Kinematic analysis of motor recovery with human adult bone marrow-derived somatic cell therapy in a rat model of stroke.

BACKGROUND: The extent to which pharmaceutical and behavioral therapies following central nervous system injury may either deter or encourage the development of compensatory movement patterns is a topic of considerable interest in neurorehabilitation. However, functional outcome measures alone are relatively insensitive to compensatory changes in movement patterns per se. OBJECTIVE: This study used both functional outcome measures and kinematic analysis of forelimb movements to examine the effects of human adult bone marrow-derived somatic cells (hABM-SCs) on motor recovery in a rat model of stroke. METHODS: Adult male Long-Evans black-hooded rats (n = 12) were trained in a forelimb reaching task and then underwent surgical middle cerebral artery occlusion, producing a stroke that impaired the trained paw. One week poststroke, animals were randomly assigned to either a hABM-SC injection or control injection group. Reaching behaviors were then compared at baseline and at 10 weeks poststroke. RESULTS: Both groups improved their outcome scores during the 10-week recovery period. However, the hABM-SC group recovered significantly more function than controls in terms of the number of pellets retrieved. Furthermore, the control group appeared to improve their functional performance by using compensatory strategies that involved an increased number of trajectory adjustments, whereas the hABM-SC group's kinematics more closely resembled prestroke movement patterns. CONCLUSIONS: This study demonstrates that kinematic measures established in stroke research on humans are also sensitive to performance differences prestroke versus poststroke in the rat model, reinforcing the utility of this method to evaluate treatments that may ultimately translate to patient populations.

Alterations in chondroitin sulfate proteoglycan expression occur both at and far from the site of spinal contusion injury.

Chondroitin sulfate proteoglycans (CSPGs) present an inhibitory barrier to axonal growth and plasticity after trauma to the central nervous system. These extracellular and membrane bound molecules are altered after spinal cord injuries, but the magnitude, time course, and patterns of expression following contusion injury have not been fully described. Western blots and immunohistochemistry were combined to assess the expression of four classically inhibitory CSPGs, aggrecan, neurocan, brevican and NG2, at the lesion site and in distal segments of cervical and thoracic spinal cord at 3, 7, 14 and 28 days following a severe mid-thoracic spinal contusion. Total neurocan and the full-length (250 kDa) isoform were strongly upregulated both at the lesion epicenter and in cervical and lumbar segments. In contrast, aggrecan and brevican were sharply reduced at the injury site and were unchanged in distal segments. Total NG2 protein was unchanged across the injury site, while NG2+ profiles were distributed throughout the lesion site by 14 days post-injury (dpi). Far from the lesion, NG2 expression was increased at lumbar, but not cervical spinal cord levels. To determine if the robust increase in neurocan at the distal spinal cord levels corresponded to regions of increased astrogliosis, neurocan and GFAP immunoreactivity were measured in gray and white matter regions of the spinal enlargements. GFAP antibodies revealed a transient increase in reactive astrocyte staining in cervical and lumbar cord, peaking at 14 dpi. In contrast, neurocan immunoreactivity was specifically elevated in the cervical dorsal columns and in the lumbar ventral horn and remained high through 28 dpi. The long lasting increase of neurocan in gray matter regions at distal levels of the spinal cord may contribute to the restriction of plasticity in the chronic phase after SCI. Thus, therapies targeted at altering this CSPG both at and far from the lesion site may represent a reasonable addition to combined strategies to improve recovery after SCI.

Deposition of hierarchical Cd(OH)2 anisotropic nanostructures at the water-toluene interface and their use as sacrificial templates for CdO or CdS nanostructures.

Hierarchical anisotropic structures ranging from triangular 'platelets' to nanofibres of Cd(OH)2 are synthesized at a water-toluene interface; the nanowires are used as sacrificial templates to produce CdO wires and CdS nanostructures, preserving many structural aspects.

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.

Delayed treatment with monoclonal antibody IN-1 1 week after stroke results in recovery of function and corticorubral plasticity in adult rats.

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.