Nerve growth factor (NGF) regulates the nociceptive properties of a subset of small diameter sensory neurons by increasing the expression of the heat-sensing transient receptor potential (TRP) channel, TRPV1. This action involves activation of the tyrosine kinase receptor (Trk) A/p38 MAPK pathway. Recent studies indicate that activation of TrkA promotes superoxide generation via NADPH oxidase. In this study, we determined whether the NADPH oxidase pathway is involved in NGF-stimulated TRPV1 expression using a rat pheochromocytoma 12 line and rat dorsal root ganglion neurons. Treatment of these cells with NGF (100 ng/mL) increased TRPV1 protein expression (approx. twofold) but not mRNA. This increase was mimicked by H 2 O 2 and attenuated by catalase and inhibitors of NADPH oxidase. NGF stimulated NADPH oxidase activity, while 24 h exposure further increased expression of the Rac1 and gp91 phox subunits of the holoenzyme. Inhibition of NADPH oxidase by transient transfection of a dominant negative Rac1 mutant (RacN17) plasmid blocked NGF-stimulated TRPV1 protein expression, while expression of a constitutively active Rac1 increased basal and NGF-stimulated TRPV1 levels. Inhibition of NADPH oxidase activity also attenuated NGF-dependent p38 MAPK activation. We conclude that the Rac1/NADPH oxidase pathway regulates p38 activation and TRPV1 expression which aids in the maintenance of peripheral neuron integrity and pain perception.
Plasma cell granuloma (PCG) is an uncommon non-neoplastic mass lesion of unknown etiology. It is characterized by a polyclonal proliferation of chronic inflammatory cells, mostly mature plasma and other mononuclear cells. PCGs arising in the central nervous system are particularly rare. We report two additional cases of intracranial PCG exclusively involving the brain parenchyma. A 47 year-old woman, presenting with partial motor seizures and fluent aphasia, underwent complete excision of a well-demarcated, enhancing left parietal mass. The second patient was a 56 year-old man presenting with headaches and right-sided weakness who underwent stereotactic biopsy of an ill-defined, heterogeneously enhancing lesion in the left basal ganglia. Immunohistochemical analysis of surgical specimens showed polyclonal plasma cells and mature lymphocytes but no etiological agent. A histopathologic diagnosis of intracranial PCG was made in both cases. PCG should be part of the differential diagnosis of enhancing mass lesions of the brain. The etiology and natural history of these tumor-like lesions is not fully understood. Complete surgical excision appears to be curative. Lesions where total resection is not possible may benefit from adjuvant treatment including corticosteroids and possibly radiation therapy.
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