Intrathecal injection of dexmedetomidine ameliorates chronic neuropathic pain via the modulation of MPK3/ERK1/2 in a mouse model of chronic neuropathic pain

ABSTRACT

Objective: Despite the application of dexmedetomidine (DEX) as a perioperative adjuvant in local analgesia, the exact analgesic mechanism underpinning chronic neuropathic pain (CNP) awaits our elucidation.

Methods: We investigated the molecular mechanisms of the anti-nociceptive effect of DEX on neuropathic pain in a mouse model induced by chronic constriction injury (CCI).

Results: DEX administration significantly increased the paw withdrawal latency (PWL) values 0.5 to 2 h post-injection in CCI-induced CNP mice at day 5 to 21 versus dimethyl sulfoxide (DMSO)-treated mice, confirming its analgesic effect. The c-Fos expression was significantly elevated in CCI mice versus the sham-operated group, whereas the elevation was mitigated by DEX injection. Subsequently, the involvement of MKP1 and MKP3 in the pathogenesis of chronic neuropathic pain was evaluated. Western blotting analyses revealed significant decrease in both MKP1 and MKP3 in the spinal cord in CCI group versus the sham group. DEX markedly elevated the MKP3 expression and modestly reduced the MKP1 expression, with insignificant difference in the latter. Co-injection of BCI (an MKP3 inhibitor) and DEX evidently reduced the PWL values in CCI mice. Furthermore, DEX significantly downregulated the phosphorylation of extracellular-signal-regulated kinase (ERK) 1/2, down-stream effector of MKP3 in CCI mice, whereas the downregulation was reversed by BCI.

Conclusion: We confirmed that DEX exerts the analgesic effect on chronic neuropathic pain via the regulation of MKP3/ERK1/2 signaling pathway, which may contribute to clarification of the molecular mechanism and novel therapy for chronic neuropathic pain.     

Mowat–Wilson syndrome: the first report of an association with central nervous system tumors

Mowat–Wilson syndrome (MWS) is a rare genetic condition where variable and multiple congenital anomalies including Hirschsprung's disease, intellectual disability, and prominent facial features are present. At molecular level, MWS is characterized by many different described mutations in the zinc finger E-box protein 2 (ZEB2) gene, ultimately leading to loss of gene function. This report is the first to describe the association of MWS with two different asynchronous malignant brain tumors (medulloblastoma and glioblastoma) occurring in a child.     

Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma

Prevalence of neuropathic pain is high after major surgery. However, effective treatment for preventing neuropathic pain is lacking. Here we report that perisurgical treatment of neuroprotectin D1/protectin D1 (NPD1/PD1), derived from docosahexaenoic acid, prevents nerve injury‐induced mechanical allodynia and ongoing pain in mice. Intrathecal post‐treatment of NPD1/PD1 also effectively reduces established neuropathic pain and produces no apparent signs of analgesic tolerance. Mechanistically, NPD1/PD1 treatment blocks nerve injury‐induced long‐term potentiation, glial reaction, and inflammatory responses, and reverses synaptic plasticity in the spinal cord. Thus, NPD1/PD1 and related mimetics might serve as a new class of analgesics for preventing and treating neuropathic pain. Ann Neurol 2013;74:490–495     

Clinical features and management of intracranial subependymomas in children

Subependymoma is a rare low-grade glioma of the central nervous system that occurs most commonly in middle-aged and elderly men and rarely in children. Only a few paediatric patients with subependymomas have been reported. The authors retrospectively analysed five paediatric patients (4 males and 1 female; mean age 8.6 years; age range 5–13 years) at a single institute from July 1998 to April 2009 and summarised the clinical characteristics and management of paediatric intracranial subependymoma. The most common symptom in these five paediatric patients with subependymoma was intracranial hypertension. The tumours were located in the fourth ventricle in two patients, in the fourth ventricle with extension to the cerebellopontine angle (CPA) in one patient; in the right CPA exclusively in one patient, and intraparenchymally in the left parietal lobe in one patient, the latter two of which are rare locations for subependymoma. Surgery was performed on all five patients. The surgical approach was selected as appropriate for the tumor location. Total resection was achieved in three patients, and subtotal resection in two. All five patients had good outcomes without recurrence. We conclude that surgery is the optimal therapy for paediatric patients with intracranial subependymoma.     

Case Report of Rapid-eye-movement(REM) sleep behavior disorder

Summary

A 23-year-old female student presented with a five-year history of abnormal sleep in which she would sit up or stand up for brief periods in the early morning, talk loudly for a couple of minutes and then lie back down. When woken by family members she would remember vivid dreams and nightmares. In one episode she had a fall that resulted in a subdural hematoma. On presentation at the psychiatric hospital she had a normal mental status exam except for being mildly depressed and anxious about the chronic fatigue from poor sleep. Overnight polysomnography (PSG) showed multiple waking periods each night, poor sleep efficiency and a lack of normal muscle paralysis during REM sleep. The patient was diagnosed with REM Sleep Behavior Disorder and treated with 1 mg clonazepam nightly. Her sleep improved dramatically and remained better at a six-month follow-up, but repeat PSG exam found that the lack of muscle paralysis during REM sleep remained.     

Oculomotor Nerve Injury Induces Nuerogenesis in the Oculomotor and Edinger–Westphal Nucleus of Adult Dog

Technical developments have extensively promoted experimental and clinical studies on cranial nerve regeneration, but intracranial nerve recovery is still an unexplored research area compared to peripheral nerve repair. In this study, we researched whether neurogenesis occurs in adult oculomotor (OMN) and Edinger–Westphal nucleus (EWN) or not after oculomotor nerve injury. To assess cell proliferation in response to unilateral oculomotor nerve crush (ONC) in adult beagle dog, repetitive 5-bromo-2′-deoxyuridine (BrdU) intravenous injections were performed during 3 or 7 days before the dogs were euthanized 2 h after the last injection on days 3, 7, 14, and 28 post-ONC. The proliferating cell types were investigated with three cell phenotypic markers and confocal microscopy on serial sections throughout the whole extent of OMN and EWN. BrdU-positive nuclei were detected in bilateral OMNs and EWNs from 3 to 28 days after ONC with the peak value at 3 days. Confocal analysis revealed that partial BrdU-positive cells colocalized with nestin or βIII-tubulin or GFAP, and the number of every kind of double-labeled cell maintained an increased tendency from 3 to 28 days post-ONC. Neither single-labeled BrdU-positive nuclei nor double-labeled cells were detected in the subependymal layer of cerebral aqueduct (SELCA) of all unilateral ONC dogs; also, they were not observed in the OMNs, EWNs, and SELCA of intact and sham-operated dog. These findings demonstrate that ONC can trigger continual mitotic activity, proliferation of NSCs, neurogenesis, and astrogliogenesis in the OMN and EWN of adult dogs.     

A functional modified graphene oxide/nanodiamond/nano zinc oxide composite for excellent vulcanization properties of natural rubber

A modified graphene oxide/nanodiamond/nanozinc oxide (MGO/ND/nanoZnO) functional hybrid filler is designed and prepared to improve the vulcanization efficiency of a rubber composite and to reduce the use of ZnO. ND was grafted onto graphite oxide with the aid of 4,4′-methylene diphenyl diisocyanate (MDI). NanoZnO, with high surface activity, was then loaded onto the MGO/ND complex through the wet chemical method, in order to synthesize the MGO/ND/nanoZnO functional hybrid filler. Rubber composites were prepared using the rubber latex composite method and their vulcanization behaviors were investigated. Our results show that the MGO/ND/nanoZnO functional hybrid filler can remarkably improve the vulcanization behaviors of the rubber composite. Compared with that of pure natural rubber (NR), the vulcanization activation energy of the rubber composite was reduced by approximately 16%. Moreover, the vulcanization efficiency can be improved by 63% (i.e., the optimum cure time is shortened from the original 405 s to 150 s) after the same amount of traditional ZnO was replaced by the functional hybrid filler loaded with 1 wt% nanoZnO. The prepared MGO/ND/nanoZnO functional hybrid filler thus provides a promising alternative to improve the vulcanization efficiency of rubber composites.

A modified graphene oxide/nanodiamond/nanozinc oxide (MGO/ND/nanoZnO) functional hybrid filler is designed and prepared to improve the vulcanization efficiency of a rubber composite and to reduce the use of ZnO.     

Novel rhodamine dye with large Stokes shifts by fusing the 1,4-diethylpiperazine moiety and its applications in fast detection of Cu2+

Rhodamine dyes were widely developed for designing probes due to their excellent photophysical properties and biocompatibility. However, traditional rhodamine dyes still bear major drawbacks of short emission wavelengths (<600 nm) and narrow Stokes shifts (<30 nm), which limit their biological imaging applications. Herein, we reported a novel mitochondria-targeted fluorescent dye JRQ with near-infrared (NIR) emission wavelength and improved Stokes shift (63 nm) by tuning the donor–acceptor–donor (D–A–D) character of the rhodamine skeleton. As expected, JRQ exhibited multiple excellent properties and could accumulate in mitochondria, and can therefore be used as a signal reporter for the design of fluorescent probes by taking advantage of the fluorescence controlled mechanism of the ring opening and closing chemical processes of the spirolactone platform. By using JRQ as a precursor, a highly sensitive fluorescent probe JRQN for the fast detection of mitochondrial Cu²⁺ ions was synthesized based on the Cu²⁺-triggered specific hydrolysis mechanism because mitochondria are an important reservoir of intracellular Cu²⁺. We expect that the Stokes shift increase of rhodamine dyes via tuning the donor–acceptor–donor (D–A–D) character of the rhodamine skeleton will provide a novel synthetic approach for the development of rhodamine dyes and expansion of their applications.

A novel NIR rhodamine dye JRQ with large Stokes shift (70 nm) by fusing the 1,4-diethylpiperazine moiety in rhodamine dyes has been synthesized and utilized to design a probe.