Nogo-A expression after focal ischemic stroke in the adult rat.

BACKGROUND AND PURPOSE: The Nogo-A protein is an important inhibitor of axonal remodeling after central nervous system injuries, including ischemic stroke. Interfering with the function of Nogo-A via infusion of a therapeutic anti-Nogo-A antibody after stroke increases neuronal remodeling and enhances functional recovery in rats. In this study, we describe the regional distribution of cortical neurons expressing Nogo-A in normal rats and following middle cerebral artery occlusion (MCAO). METHODS: Normal and post-MCAO neuronal Nogo-A expression were described via immunohistochemical analyses. All brains were processed for Nogo-A and parvalbumin expression. The level of Nogo-A expression was scored for each cortical area or white matter structure of interest. The number and fluorescent intensity of layer V neurons in contralesional sensorimotor forelimb cortex were also assessed at each time point. RESULTS: Nogo-A expression was observed in both cortical pyramidal neurons and parvalbumin-positive interneurons. Neuronal expression of Nogo-A changed over time in ipsilesional and contralesional cortical areas after MCAO, becoming globally elevated at 28 days after stroke. Nogo-A expression was not observed to fluctuate greatly in the white matter after stroke, with the exception of a transient increase in Nogo-A expression in the external capsule near the stroke lesion. CONCLUSIONS: Neuronal Nogo-A expression is significantly increased at 28 days post-MCAO in all examined brain regions. Because of their robust expression of Nogo-A after stroke lesion, both excitatory and inhibitory neurons represent potential targets for anti-Nogo-A therapies in the poststroke cerebral cortex.

Neuronal plasticity and functional recovery after ischemic stroke.

Ischemic stroke affects many new patients each year. The sequelae of brain ischemia can include lasting sensorimotor and cognitive deficits, which negatively impact quality of life. Currently, treatment options for improving poststroke deficits are limited, and the development of new clinical alternatives to improve functional recovery after stroke is actively under investigation. Anti-Nogo-A immunotherapy to reduce the central nervous system inhibitory environment, cell transplantation strategies, pharmacological agents, and movement-based therapies represent emerging treatments of poststroke deficits through enhancement of neuroanatomical plasticity.

Intrathecal treatment with anti-Nogo-A antibody improves functional recovery in adult rats after stroke.

Stroke often results in devastating neurological disabilities with no specific treatment available to improve functional recovery. Neurite growth inhibitory proteins such as Nogo-A play a critical role in impeding regain of function after stroke. We have reported that treatment with anti-Nogo-A antibody using the intracerebroventricular route resulted in improvement of function and neuroplasticity in adult or aged rats after stroke. This present study tested a more clinically accessible route for applying anti-Nogo-A antibodies, the intrathecal route. Anti-Nogo-A or control antibody was administered intrathecally at lower lumbar levels 1 week after middle cerebral artery occlusion in adult rats. Our results show that anti-Nogo-A antibody delivered by this intrathecal route for 2 weeks penetrated into brain parenchyma and bound to myelin-enriched structures such as the corpus callosum and striatal white matter. Animals receiving anti-Nogo-A antibody treatment significantly improved recovery of function on the skilled forelimb reaching task as compared to stroke only and stroke/control antibody animals. These findings show that anti-Nogo-A antibody delivered through the intrathecal route is as effective in restoring lost functions after stroke as the intracerebroventricular route. This is of great importance for the future application of anti-Nogo-A immunotherapy for ischemic stroke treatment.

Axonal plasticity is associated with motor recovery following amphetamine treatment combined with rehabilitation after brain injury in the adult rat.

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.

Experimental diabetes attenuates cerebral cortical-evoked forelimb motor responses.

Poorly controlled diabetes leads to debilitating peripheral complications, including retinopathy, nephropathy, and neuropathy. Chronic diabetes also impairs the central nervous system (CNS), leading to measurable deficits in cognition, somatosensory, and motor function. The cause of diabetes-associated CNS impairment is unknown. In this study, sustained hyperglycemia resulting from insulin deficiency was shown to contribute to CNS motor dysfunction. Experimental diabetes was induced in rats by streptozotocin (STZ) injection. CNS motor function was assessed by intracortical microstimulation of the sensorimotor cortex. Experimental diabetes significantly (P < 0.01; n = 14) attenuated the number of motor cortical sites eliciting forelimb movements. The net area of the motor cortex representing the forelimb in diabetic rats was significantly reduced (4.0 +/- 0.5 [control] vs. 2.4 +/- 0.4 [STZ] mm(2); P < 0.05). Experimental diabetes attenuated the activation of some, but not all, forelimb motor cortical neurons. Insulin treatment of diabetic rats prevented the attenuation of cortical-evoked forelimb responses. Peripheral nerve-evoked responses were unaffected by this short period of diabetes, suggesting the absence of peripheral nerve dysfunction. This study showed that metabolic imbalance resulting from insulin deficiency elicits a marked attenuation of cortical-evoked motor function. Uncontrolled hyperglycemia, deficiencies of central insulin, or both may contribute to corticospinal motor dysfunction.

Behavioral recovery and anatomical plasticity in adult rats after cortical lesion and treatment with monoclonal antibody IN-1.

We have previously reported that monoclonal antibody (mAb) IN-1 treatment after ischemic infarct in adult rats results in significant recovery of skilled forelimb use. Such recovery was correlated with axonal outgrowth from the intact, opposite motor cortex into deafferented subcortical motor areas. In the present study, we investigated the effects of mAb IN-1 treatment after adult sensorimotor cortex (SMC) aspiration lesion on behavioral recovery and neuroanatomical plasticity in the corticospinal tract. Adult rats underwent unilateral SMC aspiration lesion and treatment with either mAb IN-1 or a control Ab, or no treatment. Animals were then tested over a 6-week period in the skilled forelimb use task and the skilled ladder rung walking task. We found that animals treated with mAb IN-1 after SMC lesion fully recovered the use of forelimb reaching, but showed no improvement in digit grasping as tested in the skilled forelimb use task. The mAb IN-1 treatment group was also significantly improved as compared to control groups in the skilled ladder rung walking test. Furthermore, neuroanatomical tracing revealed a significant increase in the corticospinal projections into the deafferented motor areas of the spinal cord after mAb IN-1 treatment. These results indicate that treatment with mAb IN-1 after cortical aspiration lesion induces remodeling of motor pathways resulting in recovery in only certain behavioral tasks, suggesting that the cause of brain damage influences behavioral recovery after mAb IN-1 treatment.

Functional reorganization of the motor cortex in adult rats after cortical lesion and treatment with monoclonal antibody IN-1.

We previously reported anatomical plasticity in the adult motor cortex after a unilateral sensorimotor cortex (SMC) lesion and treatment with monoclonal antibody (mAb) IN-1, which permits neurite outgrowth from the intact, opposite cortex into deafferented subcortical targets. This study was designed to investigate whether treatment with the mAb IN-1 after SMC lesion in the adult leads to functional reorganization of the intact, opposite motor cortex. Adult rats underwent unilateral SMC aspiration lesion and treatment with either mAb IN-1 or control antibody, or no treatment. After a 6 week survival period, the intact, opposite forelimb motor cortex was explored using intracortical microstimulation to evoke forelimb movements. A dramatic increase in ipsilateral movements of the lesion-impaired forelimb was found in animals treated with mAb IN-1 compared with control animals. These results resembled our previous findings of cortical reorganization in the spared hemisphere after neonatal cortical lesion and without any additional treatment. These results show that, after adult cortical lesion, treatment with mAb IN-1 induces a functional reorganization of the intact, opposite motor cortex.