RESUMEN
Upper extremity hemiplegia is a common consequence of unilateral cortical stroke. Understanding the role of the unaffected cerebral hemisphere in the motor recovery process has been encouraged, in part, by the presence of ipsilateral corticospinal projections (iCSP). We examined the neuroplastic response of the iCSP from the contralesional primary motor cortex (cM1) hand/arm area to spinal levels C5-T1 after spontaneous long-term recovery from isolated frontal lobe injury and isolated frontoparietal injury. High-resolution tract tracing, stereological, and behavioral methodologies were applied. Recovery from frontal motor injury resulted in enhanced numbers of terminal labeled boutons in the iCSP from cM1 compared with controls. Increases occurred in lamina VIII and the adjacent ventral sectors of lamina VII, which are involved in axial/proximal limb sensorimotor processing. Larger frontal lobe lesions were associated with greater numbers of terminal boutons than smaller frontal lobe lesions. In contrast, frontoparietal injury blocked this response; total bouton number was similar to controls, demonstrating that disruption of somatosensory input to one hemisphere has a suppressive effect on the iCSP from the nonlesioned hemisphere. However, compared with controls, elevated bouton numbers occurred in lamina VIII, at the expense of lamina VII bouton labeling. Lamina IX boutons were also elevated in two frontoparietal lesion cases with extensive cortical injury. Because laminae VIII and IX collectively harbor axial, proximal, and distal motoneurons, therapeutic intervention targeting the ipsilateral corticospinal linkage from cM1 may promote proximal, and possibly distal, upper-limb motor recovery following frontal and frontoparietal injury.
Asunto(s)
Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Lóbulo Frontal/patología , Lateralidad Funcional/fisiología , Lóbulo Parietal/patología , Tractos Piramidales/fisiopatología , Animales , Modelos Animales de Enfermedad , Isoquinolinas/metabolismo , Macaca mulatta , Microinyecciones , Tractos Piramidales/patologíaRESUMEN
Concurrent damage to the lateral frontal and parietal cortex is common following middle cerebral artery infarction, leading to upper extremity paresis, paresthesia, and sensory loss. Motor recovery is often poor, and the mechanisms that support or impede this process are unclear. Since the medial wall of the cerebral hemisphere is commonly spared following stroke, we investigated the spontaneous long-term (6 and 12 month) effects of lateral frontoparietal injury (F2P2 lesion) on the terminal distribution of the corticospinal projection (CSP) from intact, ipsilesional supplementary motor cortex (M2) at spinal levels C5 to T1. Isolated injury to the frontoparietal arm/hand region resulted in a significant loss of contralateral corticospinal boutons from M2 compared with controls. Specifically, reductions occurred in the medial and lateral parts of lamina VII and the dorsal quadrants of lamina IX. There were no statistical differences in the ipsilateral CSP. Contrary to isolated lateral frontal motor injury (F2 lesion), which results in substantial increases in contralateral M2 labeling in laminae VII and IX (McNeal et al. [2010] J. Comp. Neurol. 518:586-621), the added effect of adjacent parietal cortex injury to the frontal motor lesion (F2P2 lesion) not only impedes a favorable compensatory neuroplastic response but results in a substantial loss of M2 CSP terminals. This dramatic reversal of the CSP response suggests a critical trophic role for cortical somatosensory influence on spared ipsilesional frontal corticospinal projections, and that restoration of a favorable compensatory response will require therapeutic intervention.
Asunto(s)
Lóbulo Frontal/lesiones , Lóbulo Parietal/lesiones , Tractos Piramidales/patología , Animales , Femenino , Lóbulo Frontal/patología , Lóbulo Frontal/fisiopatología , Lateralidad Funcional , Mano/fisiopatología , Inmunohistoquímica , Macaca mulatta , Masculino , Actividad Motora/fisiología , Técnicas de Trazados de Vías Neuroanatómicas , Lóbulo Parietal/patología , Lóbulo Parietal/fisiopatología , Fotomicrografía , Terminales Presinápticos/patología , Tractos Piramidales/fisiopatología , Recuperación de la Función , Factores de TiempoRESUMEN
We investigated the effects of old age on the fingertip force responses that occurred when a grasped handle was pulled unexpectedly to increase the tangential load at the fingertip. These automatic responses, directed normal to the handle surface, help prevent slips between the handle and finger. Old adults (average age 78 years) responded with large peak fingertip forces compared to young adults (average age 30 years), even though the two subject groups showed similar skin slipperiness. For step-shaped loads the average response latency was the same for young and old subjects (about 80 ms). Thus, these automatic responses are not susceptible to the age-related central delays known for simple reaction-time tasks. For ramp-shaped loads the average response latency was inversely related to load rate. Response latency was 25 ms longer for the Old group versus the Young group for loads of 8 N/s, and this difference increased exponentially to a 110-ms difference for 2-N/s loads. A twofold difference in the tangential force required to evoke a response was predicted from linear regressions and can account for the latency difference (0.2 N vs 0.4 N threshold for young and old, respectively, r=0.93 for both groups). This theoretical elevation in load force threshold is consistent with degraded central information processing in old age, and the deterioration of cutaneous mechanoreceptors.
Asunto(s)
Envejecimiento/fisiología , Fuerza de la Mano/fisiología , Adulto , Anciano , Femenino , Humanos , Masculino , Neuronas Motoras/fisiología , Neuronas Aferentes/fisiología , Tiempo de Reacción/fisiología , Soporte de Peso/fisiologíaRESUMEN
A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure-activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described.
Asunto(s)
Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/metabolismo , Quinazolinas/síntesis química , 3',5'-GMP Cíclico Fosfodiesterasas , Animales , Bovinos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Perros , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In Vitro , Masculino , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Músculos , Pene/efectos de los fármacos , Pene/fisiología , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacocinética , Inhibidores de Fosfodiesterasa/farmacología , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Conejos , Ratas , Relación Estructura-ActividadRESUMEN
Phosphodiesterase type 5 (PDE5) inhibitors with improved PDE isozyme selectivity relative to sildenafil may result in agents for the treatment of male erectile dysfunction (MED) with a lower incidence of PDE-associated adverse effects. This paper describes the discovery of 14, a PDE5 inhibitor with improved potency and selectivity in vitro compared to sildenafil. This compound shows activity in a functional assay of erectile function comparable to that of sildenafil.