Modafinil Decreased Thalamic Activation in Auditory Emotional Processing: A Randomized Controlled Functional Magnetic Resonance Imaging Study.

BACKGROUND: Modafinil improves wakefulness and attention, is approved in Japan for treatment of narcolepsy, and was reported to be effective for attention-deficit/hyperactivity disorder. However, it was reported to induce emotional instability, including mania, depression, and suicidal ideation. Such side effects may be related to changes in cognitive behavior caused by the effects of modafinil on emotional recognition. However, the effects of modafinil on the neural basis of emotional processing have not been fully verified. We used functional magnetic resonance imaging to investigate the effects of modafinil on the neural basis of auditory emotional processing. METHODS: This study adopted a placebo-controlled within-subject crossover design. Data from 14 participants were analyzed. The effects of modafinil on cerebral activation and task performance during an emotional judgement task were analyzed. RESULTS: Task accuracy decreased significantly and response time of emotional judgement was significantly delayed by modafinil, as compared with placebo. Right thalamic activation in auditory emotional processing was significantly less in the modafinil condition than in the placebo condition. In addition, reduction of right thalamic activation by modafinil was positively correlated with accuracy of emotional judgement. CONCLUSIONS: Our findings suggest that modafinil acts on the right thalamus and changes behavior and brain function associated with auditory emotional processing. These results indicate that modafinil might change emotional recognition by reducing emotional activation related to social communication.

Therapeutic potential of fibrinogen γ-chain peptide-coated, ADP-encapsulated liposomes as a haemostatic adjuvant for post-cardiopulmonary bypass coagulopathy.

Fibrinogen γ-chain peptide-coated, adenosine 5'-diphosphate (ADP)-encapsulated liposomes (H12-ADP-liposomes) are a potent haemostatic adjuvant to promote platelet thrombi. These liposomes are lipid particles coated with specific binding sites for platelet GPIIb/IIIa and encapsulating ADP. They work at bleeding sites, facilitating haemostasis by promoting aggregation of activated platelets and releasing ADP to strongly activate platelets. In this study, we investigated the therapeutic potential of H12-ADP-liposomes on post-cardiopulmonary bypass (CPB) coagulopathy in a preclinical setting. We created a post-CPB coagulopathy model using male New Zealand White rabbits (body weight, 3 kg). One hour after CPB, subject rabbits were intravenously administered H12-ADP-liposomes with platelet-rich plasma (PRP) collected from donor rabbits (H12-ADP-liposome/PRP group, n = 8) or PRP alone (PRP group, n = 8). Ear bleeding time was greatly reduced for the H12-ADP-liposome/PRP group (263 ± 111 s) compared with the PRP group (441 ± 108 s, p < 0.001). Electron microscopy showed platelet thrombus containing liposomes at the bleeding site in the H12-ADP-liposome/PRP group. However, such liposome-involved platelet thrombi were not observed in the end organs after H12-ADP-liposome administration. These findings suggest that H12-ADP-liposomes could help effectively and safely consolidate platelet haemostasis in post-CPB coagulopathy and may have potential for reducing bleeding complications after cardiovascular surgery with CPB.

Effects of low-dose unfractionated heparin on early brain injury after subarachnoid hemorrhage in mice.

BACKGROUND: Sphingosine kinase (SphK) 1 has been reported as an important signaling node in anti-apoptotic signaling. Heparin is a pleiotropic drug that antagonizes many pathophysiological mechanisms. In this study, we evaluated if heparin prevents early brain injury (EBI) after subarachnoid hemorrhage (SAH) by anti-apoptotic mechanisms including SphK1. METHODS: SAH was induced by endovascular perforation in mice, which were randomly assigned to sham-operated (n = 23), SAH + vehicle (n = 36), SAH + 10U heparin pretreatment (n = 13), SAH + 30U heparin pretreatment (n = 15), SAH + 10U heparin posttreatment (n = 31), and SAH + 30U heparin posttreatment (n = 23). At 24 hours post-SAH, neurological scores, brain water content and Evans blue extravasation were evaluated. Also, the expression of SphK, phosphorylated Akt, and cleaved caspase-3 was determined by Western blotting, and cell death was examined by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling staining. RESULTS: Low-dose heparin posttreatment improved neurobehavioral function, brain edema, blood-brain barrier disruption and cell death in the cortex, associated with an increase in SphK1 and phosphorylated Akt, and a decrease in cleaved caspase-3. High-dose heparin had a tendency for increased SAH severity, which obscured the neuroprotective effects by heparin. CONCLUSIONS: Low-dose heparin posttreatment may decrease the development of post-SAH EBI through anti-apoptotic mechanisms including sphingosine-related pathway activation.

Modified Citrus Pectin Prevents Blood-Brain Barrier Disruption in Mouse Subarachnoid Hemorrhage by Inhibiting Galectin-3.

Background and Purpose- Plasma levels of galectin-3-a matricellular protein-are increased after aneurysmal subarachnoid hemorrhage (SAH), but the functional significance remains undetermined. This study was conducted to evaluate whether modified citrus pectin (MCP; galectin-3 inhibitor) prevents post-SAH early brain injury, focusing on blood-brain barrier disruption. Methods- C57BL/6 male adult mice (n=251) underwent sham or filament perforation SAH modeling, followed by a random intracerebroventricular injection of vehicle or drug at 30 minutes post-modeling. First, vehicle-treated and 0.8, 4, 16, or 32 µg MCP-treated mice were assessed by neuroscore and brain water content at 24 and 48 hours post-modeling. Second, Evans blue extravasation, Western blotting, coimmunoprecipitation and immunostaining were performed in vehicle-treated or 4 µg MCP-treated mice at 24 hours post-modeling. Third, vehicle or R-galectin-3 (recombinant galectin-3) was administered to SAH mice simultaneously with vehicle or MCP, and neuroscore and Evans blue extravasation were evaluated at 24 hours post-modeling. Fourth, vehicle or R-galectin-3 was administered to MCP-treated SAH mice at 24 hours, and neuroscore and IgG immunostaining were evaluated at 48 hours post-SAH. Results- Among tested dosages, 4 µg MCP showed the best neuroprotective effects as to preventing neurological impairments and brain edema at 24 to 48 hours post-SAH. Four micrograms MCP attenuated post-SAH blood-brain barrier disruption and galectin-3 upregulation in brain capillary endothelial cells, associated with inactivation of ERK (extracellular signal-related kinase) 1/2, STAT (signal transducer and activator of transcription)-3, and MMP (matrix metalloproteinase)-9, and the consequent preservation of a tight junction protein ZO-1 (zonula occludens-1). Coimmunoprecipitation assay demonstrated physical interactions between galectin-3 and TLR (Toll-like receptor) 4. R-galectin-3 blocked the neuroprotective effects of MCP. Conclusions- MCP prevents post-SAH blood-brain barrier disruption possibly by inhibiting galectin-3, of which the mechanisms may include binding to TLR4 and activating ERK1/2, STAT-3, and MMP-9. This study suggests galectin-3 to be a novel therapeutic target against post-SAH early brain injury.

Prospective randomized investigation implementing immunonutritional therapy using a nutritional supplement with a high blend ratio of ω-3 fatty acids during the perioperative period for head and neck carcinomas.

OBJECTIVES: The purpose of this study is to evaluate whether a nutritional supplement with a high blend ratio of ω-3 fatty acids can minimize weight loss and attenuate increases in inflammatory marker levels during the perioperative period in patients undergoing surgery for head and neck carcinoma. METHODS: Patients with ≥5% weight loss within 6 months were considered as targets for aggressive nutritional intervention. Among these patients, those with head and neck squamous cell carcinoma, who underwent major invasive surgery with free flap reconstruction were included in the present study. The patients were randomized into two groups: the 'nutritional supplementation group' and the 'non-intervention group'. The nutritional supplementation group received two packs of Prosure® (an eicosapentaenoic acid [EPA]-enriched oral nutritional supplement) per day for 28 days during the perioperative period. RESULTS: Compliance with the Prosure® dosage was very good at 6277/6720 ml (average) before surgery (93%) and 5229/6720 ml after surgery (78%), and a significant increase in EPA concentration was shown in the group that received Prosure® (P < 0.0001: Welch's t-test). However, 28 days of nutritional supplementation did not lead to further weight change or changes in the inflammatory marker levels of patients were already showing cachexia (based on weight loss). Interestingly, no further change in the mean weight was noted in these patients. The incidence of postoperative complications did not differ between the two groups. CONCLUSION: In this trial, immunonutritional therapy using a nutritional supplement with a high blend ratio of ω-3 fatty acids from 2 weeks before surgery until 2 weeks after surgery was not effective for maintaining the nutritional status of head and neck carcinoma patients.

Renal protective effect of a hydration supplemented with magnesium in patients receiving cisplatin for head and neck cancer.

BACKGROUND: Our study analyzes the effect of magnesium supplementation on nephrotoxicity in patients receiving cisplatin for head and neck cancer. METHODS: We retrospectively reviewed the medical records of patients with head and neck cancer who received two doses of cisplatin (80 mg/m2) and 5-fluorouracil (800 mg/m2) 3 weeks apart from August 2008 to October 2012. The regimen prior to 2011 (crystalloid-only) involved the administration of 1000 mL of lactated Ringer's solution on the day prior to cisplatin infusion and 2000 mL of continuous infusion of saline on the day of cisplatin infusion. The regimen after 2011 (magnesium-supplemented) did not involve hydration on the day before cisplatin administration but used 1000 mL of 0.9% saline with magnesium sulfate (20 mEq) administered for 3 hours before cisplatin infusion. RESULTS: Sixty-five patients were treated with the crystalloid-only regimen and 56 patients with the magnesium-supplemented regimen. The mean creatinine clearance in the magnesium-supplemented group decreased by 4.9 mL/kg/min, whereas that in the crystalloid-only group decreased by 15.0 mL/kg/min after two courses. In multivariate analysis, only magnesium-supplemented hydration was an independent predictive factor for preventing cisplatin-induced nephrotoxicity (odds ratio = 0.157, 95% confidence interval 0.030-0.670, P = 0.0124). CONCLUSION: We demonstrated that an intravenous hydration regimen supplemented with magnesium prevented cisplatin-induced nephrotoxicity in patients with head and neck cancer.

The Impact of Skeletal Muscle Depletion on Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Skeletal muscle depletion and sarcopenia have been reported as poor prognostic factors for several types of cancer. The aim of this study was to investigate the prognostic impact of skeletal muscle depletion and sarcopenia on the outcomes in head and neck cancer patients. METHODS: Patients with head and neck squamous cell carcinoma (HNSCC) treated from January 2013 to June 2014 were included in this study. The pretreatment cross-sectional area of skeletal muscle at the third lumbar vertebra (L3) was measured by computed tomography image analysis using the ImageJ software. L3 skeletal muscle index (SMI) and fat-free mass (FFM) were calculated. RESULTS: Eighty-five patients with HNSCC were included. The cut-off value of sarcopenia was set at SMI <46.7 cm2/m2 (males) and 30.3 cm2/m2 (females). The cut-off value of FFM was set at 42.3 kg (males) and 30.6 kg (females). Patients with a low SMI (sarcopenia) and low FFM had a significantly poorer prognosis than others, especially those who received definitive radiotherapy. Sarcopenia and low FFM are independent factors for poor prognosis in patients with HNSCC. CONCLUSION: The skeletal muscle area at L3 should be calculated when considering treatment options for head and neck cancer.

The efficacy of neuromuscular electrical stimulation with alternating currents in the kilohertz frequency to stimulate gait rhythm in rats following spinal cord injury.

BACKGROUND: Rehabilitation facilitates the reorganization of residual/regenerated neural pathways and is key in improving motor function following spinal cord injury. Neuromuscular electrical stimulation (NMES) has been reported as being clinically effective. Although it can be used after the acute phase post-injury, the optimal stimulation conditions to improve motor function remain unclear. In this paper, we examined the effectiveness of NMES with alternating currents in the kilohertz (kHz) frequency in gait rhythm stimulation therapy. METHODS: Tests were performed using 20 mature female Fischer rats. Incomplete spinal cord injuries (T9 level) were made with an IH impactor using a force of 150 kdyn, and NMES was administered for 3 days from the 7th day post-injury. The needle electrodes were inserted percutaneously near the motor point of each muscle in conscious rats, and each muscle on the left and right leg was stimulated for 15 min at two frequencies, 75 Hz and 8 kHz, to induce a gait rhythm. Motor function was evaluated using Basso, Beattie, Bresnahan (BBB) scores and three-dimensional (3D) gait analysis. Rats were divided into four groups (5 rats/group), including the NMES treatment 75-Hz group (iSCI-NMES 75 Hz), 8-kHz group (iSCI-NMES 8 kHz), injury control group (iSCI-NT), and normal group (Normal-CT), and were compared. RESULTS: There was no significant difference in BBB scores among the three groups. In 3D gait analysis, compared with the injury control group, the 8-kHz group showed a significant improvement in synergistic movement of both hindlimbs. CONCLUSION: We suggest that kHz stimulation is effective in gait rhythm stimulation using NMES.

Treatment with fibrinogen γ-chain peptide-coated, adenosine 5'-diphosphate-encapsulated liposomes as an infusible hemostatic agent against active liver bleeding in rabbits with acute thrombocytopenia.

BACKGROUND: We evaluated the hemostatic efficacy of H12-(adenosine 5'-diphosphate [ADP])-liposomes in the setting of active liver bleeding in rabbits with dilutional thrombocytopenia after massive transfusion. STUDY DESIGN AND METHODS: Acute thrombocytopenia (platelet [PLT] count < 50 × 10(9) /L) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. Liver hemorrhage was initiated by a penetrating liver injury. Subsequently, the animals received tamponade treatment for the liver hemorrhage for 5 minutes and were intravenously administered H12-(ADP)-liposomes with PLT-poor plasma (PPP), PLT-rich plasma (PRP), PPP alone, H12-(phosphate-buffered saline [PBS])-liposome/PPP, or H12-(ADP)-liposomes/PPP plus fibrinogen concentrate during the tamponade. RESULTS: Administration of H12-(ADP)-liposomes/PPP rescued 60% of the rabbits from the liver hemorrhage; PRP administration rescued 50%. In contrast, rabbits receiving PPP or H12-(PBS)-liposome/PPP achieved only 10 or 17% survival, respectively, for the first 24 hours. H12-(ADP)-liposomes/PPP as well as PRP consistently reduced bleeding volumes and shortened clotting times (CTs) in comparison to PPP administration. Specifically, bleeding volumes in the initial 5 minutes averaged 11 mL (H12-(ADP)-liposomes/PPP) and 17 mL (PRP) versus 30 mL (PPP; p < 0.05); CTs averaged 270 and 306 seconds versus 401 seconds (p < 0.05). H12-(ADP)-liposomes were observed at the bleeding site with thrombus formation, suggesting an induction of thrombi. Neither macro- nor microthrombi were detected in the lung, kidney, spleen, or liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survival. CONCLUSIONS: H12-(ADP)-liposomes might be a safe and effective therapeutic tool during damage control surgery for trauma patients with acute thrombocytopenia and massive bleeding.

Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB.

Tramadol is used for the treatment of pain, and it is generally believed to activate the µ-opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [11C]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50 mg and 50.2% at 100 mg. The estimated median effective dose (ED50) of tramadol was 98.1 mg, and the plasma concentration was 0.33 µg/ml 2 h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400 mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs).

Clinical outcome and patterns of recurrence of head and neck squamous cell carcinoma with a limited field of postoperative radiotherapy.

BACKGROUND: Postoperative radiotherapy is the standard treatment for head and neck squamous cell carcinoma having high-risk features in surgical specimens. However, its severe toxicity can be a significant problem. This study was undertaken to evaluate the efficacy of our limited-field postoperative radiotherapy with the aim of reducing morbidity by minimizing the radiation field. METHODS: Between 2000 and 2009, 154 patients with head and neck squamous cell carcinoma received limited-field postoperative radiotherapy. The reason for postoperative radiotherapy was close/positive margins in 33 patients and extracapsular extension in 91. The median radiation dose was 50 Gy (30-66.4). The radiation field covered the tumor bed without lymph node regions for close/positive margins and only involved sites of the neck region were irradiated for multiple nodes or extracapsular extension. RESULTS: With a median follow-up of 43 months for surviving patients, the 3-year overall survival and progression-free survival rates were 53.7 and 42.1%, respectively. The 3-year rates of progression-free survival of the group having major risks (i.e. close/positive margins and/or extracapsular extension) and the group with other risks were 34.7 and 62.8%, respectively (P < 0.01). Thirty-one local recurrences (20%), of which 22 were located out-of-field, and 44 regional recurrences (29%), of which 16 were located out-of-field, developed. Late toxicity of grade 3 or greater developed in only six patients (3.8%). CONCLUSIONS: Although the toxicities associated with limited-field postoperative radiotherapy could be kept to lower levels, the locoregional control rate did not seem to be sufficient. We should arrange the radiation field depending on risk factors.

Activation of different signals identified with glia cells contribute to the progression of hyperalgesia.

Hyperalgesia results from a decreased pain threshold, often subsequent to peripheral tissue damage. Recent reports revealed several promising mechanisms of hyperalgesia, but many issues remain unclear. The glial activation accompanying inflammation of neurotransmission in the spinal cord might be related to the initiation and maintenance of hyperalgesia. The present study investigated the pharmacological pain-modifying effects of mitogen-associated protein kinase (MAPK)-related inhibitors identified with glia cells over time during inflammatory pain. A model of inflammatory pain was produced by injecting mustard oil (MO) into the hind paws of rats. Following MO injection, the changes in paws flinching as the early onset of pain and paw withdrawal latency (PWL) in response to thermal stimulation were measured as delayed-onset hyperalgesia. Before and after the MO injection, one of the inhibitors, a p38-MAPK (SB), nuclear factor (NF)-κB (PDTC), BDNF-trk-B (K252a), or JNK-1 (SP), was administered and flinching and PWL were measured. In the SB, PDTC, and k252a groups, early flinching following MO injection was moderately suppressed. Hyperalgesia was significantly suppressed in the left-right difference of PWL in animals receiving SB, k252a, or PDTC pre-treatment. In animals receiving post-treatment, the suppressive effects were most potent in the SP group. The present results revealed that microglial activation resulting from the release of the phosphatase p38-MAPK, the transcription factor NF-κB, and BDNF contributes to the early stage of inflammatory pain. Astrocyte activation accompanying JNK activation contributes to subsequent hyperalgesia. Activation of different signals identified with glia cells is thought to contribute to the progression of hyperalgesia, which represents an applicable finding for the treatment of hyperalgesia.

Development of less invasive neuromuscular electrical stimulation model for motor therapy in rodents.

BACKGROUND: Combination therapy is essential for functional repairs of the spinal cord. Rehabilitative therapy can be considered as the key for reorganizing the nervous system after spinal cord regeneration therapy. Functional electrical stimulation has been used as a neuroprosthesis in quadriplegia and can be used for providing rehabilitative therapy to tap the capability for central nervous system reorganization after spinal cord regeneration therapy. OBJECTIVE: To develop a less invasive muscular electrical stimulation model capable of being combined with spinal cord regeneration therapy especially for motor therapy in the acute stage after spinal cord injury. METHODS: The tibialis anterior and gastrocnemius motor points were identified in intact anesthetized adult female Fischer rats, and stimulation needle electrodes were percutaneously inserted into these points. Threshold currents for visual twitches were obtained upon stimulation using pulses of 75 or 8 kHz for 200 ms. Biphasic pulse widths of 20, 40, 80, 100, 300, and 500 µs per phase were used to determine strength-duration curves. Using these parameters and previously obtained locomotor electromyogram data, stimulations were performed on bilateral joint muscle pairs to produce reciprocal flexion/extension movements of the ankle for 15 minutes while three-dimensional joint kinematics were assessed. RESULTS: Rhythmic muscular electrical stimulation with needle electrodes was successfully done, but decreased range of motion (ROM) over time. High-frequency and high-amplitude stimulation was also shown to be effective in alleviating decreases in ROM due to muscle fatigue. CONCLUSIONS: This model will be useful for investigating the ability of rhythmic muscular electrical stimulation therapy to promote motor recovery, in addition to the efficacy of combining treatments with spinal cord regeneration therapy after spinal cord injuries.

Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats.

OBJECTIVE: Hydrogen gas has been demonstrated to neutralize free radicals and reduce oxidative stress recently. Our objective was to determine the therapeutic effect of H2 inhalation and its antioxidative activity on early brain injury after subarachnoid hemorrhage. DESIGN: Controlled in vivo laboratory study. SETTING: Animal research laboratory. SUBJECTS: One hundred thirty-seven adult male Sprague-Dawley rats weighing 280-350 g. INTERVENTIONS: Subarachnoid hemorrhage was induced by endovascular perforation method in rats. Subarachnoid hemorrhage rats were treated with 2.9% hydrogen gas inhaled for 2 hrs after perforation. At 24 and 72 hrs, mortality, body weight, neurologic deficits, and brain water content were assessed. Blood-brain barrier permeability and apoptosis were also measured at 24 hrs. To investigate the antioxidative activity of hydrogen gas, the expression of malondialdehyde, nitrotyrosine, and 8-hydroxyguanosine, which are oxidative markers of lipid, protein, and DNA damage, respectively, were measured at 24 hrs. MEASUREMENTS AND MAIN RESULTS: Hydrogen gas significantly alleviated brain edema and blood-brain barrier disruption, reduced apoptosis, and improved neurologic function at 24 hrs but not 72 hrs after subarachnoid hemorrhage. These effects were associated with the amelioration of oxidative injury of lipid, protein, and DNA. CONCLUSIONS: Hydrogen gas could exert its neuroprotective effect against early brain injury after subarachnoid hemorrhage by its antioxidative activity.

PDGFR-α inhibition preserves blood-brain barrier after intracerebral hemorrhage.

OBJECTIVE: Perihematomal edema results from disruption of the blood-brain barrier (BBB) by key mediators, such as thrombin, following intracerebral hemorrhage (ICH). Platelet-derived growth factor receptor alpha (PDGFR-α), a tyrosine kinase receptor, was found in previous studies to play a role in orchestrating BBB impairment. In the present study, we investigated the role of PDGFR-α following ICH-induced brain injury in mice, specifically investigating its effect on BBB disruption. METHODS: Brain injury was induced by autologous arterial blood (30 µl) or thrombin (5 U) injection into mice brains. A PDGFR antagonist (Gleevec) or agonist (PDGF-AA) was administered following ICH. PDGF-AA was injected with a thrombin inhibitor, hirudin, in ICH mice. Thrombin-injected mice were given Gleevec or PDGF-AA neutralizing antibody. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, was delivered with PDGF-AA in naïve animals. Postassessment included neurological function tests, brain edema measurement, Evans blue extravasation, immunoprecipitation, western blot, and immunohistology assay. RESULTS: PDGFR-α suppression prevented neurological deficits, brain edema, and Evans blue extravasation at 24 to 72 hours following ICH. PDGFR-α activation led to BBB impairment and this was reversed by SB203580 in naïve mice. Thrombin inhibition suppressed PDGFR-α activation and exogenous PDGF-AA increased PDGFR-α activation, regardless of thrombin inhibition. Animals receiving a PDGF-AA-neutralizing antibody or Gleevec showed minimized thrombin injection-induced BBB impairment. INTERPRETATION: PDGFR-α signaling may contribute to BBB impairment via p38 MAPK-mediated matrix metalloproteinase (MMP) activation/expression following ICH, and thrombin may be the key upstream orchestrator. The therapeutic interventions targeting the PDGFR-α signaling may be a novel strategy to prevent thrombin-induced BBB impairment following ICH.

Suppressive effects of glycyrrhetinic acid derivatives on tachykinin receptor activation and hyperalgesia.

Glycyrrhetinic acid (GA), an aglycone of glycyrrhizin, isolated from the licorice root (Glycyrrhizia), and its semi-synthetic derivatives have a wide range of pharmacological effects. To investigate whether GA derivatives may be used as a new class of analgesics, we examined the effects of these compounds on human tachykinin receptors expressed in CHO-K1 cells. Among the GA derivatives examined, the disodium salt of olean-11,13(18)-dien-3ß,30-O-dihemiphthalate inhibited the mobilization of [Ca(2+)](i) induced by substance P, neurokinin A, and neurokinin B in CHO-K1 cells expressing the human NK(1), NK(2), and NK(3) tachykinin receptors, respectively. In an inflammatory pain model, Compound 5 suppressed the capsaicin-induced flinching behavior in a dose-dependent manner. Compound 5 was also effective in suppressing pain-related behaviors in the late phase of the formalin test and reducing thermal hyperalgesia in the neuropathic pain state caused by sciatic nerve injury. Collectively, Compound 5 may be an analgesic candidate via tachykinin receptor antagonism.

Delay of onset of symptoms of Japanese cedar pollinosis by treatment with a leukotriene receptor antagonist.

BACKGROUND: Leukotriene receptor antagonists (LTRAs) are effective for prophylactic treatment of pollinosis based on studies showing that administration of LTRAs prior to or at the start of the pollen season reduces symptoms and QOL disturbance at the peak of pollen dispersal. Two goals of prophylactic treatment of pollinosis are use of fewer types of drugs and delay of onset of symptoms and impairement of QOL. Therefore, this study was performed to determine if pranlukast, a LTRA, met these goals in treatment of pollinosis. METHODS: Pranlukast or placebo was administered to patients who visited our hospital immediately before the start of Japanese cedar pollen dispersal. The study was performed for 4 weeks as a double blind randomized trial. Subsequently, all patients were given pranlukast for a further 4 weeks from the peak until the end of pollen dispersal. The incidence of symptoms and use of concomitant drugs were investigated from daily nasal allergy records kept by patients. QOL was evaluated using the JRQLQ questionnaire. RESULTS: In the double blind period of the study, the percentage of patients who used concomitant drugs for nasal symptoms was significantly lower in the pranlukast group compared to the placebo group. Development of nasal symptoms (sneezing, runny nose and nasal congestion) and disturbance of daily activities were significantly delayed in the pranlukast group. No serious adverse reactions occurred in the pranlukast group and no patient withdrew from treatment with pranlukast. CONCLUSIONS: Pranlukast is effective for prophylactic treatment of pollinosis.

Thrombin inhibition by argatroban ameliorates early brain injury and improves neurological outcomes after experimental subarachnoid hemorrhage in rats.

BACKGROUND AND PURPOSE: We investigated the role of thrombin in early brain injury after subarachnoid hemorrhage (SAH). METHODS: The standard intravascular perforation model was used to produce experimental SAH in Sprague Dawley rats. Low-dose (0.3 mg/h) and high-dose (0.9 mg/h) argatroban, a direct thrombin inhibitor, were evaluated for effects on brain edema, blood-brain barrier (BBB) disruption, apoptotic cell death, inflammatory marker, and neurological outcomes after SAH. RESULTS: Both doses of argatroban attenuated BBB disruption; however, only high-dose was effective in lowering edema in all brain regions, reducing cell death, and inflammatory marker expression, and improving neurological outcomes. CONCLUSIONS: Thrombin inhibition by argatroban improves neurological outcomes and provides neuroprotection against acute events after SAH such as BBB disruption, brain edema, and cell death.

Prenatal dexamethasone exposure affects anxiety-like behaviour and neuroendocrine systems in an age-dependent manner.

Prenatal stress has been reported to alter the development of the central nervous system functions. This alteration is thought to be partly caused by increased fetal exposure to glucocorticoid. To clarify how prenatal stress affects neuroendocrine systems and behaviour in an age-dependent manner, we administered a synthetic glucocorticoid, dexamethasone, as a stressor to pregnant rats at gestational days 16-21 and examined the developmental changes in behaviour, hypothalamic corticotropin-releasing factor mRNA expression, corticosterone response and glucocorticoid receptor expression in male offspring. Prenatal dexamethasone exposure decreased corticotropin-releasing factor mRNA in the hypothalamus and disturbed the plasma corticosterone response to restraint stress in the offspring at postnatal week 4 (PW4). In contrast, it was not until PW10 that increased anxiety-like behaviour emerged in the dexamethasone-exposed offspring. In association with the acquisition of increased anxiety-like behaviour at PW10, glucocorticoid receptor expression was decreased in the amygdala in dexamethasone-exposed offspring at PW7 and PW10. Thus, our longitudinal analysis suggests that prenatal exposure to glucocorticoid hampers neuroendocrinological development in the offspring during early life, and that this disturbance results in the induction of increased anxiety-like behaviour in adulthood.