A multiplex analysis for profiling the expression of candidate genes along with epigenetic modification may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we found that partial sciatic nerve ligation most remarkably increased the expression of monocyte chemotactic protein 3 (MCP-3, known as CCL7) a total of 33 541 genes in the spinal cord, which lasted for 4 weeks. This increase in MCP-3 gene transcription was accompanied by the decreased trimethylation of histone H3 at Lys27 at the MCP-3 promoter. The increased MCP-3 expression associated with its epigenetic modification observed in the spinal cord was almost abolished in interleukin 6 knockout mice with partial sciatic nerve ligation. Consistent with these findings, a single intrathecal injection of recombinant proteins of interleukin 6 significantly increased MCP-3 messenger RNA with a decrease in the level of Lys27 trimethylation of histone H3 at the MCP-3 promoter in the spinal cord of mice. Furthermore, deletion of the C-C chemokine receptor type 2 (CCR2) gene, which encodes a receptor for MCP-3, failed to affect the acceleration of MCP-3 expression in the spinal cord after partial sciatic nerve ligation. A robust increase in MCP-3 protein, which lasted for up to 2 weeks after surgery, in the dorsal horn of the spinal cord of mice with partial sciatic nerve ligation was seen mostly in astrocytes, but not microglia or neurons. On the other hand, the increases in both microglia and astrocytes in the spinal cord by partial sciatic nerve ligation were mostly abolished in interleukin 6 knockout mice. Moreover, this increase in microglia was almost abolished by CCR2 gene deletion, whereas the increase in astrocytes was not affected in nerve-ligated mice that lacked the CCR2 gene. We also found that either in vivo or in vitro treatment with MCP-3 caused robust microglia activation. Under these conditions, intrathecal administration of MCP-3 antibody suppressed the increase in microglia within the mouse spinal cord and neuropathic pain-like behaviours after nerve injury. With the use of a functional magnetic resonance imaging analysis, we demonstrated that a single intrathecal injection of MCP-3 induced dramatic increases in signal intensity in pain-related brain regions. These findings suggest that increased MCP-3 expression associated with interleukin 6 dependent epigenetic modification at the MCP-3 promoter after nerve injury, mostly in spinal astrocytes, may serve to facilitate astrocyte-microglia interaction in the spinal cord and could play a critical role in the neuropathic pain-like state.
A submicroscopic duplication that contains the entire proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease, an X-linked central nervous system dysmyelinating disorder. Previous studies have demonstrated that carrier females for the duplication are usually asymptomatic. We describe 2 unrelated female patients who present with mild Pelizaeus-Merzbacher disease or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results have improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, has also shown clinical improvement. Interphase fluorescent in situ hybridization identified a proteolipid protein gene duplication in both patients. Interphase fluorescent in situ hybridization analyses of the family members indicated that the duplication in both patients occurred as de novo events. Neither skewing of X inactivation in the peripheral lymphocytes nor proteolipid protein gene coding alterations were identified in either patient. These findings indicate that, occasionally, females with a proteolipid protein gene duplication can manifest an early-onset neurological phenotype. We hypothesize that the remarkable clinical improvement is a result of myelin compensation by oligodendrocytes expressing one copy of proteolipid protein gene secondary to selection for a favorable X inactivation pattern. These findings indicate plasticity of oligodendrocytes in the formation of central nervous system myelin and suggest a potential role for stem cell transplantation therapies.
SUMMARY The authors estimated perceptual disturbance in children with spastic diplegia from the difference between the visual and performance IQ scores (VIQ‐PIQ) on the Wechsler Intelligence Scale for Children‐Revised (WISC‐R), having found a strong negative correlation between this score and the PQ obtained on the Frostig Developmental Test of Visual Perception (DTVP). The ratio of the areas of the posterior horns to the anterior horns (P/A) correlated negatively with visuoperceptual disturbance. This ratio can therefore be used to assess perceptual disturbance at an early age in children with spastic diplegia. RÉSUMÉ Evaluation des perturbations visitoperceptives chez t'enfant présentant line diplégie spastiqtte, en utilisant les mesures des ventricules latéraux stir les 1RM cérébrates. Les auteurs ont estimé les perturbations perceptives des enfants avec diplégie spastique à partir de la difference entré les scores aux echelles verbales et de performances a l'cchelle d'intelligence pour enfants de Weschler (QIV‐QIP) dans la forme révisée du WISC‐R, ayant trouvé une forte correlation négative entre ce score et le QP obtenu au test développemental de perception visuelle de Frostig (DTVP). Le rapport des surfaces des comes postérieures sur les comes antérieures (P/A) était corrélé négativement avec la perturbation visuoperceptive. Ce rapport peut done étre utilisé pour évaluer la perturbation perceptive à un âge précoce chez l'enfant présentant une diplégie spastique. ZUSAMMENFASSUNG Beitrteilung einer visnellen Perzeptionsstörung bei Kindern mil spastischer Diplegie unhand von Gröβeiibestinwiitngen der Seitenventrikel im MRT Die Autoren untersuchtcn Pcrzeptionsstörungen bei Kindern mil spastischer Diplegie unhand der Unterschiede zwischen den visuellen ‐ und den Handlungs‐IQ‐Scores (VIQ‐PIQ) bei der Wechsler Intelligence Scale for Children‐Revised (WISC‐R), nachdem sie eine deutliche negative Korrelation zwischen diesem Score und dem PQ beim Frostig Developmental Test of Visual Perception (DTVP) gefunden hatten. Das Verhältnis zwischen Hinterhornbereich und Vorderhombercich korrelierte negativ mil der visuellen Perzeptionsstörung. Dieses Verhältnis kann also bei Kindern mit spastlscher Diplegie zur Bestimmung der Perzeptionsstörung im frühen Lebensalter herangezogen, werden. RESUMEN Evaluación de la alteración viso‐perceptual en niños con diplegia espástica. utilizando las mediciones de los ventrículos laierales en la IRM. Los autores estimaron la alteración perceptual en niños con diplegia espástica a partir de la diferencia entre los puntajes de CI visual y de realizatión (CIV‐CIP) en la Escala de Inteligencia de Wechsles‐Revisión (WISC‐R), encontrando una fucrte correspondencia negaiiva entre este puntajc y el CP obtenido en el Test de Desarrollo de Perceptión Visual de Frostig. La relación de las áreas de las astas posteriors, con la de las anteriores se correlacionaba negativamente con la alteración viso‐perccptual. Como consccucncia esta relación puedc usarse para evaluar la alteración perceptual en niños ...
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