Bosutinib Attenuates Inflammation via Inhibiting Salt-Inducible Kinases in Experimental Model of Intracerebral Hemorrhage on Mice.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a subtype of stroke with highest mortality and morbidity. Pronounced inflammation plays a significant role in the development of the secondary brain injury after ICH. Recently, SIK-2 (salt-inducible kinase-2) was identified as an important component controlling inflammatory response. Here we sought to investigate the role of SIK-2 in post-ICH inflammation and potential protective effects of SIK-2 inhibition after ICH. METHODS: Two hundred and ninety-three male CD-1 mice were used. ICH was induced via injection of 30 µL of autologous blood. Recombinant SIK-2 was administrated 1 hour after ICH intracerebroventricularly. SIK-2 small interfering RNA was injected intracerebroventricularly 24 hours before ICH. Bosutinib, a clinically approved tyrosine kinase inhibitor with affinity to SIK-2, was given intranasally 1 hour or 6 hours after ICH. Effects of treatments were evaluated by neurological tests and brain water content calculation. Molecular pathways were investigated by Western blots and immunofluorescence studies. RESULTS: Endogenous SIK-2 was expressed in microglia and neurons. SIK-2 expression was reduced after ICH. Exogenous SIK-2 aggravated post-ICH inflammation, leading to brain edema and the neurobehavioral deficits. SIK-2 inhibition attenuated post-ICH inflammation, reducing brain edema and ameliorating neurological dysfunctions. Bosutinib inhibited SIK-2-attenuating ICH-induced brain damage. Protective effects of Bosutinib were mediated, at least partly, by CRTC3 (cyclic amp-response element binding protein-regulated transcription coactivator 3)/cyclic amp-response element binding protein/NF-κB (nuclear factor-κB) pathway. CONCLUSIONS: SIK-2 participates in inflammation induction after ICH. SIK-2 inhibition via Bosutinib or small interfering RNA decreased inflammation, attenuating brain injury. SIK-2 effects are, at least partly, mediated by CRTC3-cyclic amp-response element binding protein-NF-κB signaling pathway.

Neuroprotective Mechanisms of Melatonin in Hemorrhagic Stroke.

Hemorrhagic stroke which consists of subarachnoid hemorrhage and intracerebral hemorrhage is a dominant cause of death and disability worldwide. Although great efforts have been made, the physiological mechanisms of these diseases are not fully understood and effective pharmacological interventions are still lacking. Melatonin (N-acetyl-5-methoxytryptamine), a neurohormone produced by the pineal gland, is a broad-spectrum antioxidant and potent free radical scavenger. More importantly, there is extensive evidence demonstrating that melatonin confers neuroprotective effects in experimental models of hemorrhagic stroke. Multiple molecular mechanisms such as antioxidant, anti-apoptosis, and anti-inflammation, contribute to melatonin-mediated neuroprotection against brain injury after hemorrhagic stroke. This review article aims to summarize current knowledge regarding the beneficial effects of melatonin in experimental models of hemorrhagic stroke and explores the underlying mechanisms. We propose that melatonin is a promising neuroprotective candidate that is worthy of further evaluation for its potential therapeutic applications in hemorrhagic stroke.

Delayed Intracerebral Hemorrhage Secondary to Ventriculoperitoneal Shunt: A Case Report and Literature Review.

The ventriculoperitoneal (VP) shunt is a routine procedure for cerebrospinal fluid (CSF) diversion, and is associated with many complications. A delayed hemorrhage after the VP shunt surgery, however, is quite rare. In this study, we report a case involving late-onset hemorrhage. The 67-year-old male patient with a history of head trauma and brain surgery underwent a VP shunt placement for hydrocephalus. The surgery course was uneventful and no bleeding was revealed in the first computed tomographic (CT) scan after the procedure. However, a massive intraparenchymal and intraventricular hemorrhage occurred 8 h following adjustment of the valve system on the 8th day after surgery.Erosion of the vasculature by catheter cannulation and a sudden reduction of CSF pressure after downregulation of the valve could be one of the possible causes of the intracerebral hemorrhage (ICH).

Intracerebral schwannoma mimicking parasagittal meningioma.

A 24-year-old female patient presented to the neurological department after a seizure that lasted for 10 minutes. Magnetic resonance imaging revealed a cystic and heterogeneously enhanced giant mass in the right frontal lobe mimicking parasagittal meningioma. Surgery via a single frontal craniotomy confirmed the tumor was attached to the falx cerebri and sagittal sinus. The histological diagnosis was schwannoma. Since total resection of the tumor, the patient was seizure free. Twelve months of follow-up revealed good outcome.

LRIG1 dictates the chemo-sensitivity of temozolomide (TMZ) in U251 glioblastoma cells via down-regulation of EGFR/topoisomerase-2/Bcl-2.

In the current study, we aimed to understand the potential role of leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) in TMZ-resistance of U251 glioma cells. We established TMZ-resistant U251 clones (U251/TMZ cells), which expressed low level of LRIG1, but high levels of epidermal growth factor receptor (EGFR), topoisomerase-2 (Topo-2) and Bcl-2. Depletion of LRIG1 by the targeted RNA interference (RNAi) upregulated EGFR/Topo-2/Bcl-2 in U251 cells, and the cells were resistant to TMZ. Reversely, over-expression of LRIG1 in U251 cells downregulated EGFR/Topo-2/Bcl-2 expressions, and cells were hyper-sensitive to TMZ. Our data suggested EGFR-dependent mammalian target of rapamycin (mTOR) activation was important for Topo-2 and Bcl-2 expressions in U251/TMZ cells. The EGFR inhibitor and the mTOR inhibitor downregulated Topo-2/Bcl-2 expressions, both inhibitors also restored TMZ sensitivity in U251/TMZ cells. Finally, inhibition of Topo-2 or Bcl-2 by targeted RNAi(s) knockdown or by the corresponding inhibitor re-sensitized U251/TMZ cells to TMZ, indicating that both Topo-2 and Bcl-2 were important for TMZ resistance in the resistant U251 cells. Based on these results, we concluded that LRIG1 inhibits EGFR expression and the downstream signaling activation, interferes with Bcl-2/Topo-2 expressions and eventually sensitizes glioma cells to TMZ.

Leakage of cerebrospinal fluid and secondary intracranial infection induced by Cloward technique of cervical discectomy and fusion: presentation and treatment.

Cloward technique of cervical discectomy and fusion is a long and complex surgical procedure and instrumentation, by which complicated infection is rare in an era of routine prophylactic antimicrobial agent, especially in procedures by anterior approach. A study in the journal of Spine suggested that the incidence of unintentional laceration of the dura mater during spinal surgery might be as high as 14%.1 A majority of them are repaired intraoperatively and/or present as a spontaneous process of healing. Therefore, leakage of cerebrospinal fluid (CSF) and secondary intracranial infection induced by incidental durotomy are rare. Levi et al.2 reviewed spinal instrumentation procedures in 452 cases at a single institution, finding that 17 patients got infections in the operative areas. Infection occurred after posterior spinal instrumentation procedures (7.2%) and no infection was found after anterior instrumentation procedures regardless of the vertebral levels. Likewise, Aydinli et al.3 reported that 8 patients were complicated by acute infection out of 174 patients undergoing instrumented spinal surgery, including no anterior procedures. To our knowledge, we are the first to report a complete clinical course concerning CSF leakage and secondary intracranial infection induced by Cloward technique of cervical discectomy and fusion.

[Neuron regeneration in aged rats after intracerebral hemorrhage].

OBJECTIVE: To investigate neuron regeneration of aged rats after intracerebral hemorrhage(ICH). METHODS: ICH model was induced by intracerebral infusion of 100microL autologous blood in adult and aged (3 and 18 m of age, respectively) male Sprague-Dawley (SD) rats. Doublecortin(DCX), polysialylated neural cell adhesion protein(PSA-NCAM) and Bromodeoxyuridine (Brdu) in brain tissue were detected by Western blot analysis and immunohistochemical examination. RESULT: In aged rats, DCX levels in the ipsilateral basal ganglia and subventricular zone started to increase at 7d after ICH, peaked at 14 d [(670+/-145)% of controls, P<0.01]. Most DCX positive cells in ipsilateral striatum were BrdU positive. Though DCX content in ipsilateral basal ganglia [(2560+/-758) pixels]of ICH aged rats was much higher than that of aged rat controls [(450+/-97)pixels, P<0.01], it was still lower than that in adult rats. CONCLUSION: The results demonstrate that neuron regeneration occurs in subventricular zone in the aged rats following intracerebral hemorrhage(ICH).

Biomechanical evaluation of cranial flap fixation techniques: comparative experimental study of suture, stainless steel wire, and rivetlike titanium clamp.

OBJECTIVE: To study the techniques of cranial flap fixation (suture, stainless steel wire, and rivetlike titanium clamp) on biomechanics. METHODS: Twenty-four cadaver craniotomy flaps were reattached with either suture, stainless steel wire, or rivetlike titanium clamp. Cranial flap fixation was timed and measured for the offset between cranial flap with craniotomy skull for every fixation technique. Load-bearing tests were performed by applying an external force until the failure of the fixation system. RESULTS: Rivetlike titanium clamp required significantly less time to fix (94 +/- 13 seconds) than either suture (172 +/- 14 seconds) or stainless steel wire (399 +/- 45 seconds). The offset of cranial flap after rivetlike titanium clamp fixation (0.20 +/- 0.12 mm) was significantly smaller than either suture (2.20 +/- 0.24 mm) or stainless steel wire (1.32 +/- 0.34 mm). Rivetlike titanium clamp was also stronger than suture and stainless steel wire in the load-bearing test. CONCLUSION: Rivetlike titanium clamp is easy to use, requires less time consumption, and shows accuracy and strength.

[Growth-suppression effect of hydroxyurea on meningioma cells in vitro].

OBJECTIVE: To investigate the tumor-suppression effect of hydroxyurea on meningioma cells and its possible mechanism. METHODS: The meningioma cells were cultured in medium containing varied doses of hydroxyurea (5x10(-3)mol/L, 5x10(-4)mol/L, 5x10(-5)mol/L), the cell growth was measured by MTT method, cell apoptosis was observed with flow cytometry (FCM). RESULTS: MTT measurement demonstrated that the administration of hydroxyurea led to a dose-dependent suppression in cell proliferation and FCM showed a dose-dependent increase in apoptosis rate. CONCLUSION: Hydroxyurea can inhibit meningioma cell growth in vitro, which is most likely associated with apoptosis of the tumor cells.