RESUMEN
BACKGROUND: Combinatory intervention such as high-frequency (50-100 Hz) excitatory cortical stimulation (ECS) given concurrently with motor rehabilitative training (RT) improves forelimb function, except in severely impaired animals after stroke. Clinical studies suggest that low-frequency (≤1 Hz) inhibitory cortical stimulation (ICS) may provide an alternative approach to enhance recovery. Currently, the molecular mediators of CS-induced behavioral effects are unknown. Brain-derived neurotrophic factor (BDNF) has been associated with improved recovery and neural remodeling after stroke and thus may be involved in CS-induced behavioral recovery. OBJECTIVE: To investigate whether inhibitory stimulation during RT improves functional recovery of severely impaired rats, following focal cortical ischemia and if this recovery alters BDNF expression (study 1) and depends on BDNF binding to TrkB receptors (study 2). METHODS: Rats underwent ECS + RT, ICS + RT, or noCS + RT treatment daily for 3 weeks following a unilateral ischemic lesion to the motor cortex. Electrode placement for stimulation was either placed ipsilateral (ECS) or contralateral (ICS) to the lesion. After treatment, BDNF expression was measured in cortical tissue samples (study 1). In study 2, the TrkB inhibitor, ANA-12, was injected prior to treatment daily for 21 days. RESULTS: ICS + RT treatment significantly improved impaired forelimb recovery compared with ECS + RT and noCS + RT treatment. CONCLUSION: ICS given concurrently with rehabilitation improves motor recovery in severely impaired animals, and alters cortical BDNF expression; nevertheless, ICS-mediated improvements are not dependent on BDNF binding to TrkB. Conversely, inhibition of TrkB receptors does disrupt motor recovery in ECS + RT treated animals.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Terapia por Estimulación Eléctrica , Accidente Cerebrovascular Isquémico/rehabilitación , Corteza Motora/metabolismo , Corteza Motora/fisiopatología , Inhibición Neural/fisiología , Recuperación de la Función/fisiología , Rehabilitación de Accidente Cerebrovascular , Animales , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Miembro Anterior/fisiopatología , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/fisiopatología , Masculino , Ratas , Ratas Long-Evans , Receptor trkB/metabolismoRESUMEN
BACKGROUND Parkinson disease is characterized by the loss of neurons in the substantia nigra, and under pathological conditions, glutamate can produce excitotoxic effects on nerve cells. The astrocytic excitatory amino acid transporter (EAAT) 1 can be functionally upregulated and targeted to functional compartments, resulting in reduced excitotoxicity. levodopa is the gold standard for the treatment of Parkinson disease, but prolonged levodopa treatment often leads to the development of abnormal involuntary movements. Numerous studies suggest the potential beneficial effects of traditional Chinese medicine on Parkinson disease. MATERIAL AND METHODS We validated the efficacy of a Bushen Zhichan recipe combined with levodopa in a rodent Parkinson disease model and explored its possible mechanisms. RESULTS Rats in the combined levodopa and Bushen Zhichan recipe group performed significantly better than the control group in the open field and forelimb function experiments. The number of midbrain dopaminergic neurons in rats in the levodopa and Bushen Zhichan recipe group was greater compared to controls. The levodopa and Bushen Zhichan recipe group exhibited decreased glutamate receptors and increased γ-aminobutyric acid receptors in the striatum. At the same time, EAAT1 was increased and EAAT2 was synchronized with the number of glutamate receptors. CONCLUSIONS Our results indicate that levodopa combined with Bushen Zhichan recipe significantly improves behavior and protects dopaminergic neurons in a rodent Parkinson disease model, and suggest that the mechanism involves the decrease of excitatory amino acid toxicity and the increase in the expression of EAAT1.
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Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Miembro Anterior/efectos de los fármacos , Levodopa/farmacología , Mesencéfalo/efectos de los fármacos , Trastornos Parkinsonianos/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Cistanche , Cornus , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Dioscorea , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Transportador 1 de Aminoácidos Excitadores/efectos de los fármacos , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/efectos de los fármacos , Transportador 2 de Aminoácidos Excitadores/metabolismo , Fallopia multiflora , Miembro Anterior/fisiopatología , Haz Prosencefálico Medial , Mesencéfalo/metabolismo , Mesencéfalo/patología , Prueba de Campo Abierto/efectos de los fármacos , Oxidopamina/toxicidad , Enfermedad de Parkinson/fisiopatología , Ratas , RehmanniaRESUMEN
BACKGROUND: Motor impairments are among the major complications that develop after cortical damage caused by either stroke or traumatic brain injury. Motor cortex stimulation (MCS) can improve motor functions in animal models of stroke by inducing neuroplasticity. OBJECTIVE: In the current study, the therapeutic effect of chronic MCS was assessed in a rat model of severe cortical damage. METHODS: A controlled cortical impact (CCI) was applied to the forelimb area of the motor cortex followed by implantation of a flat electrode covering the lesioned area. Forelimb function was assessed using the Montoya staircase test and the cylinder test before and after a period of chronic MCS. Furthermore, the effect of MCS on tissue metabolism and lesion size was measured using [18F]-fluorodesoxyglucose (FDG) µPET scanning. RESULTS: CCI caused a considerable lesion at the level of the motor cortex and dorsal striatum together with a long-lasting behavioral phenotype of forelimb impairment. However, MCS applied to the CCI lesion did not lead to any improvement in limb functioning when compared to non-stimulated control rats. Also, MCS neither changed lesion size nor distribution of FDG. CONCLUSION: The use of MCS as a standalone treatment did not improve motor impairments in a rat model of severe cortical damage using our specific treatment modalities.
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Lesiones Encefálicas/terapia , Terapia por Estimulación Eléctrica/métodos , Miembro Anterior/fisiopatología , Corteza Motora/lesiones , Corteza Motora/fisiopatología , Recuperación de la Función/fisiología , Animales , Conducta Animal/fisiología , Lesiones Encefálicas/fisiopatología , Modelos Animales de Enfermedad , RatasRESUMEN
BACKGROUND: 4-Aminopyridine (4-AP) is a Food and Drug Administration-approved drug to improve motor function in people with multiple sclerosis. Preliminary results suggest the drug may act on intact neural circuits and not just on demyelinated ones. OBJECTIVE: To determine if 4-AP at clinically relevant levels alters the excitability of intact motor circuits. METHODS: In anesthetized rats, electrodes were placed over motor cortex and the dorsal cervical spinal cord for electrical stimulation, and electromyogram electrodes were inserted into biceps muscle to measure responses. The motor responses to brain and spinal cord stimulation were measured before and for 5 hours after 4-AP administration both in uninjured rats and rats with a cut lesion of the pyramidal tract. Blood was collected at the same time as electrophysiology to determine drug plasma concentration with a goal of 20 to 100 ng/mL. RESULTS: We first determined that a bolus infusion of 0.32 mg/kg 4-AP was optimal: it produced on average 61.5 ± 1.8 ng/mL over the 5 hours after infusion. This dose of 4-AP increased responses to spinal cord stimulation by 1.3-fold in uninjured rats and 3-fold in rats with pyramidal tract lesion. Responses to cortical stimulation also increased by 2-fold in uninjured rats and up to 4-fold in the injured. CONCLUSION: Clinically relevant levels of 4-AP strongly augment physiological responses in intact circuits, an effect that was more robust after partial injury, demonstrating its broad potential in treating central nervous system injuries.
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4-Aminopiridina/farmacología , Fármacos del Sistema Nervioso Central/farmacología , Médula Cervical/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Tractos Piramidales/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , 4-Aminopiridina/sangre , 4-Aminopiridina/farmacocinética , Animales , Fármacos del Sistema Nervioso Central/sangre , Fármacos del Sistema Nervioso Central/farmacocinética , Médula Cervical/lesiones , Médula Cervical/fisiología , Médula Cervical/fisiopatología , Evaluación Preclínica de Medicamentos , Estimulación Eléctrica , Electromiografía , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Femenino , Miembro Anterior/efectos de los fármacos , Miembro Anterior/fisiología , Miembro Anterior/fisiopatología , Microelectrodos , Corteza Motora/fisiología , Corteza Motora/fisiopatología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Tractos Piramidales/lesiones , Tractos Piramidales/fisiología , Tractos Piramidales/fisiopatología , Distribución Aleatoria , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
Estrogens have previously been shown to protect the brain against acute ischemic insults, by potentially augmenting cerebrovascular function after ischemic stroke. The current study hypothesized that treatment with sustained release of high-dose 17ß-estradiol (E2) at the time of reperfusion from middle cerebral artery occlusion (MCAO) in rats would attenuate reperfusion injury, augment post-stroke angiogenesis and cerebral blood flow, and attenuate lesion volume. Female Wistar rats underwent ovariectomy, followed two weeks later by transient, two-hour right MCAO (tMCAO) and treatment with E2 (n=13) or placebo (P; n=12) pellets starting at reperfusion. E2 treatment resulted in significantly smaller total lesion volume, smaller lesions within striatal and cortical brain regions, and less atrophy of the ipsilateral hemisphere after six weeks of recovery. E2-treated animals exhibited accelerated recovery of contralateral forelimb sensorimotor function in the cylinder test. Magnetic resonance imaging (MRI) showed that E2 treatment reduced the formation of lesion cysts, decreased lesion volume, and increased lesional cerebral blood flow (CBF). K(trans), a measure of vascular permeability, was increased in the lesions. This finding, which represents lesion neovascularization, was not altered by E2 treatment. Ischemic stroke-related angiogenesis and vessel formation was confirmed with immunolabeling of brain tissue and was not altered with E2 treatment. In summary, E2 treatment administered immediately following reperfusion significantly reduced lesion size, cyst formation, and brain atrophy while improving lesional CBF and accelerating recovery of functional deficits in a rat model of ischemic stroke.
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Isquemia Encefálica/tratamiento farmacológico , Estradiol/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Daño por Reperfusión/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Implantes de Medicamentos , Estradiol/sangre , Femenino , Miembro Anterior/fisiopatología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Fármacos Neuroprotectores/sangre , Ovariectomía , Distribución Aleatoria , Ratas Wistar , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Daño por Reperfusión/diagnóstico por imagen , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatología , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatologíaRESUMEN
Intensive rehabilitation is believed to induce use-dependent plasticity in the injured nervous system; however, its causal relationship to functional recovery is unclear. Here, we performed systematic analysis of the effects of forced use of an impaired forelimb on the recovery of rats after lesioning the internal capsule with intracerebral hemorrhage (ICH). Forced limb use (FLU) group rats exhibited better recovery of skilled forelimb functions and their cortical motor area with forelimb representation was restored and enlarged on the ipsilesional side. In addition, abundant axonal sprouting from the reemerged forelimb area was found in the ipsilateral red nucleus after FLU. To test the causal relationship between the plasticity in the cortico-rubral pathway and recovery, loss-of-function experiments were conducted using a double-viral vector technique, which induces selective blockade of the target pathway. Blockade of the cortico-rubral tract resulted in deficits of the recovered forelimb function in FLU group rats. These findings suggest that the cortico-rubral pathway is a substrate for recovery induced by intensive rehabilitation after ICH. SIGNIFICANCE STATEMENT: The research aimed at determining the causal linkage between reorganization of the motor pathway induced by intensive rehabilitative training and recovery after stroke. We clarified the expansion of the forelimb representation area of the ipsilesional motor cortex by forced impaired forelimb use (FLU) after lesioning the internal capsule with intracerebral hemorrhaging (ICH) in rats. Anterograde tracing showed robust axonal sprouting from the forelimb area to the red nucleus in response to FLU. Selective blockade of the cortico-rubral pathway by the novel double-viral vector technique clearly revealed that the increased cortico-rubral axonal projections had causal linkage to the recovery of reaching movements induced by FLU. Our data demonstrate that the cortico-rubral pathway is responsible for the effect of intensive limb use.
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Hemorragia Cerebral/complicaciones , Miembro Anterior/fisiopatología , Corteza Motora/fisiología , Trastornos del Movimiento/etiología , Trastornos del Movimiento/rehabilitación , Recuperación de la Función/fisiología , Núcleo Rojo/fisiología , Animales , Biotina/análogos & derivados , Biotina/metabolismo , Hemorragia Cerebral/rehabilitación , Estimulación Encefálica Profunda , Dextranos/metabolismo , Modelos Animales de Enfermedad , Doxiciclina/administración & dosificación , Miembro Anterior/efectos de los fármacos , Lateralidad Funcional/fisiología , Agonistas de Receptores de GABA-A/farmacología , Cápsula Interna/lesiones , Masculino , Destreza Motora/fisiología , Muscimol/farmacología , Vías Nerviosas/fisiología , Ratas , Ratas Wistar , Recuperación de la Función/efectos de los fármacosRESUMEN
An important strategy for promoting voluntary movements after motor system injury is to harness activity-dependent corticospinal tract (CST) plasticity. We combine forelimb motor cortex (M1) activation with co-activation of its cervical spinal targets in rats to promote CST sprouting and skilled limb movement after pyramidal tract lesion (PTX). We used a two-step experimental design in which we first established the optimal combined stimulation protocol in intact rats and then used the optimal protocol in injured animals to promote CST repair and motor recovery. M1 was activated epidurally using an electrical analog of intermittent theta burst stimulation (iTBS). The cervical spinal cord was co-activated by trans-spinal direct current stimulation (tsDCS) that was targeted to the cervical enlargement, simulated from finite element method. In intact rats, forelimb motor evoked potentials (MEPs) were strongly facilitated during iTBS and for 10 min after cessation of stimulation. Cathodal, not anodal, tsDCS alone facilitated MEPs and also produced a facilitatory aftereffect that peaked at 10 min. Combined iTBS and cathodal tsDCS (c-tsDCS) produced further MEP enhancement during stimulation, but without further aftereffect enhancement. Correlations between forelimb M1 local field potentials and forelimb electromyogram (EMG) during locomotion increased after electrical iTBS alone and further increased with combined stimulation (iTBS+c-tsDCS). This optimized combined stimulation was then used to promote function after PTX because it enhanced functional connections between M1 and spinal circuits and greater M1 engagement in muscle contraction than either stimulation alone. Daily application of combined M1 iTBS on the intact side and c-tsDCS after PTX (10 days, 27 min/day) significantly restored skilled movements during horizontal ladder walking. Stimulation produced a 5.4-fold increase in spared ipsilateral CST terminations. Combined neuromodulation achieves optimal motor recovery and substantial CST outgrowth with only 27 min of daily stimulation compared with 6h, as in our prior study, making it a potential therapy for humans with spinal cord injury.
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Terapia por Estimulación Eléctrica/métodos , Corteza Motora/fisiología , Plasticidad Neuronal/fisiología , Tractos Piramidales/fisiología , Traumatismos de la Médula Espinal/terapia , Médula Espinal/fisiología , Animales , Axones/patología , Biotina/análogos & derivados , Biotina/metabolismo , Dextranos/metabolismo , Modelos Animales de Enfermedad , Electrodos Implantados , Electromiografía , Potenciales Evocados Motores/fisiología , Femenino , Miembro Anterior/fisiopatología , Lateralidad Funcional , Locomoción/fisiología , Tractos Piramidales/lesiones , Ratas , Ratas Sprague-Dawley , VigiliaRESUMEN
PURPOSE: Forced limb-use can enhance neurogenesis and behavioral recovery as well as increasing the level of stromal cell-derived factor-1 (SDF-1) in stroke rats. We examined whether the SDF-1/CXCR4 pathway is involved in the enhanced neurogenesis and promoted behavioral recovery induced by forced limb-use in the chronic phase of stroke. METHODS: The CXCR4 antagonist, AMD3100, was used to block the SDF-1/CXCR4 pathway in the ischemic rats. Brain ischemia was induced by endothelin-1. One week after ischemia, the unimpaired forelimb of rats was immobilized for 3 weeks. The proliferation, migration, and survival of DCX-positive cells in the subventricular zone (SVZ), and the dendritic complexity of DCX-positive cells in the dentate gyrus (DG), as well as the inflammatory response in the infarcted striatum were analyzed by immunohistochemistry. Functional recovery was assessed in beam-walking and water maze tests. RESULTS: Forced limb-use enhanced the proliferation, migration, dendritic complexity and the survival of newborn neurons. Furthermore, forced limb-use suppressed the inflammatory response and improved both motor and cognitive functions after stroke. AMD3100 significantly abrogated the enhanced neurogenesis and behavioral recovery induced by forced limb-use without influencing the inflammatory response. CONCLUSIONS: SDF-1/CXCR4 pathway seems to be involved in the enhancement of neurogenesis and behavioral recovery induced by post-stroke forced limb-use.
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Fármacos del Sistema Nervioso Central/farmacología , Compuestos Heterocíclicos/farmacología , Neurogénesis/efectos de los fármacos , Receptores CXCR4/antagonistas & inhibidores , Recuperación de la Función/efectos de los fármacos , Rehabilitación de Accidente Cerebrovascular , Animales , Bencilaminas , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Isquemia Encefálica/rehabilitación , Quimiocina CXCL12/metabolismo , Ciclamas , Modelos Animales de Enfermedad , Proteína Doblecortina , Endotelina-1 , Miembro Anterior/efectos de los fármacos , Miembro Anterior/fisiopatología , Inmovilización/métodos , Inmovilización/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Manipulaciones Musculoesqueléticas/métodos , Neurogénesis/fisiología , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/fisiología , Distribución Aleatoria , Ratas Wistar , Receptores CXCR4/metabolismo , Recuperación de la Función/fisiología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatologíaRESUMEN
Chronic brain implants are accompanied by a tissue response that causes the loss of neurons in the vicinity of the implant and the formation of a glial scar that is also referred to as foreign body response. Despite immense progress in the field of brain-computer interface (BCI) research the biocompatibility of chronic brain implants remains a primary concern in device design. Excitotoxic overstimulation of NMDA-receptors by extrasynaptic glutamate plays a pivotal role in cell death in the acute phase of the tissue reaction. In this study, we examined the effect of the uncompetitive NMDA-receptor antagonist memantine locally applied during cannula implantation in the caudal forelimb area (CFA) of the motor cortex (M1) in Lister Hooded rats on their behavioural performance in a skilled reaching and a rung-ladder task as well as in the open field. Moreover, the distribution of neurons and glial cells in the vicinity of the implant were assessed. Memantine improved the performance in the behavioural paradigms compared to controls and increased the number of surviving neurons in the vicinity of the implant even above basal levels accompanied by a reduction in astrocytic scar formation directly around the implant with no effect on the microglia/macrophage activation two and six weeks after cannula implantation. These findings suggest that memantine is a potential therapeutic agent in the acute phase of chronic foreign body implantation in the motor cortex in terms of increasing the viability of neurons adjacent to the implant and of improving the behavioural outcome after surgery.
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Catéteres de Permanencia/efectos adversos , Memantina/farmacología , Corteza Motora/efectos de los fármacos , Corteza Motora/cirugía , Fármacos Neuroprotectores/farmacología , Animales , Antígenos Nucleares/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/patología , Astrocitos/fisiología , Fenómenos Biomecánicos , Proteínas de Unión al Calcio/metabolismo , Supervivencia Celular/efectos de los fármacos , Cicatriz/tratamiento farmacológico , Cicatriz/patología , Cicatriz/fisiopatología , Antagonistas de Aminoácidos Excitadores/farmacología , Miembro Anterior/fisiopatología , Proteína Ácida Fibrilar de la Glía/metabolismo , Ácido Glutámico/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/patología , Macrófagos/fisiología , Masculino , Proteínas de Microfilamentos/metabolismo , Microglía/efectos de los fármacos , Microglía/patología , Microglía/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Corteza Motora/patología , Corteza Motora/fisiopatología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/fisiología , RatasRESUMEN
Dry eye (DE) disease is commonly associated with ocular surface inflammation, an unstable tear film and symptoms of irritation. However, little is known about the role of central neural mechanisms in DE. This study used a model for persistent aqueous tear deficiency, exorbital gland removal, to assess the effects of mustard oil (MO), a transient receptor potential ankyrin (TRPA1) agonist, on eyeblink and eyewipe behavior and Fos-like immunoreactivity (Fos-LI) in the trigeminal brainstem of male rats. Spontaneous tear secretion was reduced by about 50% and spontaneous eyeblinks were increased more than 100% in DE rats compared to sham rats. MO (0.02-0.2%) caused dose-related increases in eyeblink and forelimb eyewipe behavior in DE and sham rats. Exorbital gland removal alone was sufficient to increase Fos-LI at the ventrolateral pole of trigeminal interpolaris/caudalis (Vi/Vc) transition region, but not at more caudal regions of the trigeminal brainstem. Under barbiturate anesthesia ocular surface application of MO (2-20%) produced Fos-LI in the Vi/Vc transition, in the mid-portions of Vc and in the trigeminal caudalis/upper cervical spinal cord (Vc/C1) region that was significantly greater in DE rats than in sham controls. MO caused an increase in Fos-LI ipsilaterally in superficial laminae at the mid-Vc and Vc/C1 regions in a dose-dependent manner. Smaller, but significant, increases in Fos-LI also were seen in the contralateral Vc/C1 region in DE rats. TRPA1 protein levels in trigeminal ganglia from DE rats ipsilateral and contralateral to gland removal were similar. Persistent tear reduction enhanced the behavioral and trigeminal brainstem neural responses to ocular surface stimulation by MO. These results suggested that TRPA1 mechanisms play a significant role in the sensitization of ocular-responsive trigeminal brainstem neurons in this model for tear deficient DE.
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Tronco Encefálico/fisiopatología , Síndromes de Ojo Seco/fisiopatología , Neuronas/fisiología , Canales Catiónicos TRPC/metabolismo , Ganglio del Trigémino/fisiopatología , Animales , Parpadeo/efectos de los fármacos , Parpadeo/fisiología , Tronco Encefálico/efectos de los fármacos , Fármacos del Sistema Nervioso Central/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Miembro Anterior/fisiopatología , Lateralidad Funcional , Immunoblotting , Inmunohistoquímica , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Planta de la Mostaza , Neuronas/efectos de los fármacos , Fotomicrografía , Aceites de Plantas/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Sprague-Dawley , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/agonistas , Lágrimas/efectos de los fármacos , Lágrimas/metabolismo , Ganglio del Trigémino/efectos de los fármacosRESUMEN
To investigate the potential therapeutic effects of peripheral sensory stimulation during the hyperacute phase of stroke, the present study utilized electrophysiology and photoacoustic imaging techniques to evaluate neural and vascular responses of the rat cortex following ischemic insult. We employed a rat model of photothrombotic ischemia (PTI), which targeted the forelimb region of the primary somatosensory cortex (S1FL), due to its high reproducibility in creating localized ischemic injury. We also established a hybrid, dual-modality system, including six-channel electrocorticography (ECoG) and functional photoacoustic microscopy (fPAM), termed ECoG-fPAM, to image brain functional responses to peripheral sensory stimulation during the hyperacute phase of PTI. Our results showed that the evoked cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) recovered to 84±7.4% and 79±6.2% of the baseline, respectively, when stimulation was delivered within 2.5 h following PTI induction. Moreover, neural activity significantly recovered, with 77±8.6%, 76±5.3% and 89±8.2% recovery for the resting-state inter-hemispheric coherence, alpha-to-delta ratio (ADR) and somatosensory evoked potential (SSEP), respectively. Additionally, we integrated the CBV or SO2 with ADR values as a recovery indicator (RI) to assess functional recovery after PTI. The RI indicated that 80±4.2% of neurovascular function was preserved when stimulation was delivered within 2.5h. Additionally, stimulation treatment within this optimal time window resulted in a minimal infarct volume in the ischemic hemisphere (4.6±2.1%). In contrast, the infarct volume comprised 13.7±1.7% of the ischemic hemisphere when no stimulation treatment was applied.
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Isquemia Encefálica/fisiopatología , Isquemia Encefálica/terapia , Terapia por Estimulación Eléctrica/métodos , Corteza Somatosensorial/fisiopatología , Animales , Volumen Sanguíneo/fisiología , Determinación del Volumen Sanguíneo , Isquemia Encefálica/patología , Circulación Cerebrovascular/fisiología , Modelos Animales de Enfermedad , Electroencefalografía/instrumentación , Electroencefalografía/métodos , Potenciales Evocados Somatosensoriales/fisiología , Miembro Anterior/fisiopatología , Masculino , Microscopía Acústica/instrumentación , Microscopía Acústica/métodos , Ratas Wistar , Recuperación de la Función/fisiología , Corteza Somatosensorial/patología , Factores de TiempoRESUMEN
STUDY DESIGN: This study used extracellular electrophysiology to examine neuronal hyperexcitability in the ventroposterolateral nucleus (VPL) of the thalamus in a rat model of painful radiculopathy. OBJECTIVE: The goal of this study was to quantify evoked neuronal excitability in the VPL at day 14 after a cervical nerve root compression to determine thalamic processing of persistent radicular pain. SUMMARY OF BACKGROUND DATA: Nerve root compression often leads to radicular pain. Chronic pain is thought to induce structural and biochemical changes in the brain affecting supraspinal signaling. In particular, the VPL of the thalamus has been implicated in chronic pain states. METHODS: Rats underwent a painful transient C7 nerve root compression or sham procedure. Ipsilateral forepaw mechanical allodynia was assessed on days 1, 3, 5, 7, 10, and 14 and evoked thalamic neuronal recordings were collected at day 14 from the contralateral VPL, whereas the injured forepaw was stimulated using a range of non-noxious and noxious mechanical stimuli. Neurons were classified on the basis of their response to stimulation. RESULTS: Behavioral sensitivity was elevated after nerve root compression starting at day 3 and persisted until day 14 (P < 0.049). Thalamic recordings at day 14 demonstrated increased neuronal hyperexcitability after injury for all mechanical stimuli (P < 0.024). In particular, wide dynamic range neurons demonstrated significantly more firing after injury compared with sham in response to von Frey stimulation (P < 0.0001). Firing in low threshold mechanoreceptive neurons was not different between groups. CONCLUSION: These data demonstrate that persistent radicular pain is associated with sustained neuronal hyperexcitability in the contralateral VPL of the thalamus. These findings suggest that thalamic processing is altered during radiculopathy and these changes in neuronal firing are associated with behavioral sensitivity. LEVEL OF EVIDENCE: N/A.
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Vértebras Cervicales/fisiopatología , Neuronas/fisiología , Radiculopatía/fisiopatología , Tálamo/fisiopatología , Animales , Vértebras Cervicales/patología , Electrofisiología/métodos , Potenciales Evocados/fisiología , Miembro Anterior/fisiopatología , Hiperalgesia/fisiopatología , Masculino , Dimensión del Dolor/métodos , Estimulación Física/métodos , Radiculopatía/patología , Ratas , Tálamo/patología , Factores de TiempoRESUMEN
Motor cortex stimulation (MCS) is used as a therapy for patients with refractory neuropathic pain. Experimental evidence suggests that the motor cortex (MC) is involved in the modulation of normal nociceptive response, but the underlying mechanisms have not been clarified yet. In previous studies, we demonstrated that MCS increases the nociceptive threshold of naive conscious rats by inhibiting thalamic sensory neurons and disinhibiting the neurons in periaqueductal gray (PAG), with the involvement of the opioid system. The aim of this study was to investigate the possible somatotopy of the motor cortex on MCS-induced antinociception and the pattern of neuronal activation evaluated by Fos and Egr-1 immunolabel in an attempt to better understand the relation between MC and analgesia. Rats received epidural electrode implants placed over the MC, in three distinct areas (forelimb, hindlimb or tail), according to a functional mapping established in previous studies. Nociceptive threshold was evaluated under 15-min electrical stimulating sessions. MCS induced selective antinociception in the limb related to the stimulated cortex, with no changes in other evaluated areas. MCS decreased Fos immunoreactivity (Fos-IR) in the superficial layers of the dorsal horn of the spinal cord for all evaluated groups and increased Fos-IR in the PAG, although no changes were observed in the PAG for the tail group. Egr-1 results were similar to those obtained for Fos. Data shown herein demonstrate that MCS elicits a substantial and selective antinociceptive effect, which is mediated, at least in part, by the activation of descendent inhibitory pain pathway.
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Estimulación Eléctrica/métodos , Hiperalgesia/terapia , Corteza Motora/fisiología , Umbral del Dolor/fisiología , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Electrodos , Extremidades/inervación , Miembro Anterior/fisiopatología , Lateralidad Funcional , Regulación de la Expresión Génica/fisiología , Masculino , Nociceptores/fisiología , Proteínas Oncogénicas v-fos/metabolismo , Dimensión del Dolor , Sustancia Gris Periacueductal/metabolismo , Estimulación Física/efectos adversos , Ratas , Ratas Wistar , Método Simple Ciego , Médula Espinal/metabolismo , Médula Espinal/patología , Factores de TiempoRESUMEN
T-lymphocytes promote cerebral inflammation, thus aggravating neuronal injury after stroke. Fingolimod, a sphingosine 1-phosphate receptor analog, prevents the egress of lymphocytes from primary and secondary lymphoid organs. Based on these findings, we hypothesized fingolimod treatment would reduce the number of T-lymphocytes migrating into the brain, thereby ameliorating cerebral inflammation following experimental intracerebral hemorrhage (ICH). We investigated the effects of fingolimod in two well-established murine models of ICH, implementing intrastriatal infusions of either bacterial collagenase (cICH) or autologous blood (bICH). Furthermore, we tested the long term neurological improvements by Fingolimod in a collagenase-induced rat model of ICH. Fingolimod, in contrast to vehicle administration alone, improved neurological functions and reduced brain edema at 24 and 72 h following experimental ICH in CD-1 mice (n=103; p<0.05). Significantly fewer lymphocytes were found in blood and brain samples of treated animals when compared to the vehicle group (p<0.05). Moreover, fingolimod treatment significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (INF-γ), and interleukin-17 (IL-17) in the mouse brain at 72 h post-cICH (p<0.05 compared to vehicle). Long-term neurocognitive performance and histopathological analysis were evaluated in Sprague-Dawley rats between 8 and 10 weeks post-cICH (n=28). Treated rats showed reduced spatial and motor learning deficits, along with significantly reduced brain atrophy and neuronal cell loss within the basal ganglia (p<0.05 compared to vehicle). We conclude that fingolimod treatment ameliorated cerebral inflammation, at least to some extent, by reducing the availability and subsequent brain infiltration of T-lymphocytes, which improved the short and long-term sequelae after experimental ICH in rodents.
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Corteza Cerebral/patología , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/patología , Inmunosupresores/uso terapéutico , Linfocitos/efectos de los fármacos , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Análisis de Varianza , Animales , Ganglios Basales/patología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Transfusión de Sangre Autóloga/efectos adversos , Edema Encefálico/etiología , Edema Encefálico/prevención & control , Complejo CD3/metabolismo , Recuento de Células , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/etiología , Hemorragia Cerebral/inmunología , Colagenasas/toxicidad , Modelos Animales de Enfermedad , Clorhidrato de Fingolimod , Miembro Anterior/fisiopatología , Lateralidad Funcional/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/metabolismo , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Leucocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/prevención & control , Glicoles de Propileno/farmacología , Trastornos Psicomotores/tratamiento farmacológico , Trastornos Psicomotores/etiología , Ratas , Ratas Sprague-Dawley , Percepción Espacial/efectos de los fármacos , Esfingosina/farmacología , Esfingosina/uso terapéutico , Factores de TiempoRESUMEN
Deep brain stimulation (DBS) employing high-frequency stimulation (HFS) is commonly used in the globus pallidus interna (GPi) and the subthalamic nucleus (STN) for treating motor symptoms of patients with Parkinson's disease (PD). Although DBS improves motor function in most PD patients, disease progression and stimulation-induced nonmotor complications limit DBS in these areas. In this study, we assessed whether stimulation of the substantia nigra pars reticulata (SNr) improved motor function. Hemiparkinsonian rats predominantly touched with their unimpaired forepaw >90% of the time in the stepping and limb-use asymmetry tests. After SNr-HFS (150 Hz), rats touched equally with both forepaws, similar to naive and sham-lesioned rats. In vivo, SNr-HFS decreased beta oscillations (12-30 Hz) in the SNr of freely moving hemiparkinsonian rats and decreased SNr neuronal spiking activity from 28 ± 1.9 Hz before stimulation to 0.8 ± 1.9 Hz during DBS in anesthetized animals; also, neuronal spiking activity increased from 7 ± 1.6 to 18 ± 1.6 Hz in the ventromedial portion of the thalamus (VM), the primary SNr efferent. In addition, HFS of the SNr in brain slices from normal and reserpine-treated rat pups resulted in a depolarization block of SNr neuronal activity. We demonstrate improvement of forelimb akinesia with SNr-HFS and suggest that this motor effect may have resulted from the attenuation of SNr neuronal activity, decreased SNr beta oscillations, and increased activity of VM thalamic neurons, suggesting that the SNr may be a plausible DBS target for treating motor symptoms of DBS.
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Estimulación Encefálica Profunda , Hipocinesia/terapia , Enfermedad de Parkinson Secundaria/terapia , Sustancia Negra/fisiopatología , Animales , Antipsicóticos/uso terapéutico , Ritmo beta , Miembro Anterior/inervación , Miembro Anterior/fisiopatología , Masculino , Oxidopamina/toxicidad , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/fisiopatología , Ratas , Ratas Sprague-Dawley , Reserpina/uso terapéutico , Tálamo/fisiopatologíaRESUMEN
Stroke is the dominant cause of sensorimotor disability that primarily affects the elderly. We now show that neuroplasticity and functional recovery after stroke is constrained by inhibitory chondroitin sulphates. In two blinded, randomized preclinical trials, degradation of chondroitin sulphate using chondroitinase ABC reactivated neuroplasticity and promoted sensorimotor recovery after stroke in elderly rats. Three days after stroke, chondroitinase ABC was microinjected into the cervical spinal cord to induce localized plasticity of forelimb sensorimotor spinal circuitry. Chondroitinase ABC effectively removed chondroitin sulphate from the extracellular matrix and perineuronal nets. Three different tests of sensorimotor function showed that chondroitinase ABC promoted recovery of forelimb function. Anterograde and retrograde tracing showed that chondroitinase ABC also induced sprouting of the contralesional corticospinal tract in the aged treated hemicord. Chondroitinase ABC did not neuroprotect the peri-infarct region. We show for the first time delayed chondroitinase ABC treatment promotes neuroanatomical and functional recovery after focal ischaemic stroke in an elderly nervous system.
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Envejecimiento , Condroitina ABC Liasa/administración & dosificación , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Trastornos Neurológicos de la Marcha/etiología , Plasticidad Neuronal/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Accidente Cerebrovascular , Estimulación Acústica/efectos adversos , Amidinas , Análisis de Varianza , Animales , Biotina/análogos & derivados , Biotina/metabolismo , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/etiología , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Dextranos/metabolismo , Modelos Animales de Enfermedad , Método Doble Ciego , Femenino , Miembro Anterior/fisiopatología , Lateralidad Funcional/efectos de los fármacos , Inyecciones Espinales/métodos , Masculino , Trastornos del Movimiento/etiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Lectinas de Plantas , Desempeño Psicomotor/efectos de los fármacos , Tractos Piramidales/patología , Ratas , Ratas Long-Evans , Receptores N-Acetilglucosamina , Trastornos de la Sensación/etiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/patología , Factores de TiempoRESUMEN
Studies have shown that progesterone reduces brain injury, whereas testosterone increases lesion size after ischemic stroke. This study examined the effects of progesterone and testosterone on intracerebral hemorrhage (ICH)-induced brain injury. Male Sprague-Dawley rats received an injection of 100 µL autologous whole blood into the right basal ganglia. Progesterone (16 mg/kg), testosterone (15 mg/kg) or vehicle was given intraperitoneally 2 h after ICH. Behavioral tests were performed, and the rats were killed after 24 h for brain edema measurement. Perihematomal brain edema was reduced in progesterone-treated rats compared to vehicle-treated rats (p<0.05). Progesterone also improved functional outcome following ICH (p<0.05). Testosterone treatment did not affect perihematomal edema formation, but resulted in lower forelimb placing score (p<0.05). In conclusion, progesterone can reduce brain edema and improve functional outcome, whereas testosterone may have a deleterious effect after ICH in male rats.
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Lesiones Encefálicas/tratamiento farmacológico , Hormonas Gonadales/uso terapéutico , Progesterona/uso terapéutico , Testosterona/uso terapéutico , Animales , Ganglios Basales/efectos de los fármacos , Ganglios Basales/fisiología , Conducta Animal/efectos de los fármacos , Transfusión de Sangre Autóloga/efectos adversos , Edema Encefálico/etiología , Edema Encefálico/prevención & control , Lesiones Encefálicas/etiología , Hemorragia Cerebral/complicaciones , Modelos Animales de Enfermedad , Miembro Anterior/efectos de los fármacos , Miembro Anterior/fisiopatología , Iones/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Most processing of sensation involves the cortical hemisphere opposite (contralateral) to the stimulated limb. Stroke patients can exhibit changes in the interhemispheric balance of sensory signal processing. It is unclear whether these changes are the result of poststroke rewiring and experience, or whether they could result from the immediate effect of circuit loss. We evaluated the effect of mini-strokes over short timescales (<2 h) where cortical rewiring is unlikely by monitoring sensory-evoked activity throughout much of both cortical hemispheres using voltage-sensitive dye imaging. Blockade of a single pial arteriole within the C57BL6J mouse forelimb somatosensory cortex reduced the response evoked by stimulation of the limb contralateral to the stroke. However, after stroke, the ipsilateral (uncrossed) forelimb response within the unaffected hemisphere was spared and became independent of the contralateral forelimb cortex. Within the unaffected hemisphere, mini-strokes in the opposite hemisphere significantly enhanced sensory responses produced by stimulation of either contralateral or ipsilateral pathways within 30-50 min of stroke onset. Stroke-induced enhancement of responses within the spared hemisphere was not reproduced by inhibition of either cortex or thalamus using pharmacological agents in nonischemic animals. I/LnJ acallosal mice showed similar rapid interhemispheric redistribution of sensory processing after stroke, suggesting that subcortical connections and not transcallosal projections were mediating the novel activation patterns. Thalamic inactivation before stroke prevented the bilateral rearrangement of sensory responses. These findings suggest that acute stroke, and not merely loss of activity, activates unique pathways that can rapidly redistribute function within the spared cortical hemisphere.
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Accidente Cerebrovascular/fisiopatología , Animales , Modelos Animales de Enfermedad , Miembro Anterior/patología , Miembro Anterior/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Plasticidad Neuronal , Piamadre/metabolismo , Corteza Somatosensorial/fisiología , Tetrodotoxina/farmacología , Tálamo/fisiología , Imagen de Colorante Sensible al Voltaje/métodosRESUMEN
Dyskinesia is a major side-effect of chronic l-DOPA administration, the reference treatment for Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing the L-DOPA requirement. However, inappropriate stimulation can also trigger dyskinetic movements, in both human and rodents. We investigated whether STN-HFS-evoked forelimb dyskinesia involved changes in glutamatergic neurotransmission as previously reported for L-DOPA-induced dyskinesias, focusing on the role of NR2B-containing N-methyl-D-aspartate receptors (NR2B/NMDARs). We applied STN-HFS in normal rats at intensities above and below the threshold for triggering forelimb dyskinesia. Dyskinesiogenic STN-HFS induced the activation of NR2B (as assessed by immunodetection of the phosphorylated residue Tyr(1472)) in neurons of the subthalamic nucleus, entopeduncular nucleus, motor thalamus and forelimb motor cortex. The severity of STN-HFS-induced forelimb dyskinesia was decreased in a dose-dependent manner by systemic injections of CP-101,606, a selective blocker of NR2B/NMDARs, but was either unaffected or increased by the non-selective N-methyl-D-aspartate receptor antagonist, MK-801.
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Discinesias/fisiopatología , Miembro Anterior/fisiopatología , Neuronas/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleo Subtalámico/fisiopatología , Análisis de Varianza , Animales , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Discinesias/metabolismo , Estimulación Eléctrica , Electrodos Implantados , Miembro Anterior/efectos de los fármacos , Miembro Anterior/metabolismo , Inmunohistoquímica , Masculino , Corteza Motora/metabolismo , Neuronas/efectos de los fármacos , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Estadísticas no Paramétricas , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/metabolismo , Tálamo/metabolismoRESUMEN
While intraventricular administration of epidermal growth factor (EGF) expands the proliferation of neural stem/progenitor cells in the subventricular zone (SVZ), overexpression of brain-derived neurotrophic factor (BDNF) is particularly effective in enhancing striatal neurogenesis. We assessed the induction of striatal neurogenesis and consequent functional recovery after chronic infusion of BDNF and EGF in an adult animal model of neonatal hypoxic-ischemic (HI) brain injury. Permanent brain damage was induced in CD-1 (ICR) mice (P7) by applying the ligation of unilateral carotid artery and hypoxic condition. At 6 weeks of age, the mice were randomly assigned to groups receiving a continuous 2-week infusion of one of the following treatments into the ventricle: BDNF, EGF, BDNF/EGF, or phosphate buffered saline (PBS). Two weeks after treatment, immunohistochemical analysis revealed an increase in the number of BrdU(+) cells in the SVZ and striata of BDNF/EGF-treated mice. The number of new neurons co-stained with BrdU and betaIII-tubulin was also significantly increased in the neostriata of BDNF/EGF-treated mice, compared with PBS group. In addition, the newly generated cells were expressed as migrating neuroblasts labeled with PSA-NCAM or doublecortin in the SVZ and the ventricular side of neostriata. The new striatal neurons were also differentiated as mature neurons co-labeled with BrdU(+)/NeuN(+). When evaluated post-surgical 8 weeks, BDNF/EGF-treated mice exhibited significantly longer rotarod latencies at constant speed (48 rpm) and under accelerating condition (4-80 rpm), relative to PBS and untreated controls. In the forelimb-use asymmetry test, BDNF/EGF-treated mice showed significant improvement in the use of the contralateral forelimb. In contrast, this BDNF/EGF-associated functional recovery was abolished in mice receiving a co-infusion of 2% cytosine-b-d-arabinofuranoside (Ara-C), a mitotic inhibitor. Induction of striatal neurogenesis by the intraventricular administration of BDNF and EGF promoted functional recovery in an adult animal model of neonatal HI brain injury. The effect of Ara-C to completely block functional recovery indicates that the effect may be the result of newly generated neurons. Therefore, this treatment may offer a promising strategy for the restoration of motor function for adults with cerebral palsy (CP).