Schwannoma del nervio tibial en un paciente con schwannomatosis asociada a una nueva mutación en el gen LZTR1 / Schwannoma of the posterior tibial nerve in a patient with schwannomatosis and a novel mutation of the LZTR1 gene

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Inhibition of transmitter release and attenuation of anti-retroviral-associated and tibial nerve injury-related painful peripheral neuropathy by novel synthetic Ca2+ channel peptides.

N-type Ca(2+) channels (CaV2.2) are a nidus for neurotransmitter release and nociceptive transmission. However, the use of CaV2.2 blockers in pain therapeutics is limited by side effects resulting from inhibition of the physiological functions of CaV2.2 within the CNS. We identified an anti-nociceptive peptide (Brittain, J. M., Duarte, D. B., Wilson, S. M., Zhu, W., Ballard, C., Johnson, P. L., Liu, N., Xiong, W., Ripsch, M. S., Wang, Y., Fehrenbacher, J. C., Fitz, S. D., Khanna, M., Park, C. K., Schmutzler, B. S., Cheon, B. M., Due, M. R., Brustovetsky, T., Ashpole, N. M., Hudmon, A., Meroueh, S. O., Hingtgen, C. M., Brustovetsky, N., Ji, R. R., Hurley, J. H., Jin, X., Shekhar, A., Xu, X. M., Oxford, G. S., Vasko, M. R., White, F. A., and Khanna, R. (2011) Suppression of inflammatory and neuropathic pain by uncoupling CRMP2 from the presynaptic Ca(2+) channel complex. Nat. Med. 17, 822-829) derived from the axonal collapsin response mediator protein 2 (CRMP2), a protein known to bind and enhance CaV2.2 activity. Using a peptide tiling array, we identified novel peptides within the first intracellular loop (CaV2.2(388-402), "L1") and the distal C terminus (CaV1.2(2014-2028) "Ct-dis") that bound CRMP2. Microscale thermophoresis demonstrated micromolar and nanomolar binding affinities between recombinant CRMP2 and synthetic L1 and Ct-dis peptides, respectively. Co-immunoprecipitation experiments showed that CRMP2 association with CaV2.2 was inhibited by L1 and Ct-dis peptides. L1 and Ct-dis, rendered cell-penetrant by fusion with the protein transduction domain of the human immunodeficiency virus TAT protein, were tested in in vitro and in vivo experiments. Depolarization-induced calcium influx in dorsal root ganglion (DRG) neurons was inhibited by both peptides. Ct-dis, but not L1, peptide inhibited depolarization-stimulated release of the neuropeptide transmitter calcitonin gene-related peptide in mouse DRG neurons. Similar results were obtained in DRGs from mice with a heterozygous mutation of Nf1 linked to neurofibromatosis type 1. Ct-dis peptide, administered intraperitoneally, exhibited antinociception in a zalcitabine (2'-3'-dideoxycytidine) model of AIDS therapy-induced and tibial nerve injury-related peripheral neuropathy. This study suggests that CaV peptides, by perturbing interactions with the neuromodulator CRMP2, contribute to suppression of neuronal hypersensitivity and nociception.

Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex.

The N-type voltage-gated calcium channel (Cav 2.2) has gained immense prominence in the treatment of chronic pain. While decreased channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse side effects. Targeting modulators of channel activity may facilitate improved analgesic properties associated with channel block and a broader therapeutic window. A novel interaction between Cav 2.2 and collapsin response mediator protein 2 (CRMP-2) positively regulates channel function by increasing surface trafficking. We recently identified a CRMP-2 peptide (TAT-CBD3), which effectively blocks this interaction, reduces or completely reverses pain behavior in a number of inflammatory and neuropathic models. Importantly, TAT-CBD3 did not produce many of the typical side effects often observed with Cav 2.2 inhibitors. Notably chronic pain mechanisms offer unique challenges as they often encompass a mix of both neuropathic and inflammatory elements, whereby inflammation likely causes damage to the neuron leading to neuropathic pain, and neuronal injury may produce inflammatory reactions. To this end, we sought to further disseminate the ability of TAT-CBD3 to alter behavioral outcomes in two additional rodent pain models. While we observed that TAT-CBD3 reversed mechanical hypersensitivity associated with a model of chronic inflammatory pain due to lysophosphotidylcholine-induced sciatic nerve focal demyelination (LPC), injury to the tibial nerve (TNI) failed to respond to drug treatment. Moreover, a single amino acid mutation within the CBD3 sequence demonstrated amplified Cav 2.2 binding and dramatically increased efficacy in an animal model of migraine. Taken together, TAT-CBD3 potentially represents a novel class of therapeutics targeting channel regulation as opposed to the channel itself.

Impairment of VGLUT2 but not VGLUT1 signaling reduces neuropathy-induced hypersensitivity.

Glutamate is the major excitatory neurotransmitter in the central nervous system with an important role in nociceptive processing. Storage of glutamate into vesicles is controlled by vesicular glutamate transporters (VGLUT). Null mutants for VGLUT1 and VGLUT2 were poorly viable, thus, pain-related behavior was presently compared between heterozygote VGLUT1 and VGLUT2 mice and their respective wild-type littermates using a test battery that included a variety of assays for thermal and mechanical acute nociception, and inflammatory and neuropathic pain syndromes. Behavioral analysis of VGLUT1 mutant mice did not show important behavioral changes in the pain conditions tested. Reduction of VGLUT2 also resulted in unaltered acute nociceptive and inflammatory-induced pain behavior. Interestingly, VGLUT2 heterozygote mice showed an attenuation or absence of some typical neuropathic pain features (e.g., absence of mechanical and cold allodynia after spared nerve injury). Chronic constriction injury in VGLUT2 heterozygote mice showed also reduced levels of cold allodynia, but had no impact on mechanical thresholds. Together, these data suggest that VGLUT2, but not VGLUT1, plays a role in neuropathy-induced allodynia and hypersensitivity, and might be a therapeutic target to prevent and/or treat neuropathic pain.

Myxoinflammatory fibroblastic sarcoma: investigations by comparative genomic hybridization of two cases and review of the literature.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade sarcoma of the distal extremities characterized by a myxohyaline stroma, a dense inflammatory infiltrate and virocyte- and lipoblast-like giant cells. Up to now, only two cases have been investigated cytogenetically, showing complex and heterogeneous karyotypes, in part with supernumerary ring chromosomes. We characterized two further cases of MIFS immunohistochemically and performed comparative genomic hybridization as well as DNA image cytometry analyses. Both tumors showed the characteristic histomorphological pattern of MIFS and were positive for Vimentin and CD68. Moreover, both cases presented aberrant karyotypes including distinct DNA copy number changes involving chromosome 7 and disclosed DNA aneuploidy.

Hereditary neuropathy with liability to pressure palsy combined with schwannomas of the median and medial plantar nerves.

A 42-year-old woman was surgically treated for carpal tunnel syndrome, revealing schwannoma of the median nerve. A year later, she developed a tarsal tunnel syndrome. At time of this diagnosis, hereditary neuropathy with liability to pressure palsies (HNPP) was diagnosed genetically and a schwannoma of the medial plantar nerve was treated surgically. The occurrence of HNPP and schwannomas in the same patient might be purely coincidental, but it is tempting to speculate that they share a common genetic basis.

Pharmacological sensitivity and gene expression analysis of the tibial nerve injury model of neuropathic pain.

The tibial nerve injury model is a novel, surgically uncomplicated, rat model of neuropathic pain based on a unilateral transection (neurotomy) of the tibial branch of the sciatic nerve. The aim of the present study was to describe some behavioral and molecular features of the model, and to test its sensitivity to a number of drugs which are currently used for the treatment of neuropathic pain. The model was characterized by a pronounced mechanical allodynia which was present in all subjects and a less robust thermal hyperalgesia. Mechanical allodynia developed within 2 weeks post-surgery and was reliably present for at least 9 weeks. Neurotomized rats showed no autotomy and their body weight developed normally. Gene expression in ipsilateral L5 dorsal root ganglia, analyzed by quantitative polymerase chain reaction (PCR), showed a pronounced up-regulation of galanin and vasointestinal peptide (VIP). This up-regulation developed rapidly (within 1 to 2 days following neurotomy) and remained present for at least 12 days. On the other hand, expression of calcitonin gene-related peptide (CGRP) and substance P mRNA was down-regulated 12 days following neurotomy. Mechanical allodynia was completely reversed by morphine [minimal effective dose (MED): 8 mg/kg, i.p.] and partially reversed by carbamazepine (MED: 64 mg/kg, i.p.), baclofen (MED: 3 mg/kg, i.p.) and amitriptyline (trend for efficacy at 32 mg/kg, i.p.), but not by gabapentin (50-100 mg/kg, i.p.). The finding that the tibial nerve injury model shows a robust and persistent mechanical allodynia which is sensitive to a number of established analgesics, as well as a gene expression profile which is compatible with that obtained in other models of neuropathic pain, further supports its validity as a reliable and surgically uncomplicated model for the study of neuropathic pain.