Chang-Mu Chen

Novel regimen through combination of memantine and tea polyphenol for neuroprotection against brain excitotoxicity.

NMDA receptors are abundant, ubiquitously distributed throughout the brain, fundamental to excitatory neurotransmission, and critical for normal CNS function. However, excessive glutamate overstimulates NMDA receptors, leading to increased intracellular calcium and excitotoxicity. Mitochondrial dysfunction associated with loss of Ca2+homeostasis and enhanced cellular oxidative stress has long been recognized to play a major role in cell damage associated with excitotoxicity. In this experiment, we attempted to explore whether treatment with memantine (an NMDA receptor antagonist) and tea polyphenol (an antioxidant and anti‐inflammatory agent), either alone or in combination, is effective in neuroprotection in a mouse excitotoxic injury model. Memantine (10 mg/kg/day), tea polyphenol (60 mg/kg/day), or a combination (memantine 5 mg/kg/day plus tea polyphenol 30 mg/kg/day) was administered by oral gavage for 2 consecutive days before causing excitotoxic injury. Mice received a 0.3‐μL NMDA [335 mM (pH 7.2)] injection into the left striatum. Locomotor activity was assessed 24 hr before and after excitotoxic injury. Brain synaptosomes were harvested 24 hr after excitotoxic injury for assessment of Na+, K+‐ATPase and Mg2+‐ATPase activity, reactive oxygen species production, mitochondrial membrane potential (ΔΨm), mitochondrial reductase activity (MTT test), and Ca2+concentration. The results showed that treatment with memantine could significantly rescue mitochondrial function by attenuating the decreased mitochondrial membrane potential (ΔΨm) and mitochondrial reductase activity in mouse excitotoxic injury. Treatment with tea polyphenol could significantly decrease the increased production of synaptosomal reactive oxygen species (ROS) and thus reduced the deteriorative ROS‐sensitive Na+, K+‐ATPase and Mg2+‐ATPase activity. However, neither memantine nor tea polyphenol alone could significantly improve the impaired locomotor activity unless treatment was combined. Combined treatment with memantine and tea polyphenol could significantly protect mice against excitotoxic injury by reducing the increased synaptosomal ROS production, attenuating the decreased Na+, K+‐ATPase and Mg2+‐ATPase activity, the mitochondrial membrane potential (ΔΨm), the mitochondrial reductase activity, and the increased synaptosomal Ca2+concentration. In addition, the impairment in locomotor activity was also significantly improved. Therefore, the combined treatment of memantine and tea polyphenol is more effective in neuroprotection than either memantine or tea polyphenol alone in mouse excitotoxic injury. These findings provide useful information about the potential application of memantine and tea polyphenols in preventing clinical excitotoxic injury such as brain trauma, brain ischemia, epilepsy, and Alzheimers disease.

C/EBP Homologous Protein (CHOP) Deficiency Aggravates Hippocampal Cell Apoptosis and Impairs Memory Performance

Neurodegenerative disorders are growing burdens in modern societies because of increased life expectancy. Most neurodegenerative disorders commonly possess a similar neuropathological feature - the accumulation of abnormal protein aggregates or inclusions (misfolded proteins) in the brain. One of the main functions of endoplasmic reticulum (ER) is to initiate proper protein folding to facilitate protein secretion through the induction of unfolded protein response (UPR). C/EBP homologous protein (CHOP) induction has been demonstrated to be a signaling event underlying ER stress-induced cell apoptosis. In this study, we explored the role of CHOP in the hippocampal cell apoptosis and memory performance injury under an induced ER stress condition. Adult male wild type (C57BL/6J) and CHOP knockout (CHOP−/−) mice were intracerebroventricularly injected with tunicamycin. Tunicamycin can induce ER stress and cell apoptosis in mouse hippocampus. Compared with wild type mice, CHOP−/− mice showed an enhanced hippocampal cell apoptosis, worse performance in memory-related behavioral tests, and attenuated IRE-1 expression under tunicamycin treatment. The aggravated cell apoptosis and worse memory performance in CHOP−/− mice might be due to the deficiency of CHOP protein resulted in the impaired adaptive/pathological transcriptional response, the decreased IRE-1 and XBP-1 expressions, and the increased JNK phosphorylation to cope with ER stress. Taken together, these results suggest that CHOP may play a protective role in the hippocampal cell apoptosis and impairment of memory performance.

Titanium nanoparticle inhalation induces renal fibrosis in mice via an oxidative stress upregulated transforming growth factor-β pathway.

Titanium dioxide nanoparticles (Nano-TiO2) are gradually being used extensively in clinical settings, industry, and daily life. Accumulation studies showed that Nano-TiO2 exposure is able to cause injuries in various animal organs, including the lung, liver, spleen, and kidney. However, it remains unclear whether exposure of Nano-TiO2 by inhalation causes renal fibrosis. Here, we investigated the role of reactive oxygen species (ROS)/reactive nitrogen species (RNS) related signaling molecules in chronic renal damage after Nano-TiO2 inhalation in mice. Mice were treated with Nano-TiO2 (0.1, 0.25, and 0.5 mg/week) or microparticle-TiO2 (0.5 mg/week) by nonsurgical intratracheal instillation for 4 weeks. The results showed that Nano-TiO2 inhalation increased renal pathological changes in a dose-dependent manner. No renal pathological changes were observed in microparticle-TiO2-instilled mice. Nano-TiO2 (0.5 mg/week) possessed the ability to precipitate in the kidneys, determined by transmission electron microscopy and increased serum levels of blood urea nitrogen. The expressions of markers of ROS/RNS and renal fibrosis markers, including nitrotyrosine, inducible nitric oxide synthase, hypoxia inducible factor-1α (HIF-1α), heme oxygenase 1, transforming growth factor-β (TGFβ), and collagen I, determined by immunohistochemical staining were increased in the kidneys. Furthermore, Nano-TiO2-induced renal injury could be mitigated by iNOS inhibitor aminoguanidine and ROS scavenger N-acetylcysteine treatment in transcription level. The in vitro experiments showed that Nano-TiO2 significantly and dose-dependently increased the ROS production and the expressions of HIF-1α and TGFβ in human renal proximal tubular cells, which could be reversed by N-acetylcysteine treatment. Taken together, these results suggest Nano-TiO2 inhalation might induce renal fibrosis through a ROS/RNS-related HIF-1α-upregulated TGF-β signaling pathway.

PPARγ is involved in the hyperglycemia‐induced inflammatory responses and collagen degradation in human chondrocytes and diabetic mouse cartilages

Diabetic hyperglycemia has been suggested to play a role in osteoarthritis. Peroxisome proliferator‐activated receptor‐γ (PPARγ) was implicated in several pathological conditions including diabetes and inflammation. The detailed effects and mechanisms of hyperglycemia on cartilage damage still need to be clarified. Here, we investigated the role of PPARγ in hyperglycemia‐triggered chondrocyte/cartilage damages using a human chondrocyte culture model and a diabetic mouse model. Human chondrocytes were cultured and treated with high concentration of glucose (30 mM) to mimic hyperglycemia in the presence or absence of pioglitazone, a PPARγ agonist. Streptozotocin (STZ) was used to induce mouse diabetes. Our data showed that high glucose induced the protein expressions of cyclooxygenase‐2 (COX‐2) and production of prostaglandin‐E2 (PGE2), interleukin‐6 (IL‐6), and metalloproteinase‐13 (MMP‐13), but decreased the protein expression of collagen II and PPARγ in human chondrocytes. These alterations in high glucose‐treated human chondrocytes could be reversed by pioglitazone in a dose‐dependent manner. Moreover, pioglitazone administration could also significantly reverse the hyperglycemia, formation of AGEs, productions of IL‐6 and MMP‐13, and cartilage damage in STZ‐induced diabetic mice. Taken together, these findings suggest that hyperglycemia down‐regulates PPARγ expression and induces inflammatory and catabolic responses in human chondrocytes and diabetic mouse cartilages.

Severe Rhabdomyolysis with Good Recovery in a Patient with Head Injury: Case Report

OBJECTIVE AND IMPORTANCE We report a case of head injury, in which a hyperosmolar state evolved during the course of treatment, complicated by severe rhabdomyolysis and acute renal failure, which subsequently resulted in a good recovery after intensive supportive treatment. To our knowledge, such high levels of creatine kinase in a patient with head injury and rhabdomyolysis have not been reported. CLINICAL PRESENTATION AND INTERVENTION A 19-year-old male patient with head injury sustained a compound fracture of the frontal region. He received a hyperosmolar agent to treat brain edema and developed a hyperosmolar state and diabetes insipidus 1 day after the accident. There were no obvious associated injuries at physical examination. After admission to the intensive care unit, the patient developed myoglobinuria and rhabdomyolysis; serum creatine kinase was elevated to a peak of 650,000 IU/L. Four days later, acute renal failure was noted. The patients myoglobinuria and rhabdomyolysis gradually declined, and he eventually recovered from acute renal failure after supportive treatment and dialysis. CONCLUSION We postulate that the hyperosmolar state of the patient was the major cause of his severe rhabdomyolysis. Associated hypokalemia and hypophosphatemia are also predisposed to rhabdomyolysis. The most serious complication in rhabdomyolysis is acute renal failure, but most patients who receive supportive treatment and can survive despite the complications can expect to have normal renal function restored.

A Proposed Method to Comprehensively Define Outcomes in Acoustic Tumor Patients Undergoing CyberKnife Management

Background: Vestibular assessment in patients with acoustic tumor (so-called vestibular schwannoma, VS) via ocular vestibular-evoked myogenic potential (oVEMP) and cervical VEMP (cVEMP) tests are not often discussed in the neurosurgical literature. Objectives: This study conducted physiological and morphological assessments for VS patients before and after CyberKnife radiosurgery. Methods: Twenty patients with unilateral VS underwent a battery of tests comprising facial nerve function test, audiometry, and caloric, oVEMP and cVEMP tests before and 2 years after CyberKnife treatment at a mean dosage of 18 Gy in 3 fractions. Results: The abnormal percentages of caloric, oVEMP and cVEMP tests did not significantly differ before and after Cyberknife treatment, indicating that preservation of the superior and inferior vestibular nerves can be achieved after radiosurgery. Median tumor volumes, 1.49 cm3 before treatment versus 0.97 cm3 at 2 years after treatment, differed significantly. Conclusions: The use of oVEMP and cVEMP tests in VS patients before stereotactic radiosurgery may help to evaluate the tumor origin from the superior or inferior vestibular nerve. It takes a short time and costs less, and it would be practical to make this a routine examination in VS patients having stereotactic radiosurgery.

Green Tea Catechin Prevents Hypoxia/Reperfusion-Evoked Oxidative Stress-Regulated Autophagy-Activated Apoptosis and Cell Death in Microglial Cells

Defective activation and proliferation in microglial cells has been suggested to be associated with the increase of cerebral ischemia/reperfusion injury. We investigated the protection and molecular mechanism of green tea catechin on hypoxia/reperfusion-induced microglial cell injury in vitro. Microglial cells were cultured in hypoxia condition (O2 < 1%) and then re-incubated to the complete normal culture medium (reperfusion). Hypoxia/reperfusion obviously decreased cell viability and induced apoptosis in microglial cells, but not in neuronal cells. Catechin significantly inhibited the hypoxia/reperfusion-induced decreased cell viability and increased reactive oxygen species (ROS) and apoptosis in microglia. The administration of both PI3K/Akt inhibitor LY294002 and mTOR inhibitor rapamycin demonstrated that Akt/mTOR-regulated autophagy was involved in the hypoxia/reperfusion-induced microglia apoptosis/death. Catechin up-regulated the Akt and mTOR phosphorylation and inhibited the hypoxia/reperfusion-induced autophagy in microglia. These results suggest that hypoxia/reperfusion can evoke autophagy-activated microglia apoptosis/death via an ROS-regulated Akt/mTOR signaling pathway, which can be reversed by catechin.

Spontaneous healing of retroperitoneal chylous leakage following anterior lumbar spinal surgery: a case report and literature review.

Cisterna chyli is prone to injury in any retroperitoneal surgery. However, retroperitoneal chylous leakage is a rare complication after anterior spinal surgery. To the best of our knowledge, only ten cases have been reported in the English literature. We present a case of a 49-year-old man who had lumbar metastasis and associated radiculopathy. He had transient retroperitoneal chylous leakage after anterior tumor decompression, interbody bony fusion, and instrumental fixation from L2 to L4. The leakage stopped spontaneously after we temporarily clamped the drain tube. Intraperitoneal ascites accumulation developed thereafter due to nutritional loss and impaired hepatic reserves. We gathered ten reported cases of chylous leak after anterior thoracolumbar or lumbar spinal surgery, and categorized all these cases into two groups, depending on the integrity of diaphragm. Six patients received anterior spinal surgery without diaphragm splitting. Postoperative chylous leak stopped after conservative treatment. Another five cases received diaphragm splitting in the interim of anterior spinal surgery. Chylous leakage stopped spontaneously in four patients. The remaining one had a chylothorax secondary to postop chyloretroperitoneum. It was resolved only after surgical intervention. In view of these cases, all the chylous leakage could be spontaneously closed without complications, except for one who had a secondary chylothorax and required thoracic duct ligation and chemopleurodesis. We conclude that intraoperative diaphragm splitting or incision does not increase the risk of secondary chylothorax if it was closed tightly at the end of the surgery and the chest tube drainage properly done.

Differentiating cerebellopontine angle meningioma from schwannoma using caloric testing and vestibular-evoked myogenic potentials.

OBJECTIVE This study utilized audiometry, and caloric, ocular vestibular-evoked myogenic potential (oVEMP) and cervical VEMP (cVEMP) tests to differentiate between cerebellopontine angle (CPA) meningioma and schwannoma. PATIENTS AND METHODS Eleven CPA meningioma patients with mean tumor size 2.8±1.4 cm and another 11 CPA schwannoma patients with mean tumor size 2.7±1.0 cm were enrolled in this study. All patients underwent a battery of audiovestibular function tests. RESULTS The two groups did not differ significantly in terms of clinical manifestation. The abnormal percentage of caloric test in the meningioma group was 36%, compared to 91% in the schwannoma group, and thus both groups differed significantly. However, such difference was not observed between the two groups regardless of mean hearing level, oVEMP test and cVEMP test. CONCLUSION Combined caloric with oVEMP test results may help differentiate a CPA tumor. Correlation between the caloric and oVEMP test results in a CPA tumor indicates a schwannoma nature, while dissociation between the caloric and oVEMP test results depicts a meningioma character.

Correlating vestibular schwannoma size with vestibular-evoked myogenic potential results.

Objectives: The maximum size of the vestibular schwannoma (VS) that is compatible with preservation of the function of the vestibular nerve in performing stereotactic radiosurgery remains unclear. This study utilized ocular vestibular-evoked myogenic potential (oVEMP) and cervical VEMP (cVEMP) test results to correlate with the size of VS. Design: Fifty patients with unilateral VS underwent audiometry, and caloric, oVEMP and cVEMP tests. Tumor size from magnetic resonance imaging was measured on the axial plane, and the relationships between tumor size and each test result were analyzed. Results: The pure-tone average from four frequencies did not significantly predict tumor size. Alternatively, oVEMP and cVEMP responses remained significant predictors for tumor size in the regression model, namely, tumor size (cm) = 0.62 × (oVEMP response) + 1.39 × (cVEMP response), where oVEMP and cVEMP responses were regarded as binary variables, in which 1 and 0 reflect abnormal and normal responses, respectively. This model explained 76% of the variance. Accordingly, the estimated VS size exhibiting abnormal oVEMPs and cVEMPs is >2.01 (0.62 +1.39) cm. Conclusions: When VS size is <2.0 cm, preservation of the function of superior/inferior vestibular nerve indicated by the oVEMP/cVEMP test is achievable. Therefore, both oVEMP and cVEMP tests may serve as supplementary tools for determining treatment option in VS patients.