ABSTRACT
Clinical and laboratory studies have suggested that amphetamine treatment when paired with rehabilitation results in improved recovery of function after stroke or traumatic brain injury. In the present study, we investigated whether new anatomical pathways developed in association with improved motor function after brain damage and amphetamine treatment linked with rehabilitation. Following a unilateral sensorimotor cortex lesion in the adult rat, amphetamine (2 mg/kg) was administered in conjunction with physiotherapy sessions on postoperative days two and five. Physiotherapy was continued twice daily for the first 3 weeks after injury, and then once daily until week six. Performance on skilled forelimb reaching and ladder rung walking was used to assess motor improvement. Our results show that animals with sensorimotor cortical lesions receiving amphetamine treatment linked with rehabilitation had significant improvement in both tasks. Neuroanatomical tracing of efferent pathways from the opposite, non-damaged cortex resulted in the novel finding that amphetamine treatment linked with rehabilitation, significantly increased axonal growth in the deafferented basilar pontine nuclei. These results support the notion that pharmacological interventions paired with rehabilitation can enhance neuronal plasticity and thereby improve functional recovery after CNS injury.
Subject(s)
Amphetamine/pharmacology , Brain Injuries/drug therapy , Brain Injuries/rehabilitation , Motor Cortex/drug effects , Neuronal Plasticity/drug effects , Recovery of Function/drug effects , Amphetamine/therapeutic use , Animals , Axons/drug effects , Axons/physiology , Axons/ultrastructure , Biotin/analogs & derivatives , Brain Injuries/physiopathology , Central Nervous System Stimulants/pharmacology , Central Nervous System Stimulants/therapeutic use , Dextrans , Disease Models, Animal , Efferent Pathways/drug effects , Efferent Pathways/physiology , Growth Cones/drug effects , Growth Cones/physiology , Growth Cones/ultrastructure , Male , Motor Cortex/injuries , Motor Cortex/physiopathology , Nerve Regeneration/drug effects , Nerve Regeneration/physiology , Neuronal Plasticity/physiology , Paresis/drug therapy , Paresis/physiopathology , Paresis/rehabilitation , Physical Therapy Modalities , Pyramidal Tracts/drug effects , Pyramidal Tracts/physiology , Rats , Rats, Long-Evans , Recovery of Function/physiology , Treatment OutcomeABSTRACT
Our work has shown that following focal ischemic lesion in adult rats, neutralization of the axon growth inhibitor Nogo-A with the monoclonal antibody (mAb) IN-1 results in functional recovery. Furthermore, new axonal connections were formed from the contralesional cortex to subcortical areas corresponding to the observed functional recovery. The present study investigated whether dendritic changes, also known to subserve functional recovery, paralleled the axonal plasticity shown after ischemic lesion and treatment with mAb IN-1. Golgi-Cox-stained layer V pyramidal neurons in the contralesional sensorimotor cortex were examined for evidence of dendritic sprouting. Results demonstrated increased dendritic arborization and spine density in the mAb IN-1-treated animals with lesion. Interestingly, administration of mAb IN-1 without lesion resulted in transient dendritic outgrowth with no change in spine density. These results suggest a novel role for Nogo-A in limiting dendritic plasticity after stroke.
Subject(s)
Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Dendrites/pathology , Myelin Proteins/metabolism , Neuronal Plasticity , Stroke/metabolism , Stroke/pathology , Animals , Axons/metabolism , Axons/pathology , Dendrites/metabolism , Male , Middle Cerebral Artery/surgery , Nerve Regeneration/physiology , Nogo Proteins , Rats , Rats, Long-Evans , Tissue DistributionABSTRACT
Stroke is a prevalent and devastating disorder, and no treatment is currently available to restore lost neuronal function after stroke. One unique therapy that improves recovery after stroke is neutralization of the neurite inhibitory protein Nogo-A. Here, we show, in a clinically relevant model, improved functional recovery and brain reorganization in the aged and adult rat when delayed anti-Nogo-A therapy is given after ischemic injury. These results support the efficacy of Nogo-A neutralization as treatment for ischemic stroke, even in the aged animal and after a 1-week delay, and implicate neuronal plasticity from unlesioned areas of the central nervous system as a mechanism for recovery.
Subject(s)
Antibodies, Monoclonal/pharmacology , Myelin Proteins/antagonists & inhibitors , Recovery of Function , Stroke/physiopathology , Stroke/therapy , Age Factors , Animals , Brain Ischemia/physiopathology , Brain Ischemia/therapy , Disease Models, Animal , Myelin Proteins/immunology , Neurites/physiology , Neuronal Plasticity , Nogo Proteins , RatsABSTRACT
Neuronal death due to ischemic stroke results in permanent deficits in sensory, language, and motor functions. The growth-restrictive environment of the adult central nervous system (CNS) is an obstacle to functional recovery after stroke and other CNS injuries. In this regard, Nogo-A is a potent neurite growth-inhibitory protein known to restrict neuronal plasticity in adults. Previously, we have found that treatment with monoclonal antibody (mAb) IN-1 to neutralize Nogo-A immediately after stroke enhanced motor cortico-efferent plasticity and recovery of skilled forelimb function in rats. However, immediate treatment for stroke is often not clinically feasible. Thus, the present study was undertaken to determine whether cortico-efferent plasticity and functional recovery would occur if treatment with mAb IN-1 was delayed 1 week after stroke. Adult rats were trained on a forelimb-reaching task, and the middle cerebral artery was occluded to induce focal cerebral ischemia to the forelimb sensorimotor cortex. After 1 week, animals received mAb IN-1 treatment, control antibody, or no treatment, and were tested for 9 more weeks. To assess cortico-efferent plasticity, the sensorimotor cortex opposite the stroke lesion was injected with an anterograde neuroanatomical tracer. Behavioral analysis demonstrated a recovery of skilled forelimb function, and anatomical studies revealed neuroplasticity at the level of the red nucleus in animals treated with mAb IN-1, thus demonstrating the efficacy of this treatment even if administered 1 week after stroke.
