Background and Purpose-Brain-derived neurotrophic factor (BDNF) is involved in neuronal survival, synaptic plasticity, learning and memory, and neuroplasticity. Further, exogenous treatment with BDNF or exposing animals to enrichment and exercise regimens, which also increase BDNF, enhances behavioral recovery after brain injury. Thus, the beneficial effects of rehabilitation in promoting recovery after stroke may also depend on BDNF. We tested this hypothesis by evaluating the contribution of BDNF to motor skill relearning after endothelin-1-induced middle cerebral artery occlusion in rats. Methods-Antisense BDNF oligonucleotide, which blocks the expression of BDNF (or saline vehicle) was infused into the contralateral lateral ventricle for 28 days after ischemia. Animals received either a graduated rehabilitation program, including running exercise and skilled reaching training, which simulates clinical practice, or no rehabilitation. Functional recovery was assessed with a battery of tests that measured skilled reaching, forelimb use asymmetry, and foraging ability. Results-Rehabilitation significantly improved skilled reaching ability in the staircase task. Antisense BDNF oligonucleotide effectively blocked BDNF mRNA, and negated the beneficial effects of rehabilitation on recovery of skilled reaching. Importantly, antisense BDNF oligonucleotide did not affect reaching with the unaffected limb, body weight, infarct size, or foraging ability, indicating the treatment was specific to relearning of motor skill after ischemia. Conclusions-This study is the first to identify a critical role for BDNF in rehabilitation-induced recovery after stroke, and our results suggest that new treatments to enhance BDNF would constitute a promising therapy for promoting recovery of function after stroke.

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In many recovering hemiparetic stroke patients, movement of the affected limb elicits ipsilateral activation of sensorimotor areas within the undamaged hemisphere, which is not observed in control subjects. Following middle cerebral artery occlusion, rats received intensive enriched-rehabilitation (ER) of the impaired forelimb for 4 weeks. Weekly assessments on a skilled reaching test demonstrated significant improvement in ischemic animals over 4 weeks of ER (P < 0.05). We hypothesized that if the undamaged forelimb motor cortex contributed to improved forelimb function, then inhibition of neural activity within this region should reinstate (at least some of) the initial motor impairment. After 3 and 4 weeks of ER, animals received a microinjection of lidocaine hydrochloride into the undamaged motor cortex and were re-assessed on reaching ability. The behavioral effect of lidocaine challenge was dependent on the size of the infarct: animals with large infarcts were rendered unable to retrieve any food pellets and had great difficulty even contacting a pellet with the affected forepaw. Small-infarct animals were only moderately affected (25% reduction in success) by lidocaine, an effect similar to that observed in control animals. Qualitative assessments of recovered reaching after 4 weeks of rehabilitation revealed that impairments in forelimb lift, advance and aim were exacerbated (P < 0.05) following lidocaine-inactivation of the undamaged motor cortex of animals with large ischemic infarcts. In animals with small infarcts, lidocaine challenge only impaired limb advance. Thus, recruitment of the undamaged hemisphere may depend on the functional integrity of the remaining sensorimotor system. These data suggest that, in the rat, the undamaged (ipsilateral) motor system may contribute to compensatory recovery of the affected forelimb.

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This study reaffirms the benefits of early rehabilitation for functional recovery after stroke. However, "tune-up" therapy provided no benefit in ischemic animals regardless of earlier rehabilitation experience. It is possible that alternative approaches in the chronic phase may prove more effective.

Previous studies have suggested that increased norepinephrine plays an important role in recovery of function after brain injury; however, the majority of these studies used drugs that are known to also affect other monoamines to increase or decrease norepinephrine. The purpose of the present study was to determine if norepinephrine is required to promote recovery after ischemia. A form of enriched rehabilitation was used to rehabilitate animals after ischemia and the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine was used to selectively destroy norepinephrine projections from the locus coeruleus. Three sensorimotor tests were used to evaluate the recovery of the animals. Depletion of norepinephrine improved sensorimotor recovery in standard-housed animals and did not impede recovery in the rehabilitation groups. Dopamine beta hydroxylase staining was used to confirm N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine-depleted terminal norepinephrine levels. The amount of norepinephrine terminal staining negatively correlated with recovery of function in the staircase test after ischemia. In addition, enriched rehabilitation increased, but depletion of norepinephrine had no effect on, brain-derived neurotrophic factor protein levels, which have also been linked to improved recovery of function. Together the above findings question the previously postulated role of norepinephrine in recovery of function after stroke.