see detailed Methods in the online-only Data Supplement). Behavioral TestingAnimals were trained on the staircase (pellet grasping/retrieving), beam (paw placement/balance), and cylinder (asymmetrical limb use for postural support) tasks 2 weeks before ischemia, and baseline abilities were assessed 3 days before stroke. Subsequent testing was performed 5 days after stroke and at poststroke weeks 4, 7, and 10 ( Figure 1). Animals that did not meet preset training performance criteria (n=5), or were functionally unimpaired after stroke (n=12), were excluded. Behavioral data are presented as a percentage of prestroke performance. Surgical ProceduresAfter baseline behavioral testing, rats were anesthetized with isoflurane and delivered 2 stereotaxic injections of endothelin-1 (2 μL/ Background and Purpose-Rehabilitation is the only treatment option for chronic stroke deficits, but unfortunately, it often provides incomplete recovery. In this study, a novel combination of growth factor administration and rehabilitation therapy was used to facilitate functional recovery in a rat model of cortical stroke. Methods-Ischemia was induced via injection of endothelin-1 into the sensorimotor cortex. This was followed by either a 2-week infusion of epidermal growth factor and erythropoietin or artificial cerebrospinal fluid into the ipsilateral lateral ventricle. Two weeks after ischemia, animals began an 8-week enriched rehabilitation program. Functional recovery was assessed after ischemia using the Montoya staircase-reaching task, beam-traversing, and cylinder test of forelimb asymmetry. Results-The combination of growth factor infusion and rehabilitation led to a significant acceleration in recovery in the staircase task. When compared with controls, animals receiving the combination treatment attained significant recovery of function at 4 weeks after stroke, whereas those receiving rehabilitation alone did not recover until 10 weeks. Significant recovery was also observed on the beam-traversing and cylinder tasks. Conclusions-Combining behavioral rehabilitation with growth factor infusion accelerates motor recovery. These data suggest a promising new avenue of combination therapies that may have the potential to reduce the rehabilitation time necessary to recover from sensorimotor deficits arising from stroke.

Synergistic Effects of Enriched Environment and Task-Specific Reach Training on Poststroke Recovery of Motor Function

“…This concept is underscored by recent evidence that further combination of reaching+enrichment with application of neuroplasticity-promoting factors accelerates the rate of recovery beyond what is possible with only reachi ng+enrichment. 6,25,30 The secondary objective of the study was to assess the generalizability of a recent predictive model of stroke recovery across rodent forelimb grasping tasks. Previously, we demonstrated that rehabilitation intensity, cortical infarct volume, and initial poststroke impairment could be used to predict the final level of forelimb recovery in the Montoya staircase task.…”

“…3 Previous rodent focal ischemia experiments indicate that environmental enrichment in combination with intensive taskspecific rehabilitation (ie, reach training) promotes recovery of both task-specific (ie, staircase/single pellet) and generalized motor functions (ie, beam walking/cylinder). [4][5][6] Surprisingly, despite the efficacy of this rehabilitation strategy, the respective contribution of each of these components to functional recovery has not been directly compared.…”

“…16,27 A similar concept has been successfully applied in previous studies by combining rehabilitation therapy with administration of various plasticity-promoting factors. 6,16,18,25,[28][29][30] The primary objective of the study sought to assess the efficacy of this adjunctive treatment strategy by using environmental enrichment and task-specific reach training both independently and in combination. We hypothesized that coadministration of these therapies would have a synergistic effect on motor recovery resulting in superior performance than either element alone.…”

The Effects of Delayed Reduction of Tonic Inhibition on Ischemic Lesion and Sensorimotor Function

“…40 In two studies by Biernaskie and Corbett, 40 after stereotaxic microinjection of ET-1 to the distal portion of the middle cerebral artery, recovery to~50% of prestroke ability on the Montoya staircase test was shown by 40 days after ischemic insult with enriched rehabilitation therapy initiated within the first week after stroke. Jeffers et al 24 in turn reported that after 2 weeks of epidermal growth factor and erythropoietin infusion into the ipsilateral ventricle and an additional 2 weeks of enriched rehabilitation therapy, animals recovered to~55% of their prestroke performance; and further on, at 10 weeks after stroke, reached~60% of their prestroke performance level. Of note, however, Biernaskie et al and Jeffers et al observed more severe deficits in skilled reaching ability 1 week after ischemic insult (~20% and~25% of prestroke performance, respectively) than those observed in the present study (~34% of prestroke performance).…”

How Can You Mend a Broken Brain? - Neurorestorative Approaches to Stroke Recovery

“…After stroke, skilled use of the affected hand (or paw) is highly resistant to recovery in both humans and animals. In rats, enriched rehabilitation produces substantial improvements in the recovery of skilled reaching [25,34,35,36,67]. The protocol consists of enriched housing ( a ) and/or running exercise ( b ) in combination with several hours of daily reach training ( c ) of the impaired limb.…”