Honey bee venom melittin increases the oxidant activity of cisplatin and kills human glioblastoma cells by stimulating the TRPM2 channel.

Melittin (MLT) treatment is believed to enhance tumor cell death, apoptotic, and oxidative cytotoxic effects of cisplatin (CSP) via the modulation of Ca2+ channels in several cancer lines. The activation of TRPM2 mediated anticancer and CSP resistance actions via mitochondrial Ca2+ and Zn2+ accumulation-induced mitochondrial reactive free oxygen species (MitSOX) in the glioblastoma cells. The aim was to elucidate the effects of CSP and MLT combination via the TRPM2 stimulation on the tumor cell viability, cell number, cell death (propidium iodide/Hoechst rate), apoptosis, and MitSOX levels in the DBTRG-05MG cells. In the DBTRG-05MG cells, we induced four groups as control, MLT (2.5 µg/ml for 24 h), CSP (25 µM for 24 h), and CSP + MLT. The CSP-induced intracellular Ca2+ influxes to the TRPM2 activation were increased in the cells from coming H2O2 and ADP-Ribose. The influxes were decreased in the cells by the incubations of TRPM2 antagonists (ACA and carvacrol). The incubation of CSP increased the parameters of intracellular Ca2+ responses, mitochondria function, cytosolic free Zn2+ accumulation, apoptosis (caspase -3, -8, and -9), and MitSOX generation in the tumor cells. After the treatment of MLT with/without CSP, the parameters were further increased in the cells. In conclusion, the treatment of MLT increased the anticancer, tumor cell death, apoptotic, and oxidant effects of CSP in the glioblastoma tumor cells via activating the TRPM2. As a result, TRPM2 stimulation by MLT may be utilized as a successful agent in the CSP treatment of glioblastoma tumors.

Transoral penetrating upper cervical injury: a case report.

Transoral penetrating foreign body injury of the neck involving the cervical spine is a rare condition. We present an injury caused by transoral penetration of a broken piece of a wooden plank into the neck with injury to the upper cervical spine in a 31-year-old male patient. The foreign body was removed transorally with the patient making a full recovery under close observation and was discharged and followed up with no complications. This paper highlights the types of neck injuries, the key points to be considered in zone III neck injury in light of existing literature and a discussion on the management of these patients.

Melatonin and Selenium Suppress Docetaxel-Induced TRPV1 Activation, Neuropathic Pain and Oxidative Neurotoxicity in Mice.

Docetaxel (DT) has been reported to positive therapeutic actions in the treatment of glioblastoma, breast tumors, and prostate cancers. However, it can also induce peripheral neuropathic pain and neurotoxicity as adverse effects. Expression level of TRPV1 cation channel is high in dorsal root ganglion (DRG), and its activation via capsaicin and reactive oxygen species (ROS) mediates peripheral neuropathic pain in mice. As cancer is known to increase the levels of ROS, the protective roles of melatonin (MT) and selenium (Se) were evaluated on the TRPV1-mediated neurotoxicity and pain in the DT-treated mice. Mice and TRPV1 expressing SH-SY5Y cells were equally divided into control, MT, Se, DT, DT+MT, and DT+Se groups. In the results of pain tests in the mice, we observed a decrease in DT-mediated mechanical and heat neuropathic pain by MT and Se. The results of plate reader assay and laser confocal microscopy image analyses indicated a protective role of MT and Se on the DT-induced increase of mitochondrial ROS, cytosolic ROS, apoptosis, lipid peroxidation, intracellular free Zn2+, Ca2+, and caspase-3 and -9 levels in the DRG and SH-SY5Y cells. MT and Se modulated DT-induced decreases of total antioxidant status, reduced glutathione and glutathione peroxidase in the DRG. However, the effects of DT were not observed in the non-TRPV1 expressing SH-SY5Y cells. Hence, MT and Se mediated protective effects against DT-induced adverse peripheral oxidative neurotoxicity and peripheral pain. These effects may be attributed to potent antioxidant properties of MT and Se.

Pregabalin reduces oxaliplatin-induced oxidative neurotoxicity through modulation of TRPV1 channels in DBTRG neuronal cell line.

As a member of the platinum drug group, oxaliplatin (OXAL) is used to treat brain tumors, although its use is limited through excessive calcium ion (Ca) influx and reactive oxygen species (ROS) production in neurons. The Ca permeable transient receptor potential vanilloid 1 (TRPV1) channel is activated by ROS, and its activity might be reduced by the antioxidant property of pregabalin (PREGAB). This study aimed to investigate the protective action of PREGAB against OXAL-induced oxidative neurotoxicity in human glioblastoma (DBTRG) cells. The DBTRG cells were divided into four treatment groups: control, PREGAB (500 µM for 1 h), OXAL (25 µM for 24 h), and PREGAB + OXAL. In the laser confocal microscope and plate reader analyses, apoptosis, mitochondrial membrane depolarization (JC-1), cell death (propidium iodide/Hoechst rate), and ROS-level production increased by activating TRPV1 in the cells using the OXAL treatment, although the cell viability values decreased. However, these values were recovered in the PREGAB + OXAL group using PREGAB and TRPV1 inhibitor (capsazepine) treatments. In the patch-clamp analyses, OXAL-induced TRPV1 channel activation in the OXAL group also decreased in the PREGAB + OXAL group using the PREGAB and capsazepine treatments. In conclusion, the apoptosis and oxidant actions of OXAL were increased by activation of the TRPV1 channel, but this effect was diminished by the PREGAB treatment. PREGAB treatment has the potential to be an effective strategy in the treatment of OXAL-induced oxidative neurotoxicity.

Regeneration of mechanical sciatic nerve injury is affected by cold and heat exposure: involvements of the TRPM2 and TRPM8 channels.

BACKGROUND: Mechanical sciatic nerve (MSN) injury has a high rate within trauma cases. Heat and cold exposure in the treatments of MSN injuries have been clinically used in human. The MSN injury results in apoptosis, overload Ca2+ influx, and reactive oxygen species (ROS) generation in the sciatic nerve. TRPM2 and TRPM8 cation channels are activated by ROS. TRPM2 is activated by warmth (36-38°C) and heat (45-47°C), although TRPM8 is activated by cold (0-25°C). Heat or cold exposure may aid recovery MSN injury through modulation of TRPM2 and TRPM8 in sciatic nerve. OBJECTIVE: The protective roles of cold and heat treatments via modulation of TRPM2 and TRPM8 were evaluated on MSN injury-induced neurotoxicity in in vitro models of mouse and the SH-SY5Y cell line. METHOD: The mice sciatic nerves and SH-SY5Y cells were divided into control (37°C), cold (10°C), and moderate heat (40°C) groups. RESULTS: Our data identified a decrease in injury diameter in the neurons following heat exposure, but not cold exposure. In addition, the results of laser confocal microscopy analyses were indicative of a protective role of TRPM8 antagonist (ACA) against cold-induced increases in Ca2+ influx in the sciatic nerve and TRPM8 expressing SH-SY5Y cells. The results of the automatic plate reader and laser confocal microscope assays indicated a protective role of heat treatment against MSN injury-induced increases in apoptosis, mitochondrial ROS, cytosolic ROS, caspase -3, and -9 in the neurons. CONCLUSIONS: The heat treatment via possible modulation of TRPM2 channel and heat shock proteins induced protective actions against injury-mediated increases of oxidative stress, excitotoxicity, and apoptosis in the sciatic nerve and SH-SY5Y cells.

Spinal meningiomas: 61 cases with predictors of early postoperative surgical outcomes.

BACKGROUND: Spinal meningiomas are benign, well-circumscribed and slowly-growing intradural tumors that compress the spinal cord. Hereby, a retrospective review of 61 spinal meningioma cases evaluated in terms of demographic, clinical, pathological and radiological features to predict the early postoperative functional outcomes. METHODS: Patients' records and MRI images of all the histologically confirmed spinal meningioma cases that underwent surgical resection at two university hospitals from January 2005 to June 2016 were retrospectively reviewed. Demographic data, clinical findings, radiological features and pathology reports were reviewed. Univariate and multivariate logistic regression analyses were used to evaluate the impact of each factor on the early 3-month post-surgical functional outcome. A receiver operating characteristic (ROC) curve was used to predict the power of the model. RESULTS: Sixty-one cases of spinal meningiomas were operated: 13 males (21%) and 48 females (79%). Mean age was 60.5 years and ranged from 24 to 92 years. Patients presented with back pain (57%), motor deficits (47.5%), sensory deficits (18%) and sphincteric dysfunction (11.5%). One case (1.6%) showed an additional extradural growth. There were 40 thoracic, nine cervical, five cervicothoracic, five thoracolumbar, and two lumbar cases. Only four cases (6.6%) showed atypical pathological features (WHO grade II). At 3-month follow-up, 46 patients (75.4%) had either functionally improved or remained stable. Fifteen patients (24.6%) had "worse" functional outcome. Three variables showed statistically significant odds ratio for improved outcomes (OR): pre-surgical motor deficit (OR=5; P=0.005); presurgical sensory disturbance (OR=3.5; P=0.026); pre-surgical myelopathy (OR=3.5; P=0.026). Multivariate analysis showed increased OR for cross-sectional ratio, pre-surgical myelopathy, pre-surgical radiculopathy and non-cervical location of tumor (1.59, 3.46, 3.2, 1.63/3.56, respectively). Although none has reached statistical significance (P>0.05), the receiver operating characteristic (ROC) curve showed an area under the curve (AUC) of 0.74. CONCLUSIONS: The independent predictors of the early postoperative functional outcomes of spinal meningioma resections may include pre-surgical motor deficit, sensory deficit and myelopathy.

The Correlation of Meralgia Paresthetica and Spinal Surgery in Prone Position.

AIM: To investigate the incidence, risk factors, and recovery of patients with meralgia paresthetica (MP) following posterior spine surgery. MATERIAL AND METHODS: Patients who underwent posterior spine surgeries in prone position at the authors’ clinics were included in this study. Patients with preoperative MP were excluded. RESULTS: Among the 560 patients who underwent spine surgery in prone position, 117 (21%) had impaired sensation along the anterolateral aspect of the thigh. One hundred three of them were treated with conservative treatment, whereas 14 underwent surgery for MP. CONCLUSION: Conservative treatment is the first option for MP. Patients who do not recover with conservative treatment may undergo surgical treatment.

Mitochondrial oxidative stress-induced brain and hippocampus apoptosis decrease through modulation of caspase activity, Ca2+ influx and inflammatory cytokine molecular pathways in the docetaxel-treated mice by melatonin and selenium treatments.

Docetaxel (DOCE) is widely used to treat several types of glioblastoma. Adverse effects DOCE seriously limit its clinical use in several tissues. Its side effects on brain cortex and hippocampus have not been clarified yet. Limited data indicated a protective effect of melatonin (MLT) and selenium (SELEN) on DOCE-induced apoptosis, Ca2+ influx and mitochondrial reactive oxygen species (ROS) in several tissues except brain and hippocampus. The purpose of this study is to discover the protective effect of MLT and SELEN on DOCE-induced brain and hippocampus oxidative toxicity in mice. MLT and SELEN pretreatments significantly ameliorated acute DOCE-induced mitochondrial ROS production in the hippocampus and brain tissues by reducing levels of lipid peroxidation, intracellular ROS production and mitochondrial membrane depolarization, while increasing levels of total antioxidant status, glutathione, glutathione peroxidase, MLT, α-tocopherol, γ-tocopherol, vitamin A, vitamin C and ß-carotene in the tissues. Furthermore, MLT and SELEN pretreatments increased cell viability and TRPM2 channel activation in the hippocampus and brain followed by decreased activations of TNF-α, IL-1ß, IL-6, and caspase -3 and - 9, suggesting a suppression of calcium ion influx, apoptosis and inflammation responses. However, modulator role of SELEN on the values in the tissues is more significant than in the MLT treatment. MLT and SELEN prevent DOCE-induced hippocampus and brain injury by inhibiting mitochondrial ROS and cellular apoptosis through regulating caspase -3 and - 9 activation signaling pathways. MLT and SELEN may serve as potential therapeutic targets against DOCE-induced toxicity in the hippocampus and brain.

Selenium Enhances the Apoptotic Efficacy of Docetaxel Through Activation of TRPM2 Channel in DBTRG Glioblastoma Cells.

The rate of mitosis of cancer cells is significantly higher than normal primary cells with increased metabolic needs, which in turn enhances the generation of reactive oxygen species (ROS) production. Higher ROS production is known to increase cancer cell dependence on ROS scavenging systems to counteract the increased ROS. Therapeutic options which selectively modulate the levels of intracellular ROS in cancers are likely candidates for drug discovery. Docetaxel (DTX) has demonstrated antitumor activity in preclinical and clinical studies. It is thought that DTX induces cell death through excessive ROS production and increased Ca2+ entry. The Ca2+ permeable TRPM2 channel is activated by ROS. Selenium (Se) has been previously used to stimulate apoptosis for the treatment of glioblastoma cells resistant to DTX. However, the potential mechanism(s) of the additive effect of DTX on TRPM2 channels in cancer cells remains unclear. The aim of this study was to evaluate the effect of combination therapy of DTX and Se on activation of TRPM2 in DBTRG glioblastoma cells. DBTRG cells were divided into four treatment groups: control, DTX (10 nM for 10 h), Se (1 µM for 10 h), and DTX+Se. Our study showed that apoptosis (Annexin V and propidium iodide), mitochondrial membrane depolarization (JC1), and ROS production levels were increased in DBTRG cells following treatment with Se and DTX respectively. Cell number and viability, and the levels of apoptosis, JC1, ROS, and [Ca2+]i, induced by DTX, were further increased following addition of Se. We also observed an additive increase in the activation of the NAD-dependent DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP-1) activity, which was accompanied by a decline in its essential substrate NAD+. As well, the Se- and DTX-induced increases in intracellular Ca2+ florescence intensity were decreased following treatment with the TRPM2 antagonist N-(p-amylcinnamoyl) anthranilic acid (ACA). Therefore, combination therapy with Se and DTX may represent an effective strategy for the treatment of glioblastoma cells and may be associated with TRPM2-mediated increases in oxidative stress and [Ca2+]i.

Surgical options for meralgia paresthetica: long-term outcomes in 13 cases.

BACKGROUND: Meralgia paresthetica is an entrapment neuropathy of the lateral femoral cutaneous nerve that may cause paresthesias, pain, and sensory loss of the anterior and lateral thigh. Treatment is primarily medical. Surgery is an option for patients who do not respond to medical treatments. METHODS: Patients whose symptoms did not improve after medical and conservative treatment for at least 3 months were included in this study. These patients underwent neurolysis and decompression surgery and had a mean postoperative follow-up of 38 months. Their pain levels were assessed by the VAS scoring system. RESULTS: In 8 (61.5%) patients, the symptoms completely resolved within the first 3 months. In 5 (38.5%) patients, the complaints persisted partially and the recovery was observed after 12 months. In patients having a metabolic etiology, the duration of recovery was up to 12 months. CONCLUSION: The long term results of surgery are good though only partial improvemnts in reported pain were seen in the early postoperative period, especially in patients with a metabolic etiology.

Long term exposure to cell phone frequencies (900 and 1800 MHz) induces apoptosis, mitochondrial oxidative stress and TRPV1 channel activation in the hippocampus and dorsal root ganglion of rats.

Mobile phone providers use electromagnetic radiation (EMR) with frequencies ranging from 900 to 1800 MHz. The increasing use of mobile phones has been accompanied by several potentially pathological consequences, such as neurological diseases related to hippocampal (HIPPON) and dorsal root ganglion neuron (DRGN). The TRPV1 channel is activated different stimuli, including CapN, high temperature and oxidative stress. We investigated the contribution TRPV1 to mitochondrial oxidative stress and apoptosis in HIPPON and DRGN following long term exposure to 900 and 1800 MHz in a rat model. Twenty-four adult rats were equally divided into the following groups: (1) control, (2) 900 MHz, and (3) 1800 MHz exposure. Each experimental group was exposed to EMR for 60 min/ 5 days of the week during the one year. The 900 and 1800 MHz EMR exposure induced increases in TRPV1 currents, intracellular free calcium influx (Ca2+), reactive oxygen species (ROS) production, mitochondrial membrane depolarization (JC-1), apoptosis, and caspase 3 and 9 activities in the HIPPON and DRGN. These deleterious processes were further increased in the 1800 MHz experimental group compared to the 900 MHz exposure group. In conclusion, mitochondrial oxidative stress, programmed cell death and Ca2+ entry pathway through TRPV1 activation in the HIPPON and DRGN of rats were increased in the rat model following exposure to 900 and 1800 MHz cell frequencies. Our results suggest that exposure to 900 and 1800 MHz EMR may induce a dose-associated, TRPV1-mediated stress response.

Lazaroid U-74389G attenuates edema in rat brain subjected to post-ischemic reperfusion injury.

The aim of the present study was to determine the potential therapeutic value of 21-aminosteroid U-74389G, on blood-brain barrier (BBB) breakdown and edema in association with the changes in synaptosomal Na(+)/K(+) and Mg(2+)/Ca(2+)-ATPase activities in rat brain subjected to post-ischemic reperfusion injury. Brain ischemia was achieved by means of four-vessel occlusion model for 25 min and animals were sacrificed after 12 h reperfusion. An increase of cerebral tissue water content, blood-brain disruption and the changes of synaptosomal Na(+)/K(+) and Mg(2+)/Ca(2+)-ATPases activities were evaluated. U-74389G was given intraperitoneally at two times as 5 mg/kg at 10 min prior to ischemia and at the beginning of reperfusion. Edema was determined by means of wet-dried weight method, and BBB of extravasation of Evan's blue dye. Extravasation of Evan's blue dye into brain following ischemia and reperfusion was 2.4-fold of control value and brought close to control levels by the effect of U-74389G (p<0.001). Post-ischemic reperfusion injury caused an increase of 3.7% in tissue water content of whole brain and administration of U-74389G lowered the cerebral edema (p<0.001). The loses in the Na(+)/K(+)-ATPase and Mg(2+)/Ca(2+)-ATPase activities occurred as 42.1% (p<0.01) and 65.7% (p<0.001) of control value, respectively. While Mg(2+)/Ca(2+)-ATPase activity was enhanced compared to vehicle-treated group of animals (p<0.01), Na(+)/K(+)-ATPase activity was fully recovered when compared to control by U-74389G (p>0.05). U-74389G also significantly attenuated neuronal necrosis (p<0.001) which was determined in the hippocampal CA1 subfield. Blood-brain barrier protection, attenuation of brain edema and neuronal necrosis concomitant with the stabilizing of membrane-bound enzymes brought about by the effect of U-74389G suggest that 21-aminosteroids are worthy of consideration in the acute treatment of cerebral ischemia.