Effect of Tucatinib on Cardiac Repolarization in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Tucatinib is a selective tyrosine kinase inhibitor of the human epidermal growth factor receptor 2 (HER2) approved to treat metastatic HER2-positive breast and colorectal cancers. The International Council for Harmonisation of Technical Requirements for Human Use (ICH) E14 guideline mandates that new drugs are assessed for potential effects on cardiac repolarization through electrocardiogram (ECG) evaluation in a QT/corrected QT (TQT) study. METHODS: We evaluated the effect of tucatinib on cardiac repolarization in healthy volunteers in a phase I, randomized, partially double-blind, placebo-and positive-controlled three-period crossover study. The primary endpoint was the placebo-corrected change from baseline in QT interval values, corrected for heart rate using Fridericia's method (ΔΔQTcF). RESULTS: After achieving steady-state tucatinib exposures with 300 mg twice daily, the observed ΔΔQTcF ranged from -2.9 msec at 2 hours post-dose to 0 msec at 4 hours post-dose. The upper bound of the 90% confidence interval (CI) was below 5 ms at all post-dose timepoints. Assay sensitivity was confirmed as the lower bound of the 90% CI and was >5 ms following moxifloxacin dosing. As the mean ΔΔQTcF of tucatinib was predicted to be -  1.80 ms (90% CI -  3.90, 0.30) at clinically relevant tucatinib concentrations (511 ng/mL), an effect of tucatinib on QTcF exceeding 10 ms was excluded within observed ranges of tucatinib (up to ~1000 ng/mL). Tucatinib had no clinically relevant effect on heart rate or cardiac conduction. The safety profile of tucatinib was manageable after multiple doses. CONCLUSION: Tucatinib had no clinically relevant effects on studied ECG parameters. This study constitutes a clearly negative TQT study per ICH E14 guidance. CLINICAL TRIAL REGISTRATION: This trial (NCT03777761) was registered on 17 December 2018.

Protection of high-frequency low-intensity pulsed electric fields and brain-derived neurotrophic factor for SH-SY5Y cells against hydrogen peroxide-induced cell damage.

Neurodegenerative diseases (NDDs) pose a significant global health threat. In particular, Alzheimer disease, the most common type causing dementia, remains an incurable disease. Alzheimer disease is thought to be associated with an imbalance of reactive oxygen species (ROS) in neurons, and scientists considered ROS modulation as a promising strategy for novel remedies. In the study, human neural cell line SH-SY5Y was used in probing the effect of combining noninvasive high-frequency low-intensity pulsed electric field (H-LIPEF) and brain-derived neurotrophic factor (BDNF) in protection against hydrogen peroxide (H2O2)-induced neuron damage. Our result finds that the combination approach has intensified the neuroprotective effect significantly, perhaps due to H-LIPEF and BDNF synergistically increasing the expression level of the phosphorylated epidermal growth factor receptor (p-EGFR), which induces the survival-related mitogen-activated protein kinases (MAPK) proteins. The study confirmed the activation of extracellular signal-regulated kinase (ERK) and the downstream pro-survival and antioxidant proteins as the mechanism underlying neuron protection. These findings highlighted the potential of H-LIPEF combined with BDNF in the treatment of NDDs. Furthermore, BDNF-mimetic drugs combining with noninvasive H-LIPEF to patients is a promising approach worthy of further research. This points to strategies for selecting drugs to cooperate with electric fields in treating neurodegenerative disorders.

Thermal cycling-hyperthermia ameliorates Aß25-35-induced cognitive impairment in C57BL/6 mice.

Despite continuation of some controversies, Alzheimer's disease (AD), the most common cause of dementia nowadays, has been widely believed to derive mainly from excessive ß-amyloid (Aß) aggregation, that would increase reactive oxygen species (ROS) and induce neuroinflammation, leading to neuron loss and cognitive impairment. Existing drugs on Aß have been ineffective or offer only temporary relief at best, due to blood-brain barrier or severe side effects. The study employed thermal cycling-hyperthermia (TC-HT) to ease the Aß-induced cognitive impairments and compared its effect with continuous hyperthermia (HT) in vivo. It established an AD mice model via intracerebroventricular (i.c.v.) injection of Aß25-35, proving that TC-HT is much more effective in alleviating its performance decline in Y-maze and novel object recognition (NOR) tests, in comparison with HT. In addition, TC-HT also exhibits a better performance in decreasing the hippocampal Aß and ß-secretase (BACE1) expressions as well as the neuroinflammation markers-ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) levels. Furthermore, the study finds that TC-HT can elevate more protein expressions of insulin degrading enzyme (IDE) and antioxidative enzyme superoxide dismutase 2 (SOD2) than HT. In sum, the study proves the potential of TC-HT in AD treatment, which can be put into application with the use of focused ultrasound (FUS).

Unconventional quantum vortex matter state hosts quantum oscillations in the underdoped high-temperature cuprate superconductors.

A central question in the underdoped cuprates pertains to the nature of the pseudogap ground state. A conventional metallic ground state of the pseudogap region has been argued to host quantum oscillations upon destruction of the superconducting order parameter by modest magnetic fields. Here, we use low applied measurement currents and millikelvin temperatures on ultrapure single crystals of underdoped [Formula: see text] to unearth an unconventional quantum vortex matter ground state characterized by vanishing electrical resistivity, magnetic hysteresis, and nonohmic electrical transport characteristics beyond the highest laboratory-accessible static fields. A model of the pseudogap ground state is now required to explain quantum oscillations that are hosted by the bulk quantum vortex matter state without experiencing sizable additional damping in the presence of a large maximum superconducting gap; possibilities include a pair density wave.

Intrinsic Bulk Quantum Oscillations in a Bulk Unconventional Insulator SmB6.

The finding of bulk quantum oscillations in the Kondo insulator SmB6 proved a considerable surprise. Subsequent measurements of bulk quantum oscillations in other correlated insulators including YbB12 lent support to our discovery of a class of bulk unconventional insulators that host bulk quantum oscillations. Here we perform a series of experiments to examine evidence for the intrinsic character of bulk quantum oscillations in floating zone-grown single crystals of SmB6 that have been the subject of our quantum oscillation studies. We present results of thermodynamic, transport, and composition analysis experiments on pristine floating zone-grown single crystals of SmB6 and compare quantum oscillations with metallic LaB6 and elemental aluminum. These results establish the intrinsic origin of quantum oscillations from the insulating bulk of floating zone-grown SmB6. The similarity of the Fermi surface in insulating SmB6 with the conduction-electron Fermi surface in metallic hexaborides is at the heart of a theoretical mystery.

Lactoferrin Protects Hyperoxia-Induced Lung and Kidney Systemic Inflammation in an In Vivo Imaging Model of NF-κB/Luciferase Transgenic Mice.

PURPOSE: High levels of oxygen are usually used in ventilatory support and extracorporeal membrane oxygenation (ECMO) in the intensive care unit of hospitals. Hyperoxia may induce the production of reactive oxygen species (ROS) that can cause lung damage and even systemic injury. In this study, the NF-κB/luciferase transgenic mouse model with non-invasive real-time in vivo imaging was established to test the functions of lactoferrin (LF) in antioxidant and anti-inflammation. PROCEDURES: The NF-κB/luciferase transgenic mice were used to assess the effects of oral administration of LF on attenuation of the systemic inflammatory response and organ damage after 72 h of hyperoxia (FiO2 > 95 %) exposure via monitoring using an in vivo imaging system (IVIS). RESULTS: Using luciferase IVIS imaging, we found that the lungs and kidneys were the most evidently affected organs after hyperoxia treatment. The groups treated with low dose (150 mg/kg) or high dose (300 mg/kg) of LF had lower luciferase expression and less injury, with a dose-dependent effect on the lungs and kidneys. Moreover, ROS, mitogen-activated protein kinases (MAPK), and pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) expression levels were all significantly decreased (P < 0.01), and the protein level of IκB was statistically increased (P < 0.01) after LF treatment. CONCLUSIONS: Our results suggest that hyperoxia can induce systemic inflammation, and the oral administration of LF as a natural antioxidant decreases the production of ROS, attenuates inflammation, and lessens kidney and lung injuries from hyperoxia via the use of live image monitoring of the response in NF-kB/luciferase transgenic mice.

A rare case of acute respiratory distress syndrome caused by use of gadolinium-based magnetic resonance imaging contrast media.

Gadolinium-based magnetic resonance imaging (MRI) contrast is generally considered to be stable and safe. Adverse reactions due to MRI contrast agents are classified into allergic-like reactions and physiological reactions. Acute respiratory distress syndrome (ARDS) caused by gadolinium-based MRI contrast is extremely rare. Due to the immediate and severe nature of ARDS, medical practitioners may seek after other aetiologies other than MRI-contrast-induced ARDS for patients' clinical manifestations such as acute-onset difficulty of breathing. It is crucial to keep in mind the possibility of ARDS after gadolinium injection, as missing the diagnosis leads to a high mortality. A clear clinical scenario of ARDS induced by gadobutrol (Gadovist, Bayer Inc., Toronto, Canada) was presented in our patient who did not develop symptoms of anaphylaxis. We successfully managed the patient with methylprednisolone and bilevel positive airway pressure ventilation and the patient was discharged in stable condition on day 6.

Oral immunotherapy with the ingestion of house dust mite extract in a murine model of allergic asthma.

BACKGROUND: Allergen-specific immunotherapy (ASIT) has the potential to modify allergic diseases, and it is also considered a potential therapy for allergic asthma. House dust mite (HDM) allergens, a common source of airborne allergen in human diseases, have been developed as an immunotherapy for patients with allergic asthma via the subcutaneous and sublingual routes. Oral immunotherapy with repeated allergen ingestion is emerging as another potential modality of ASIT. The aim of this study was to evaluate the therapeutic efficacy of the oral ingestion of HDM extracts in a murine model of allergic asthma. METHODS: BABL/c mice were sensitized twice by intraperitoneal injection of HDM extracts and Al(OH)3 on day 1 and day 8. Then, the mice received challenge to induce airway inflammation by intratracheal instillation of HDM extracts on days 29-31. The treatment group received immunotherapy with oral HDM extracts ingestion before the challenge. All the mice were sacrificed on day 32 for bronchoalveolar inflammatory cytokines, mediastinal lymph node T cells, lung histology, and serum HDM-specific immunoglobulins analyses. RESULTS: Upon HDM sensitization and following challenge, a robust Th2 cell response and eosinophilic airway inflammation were observed in mice of the positive control group. The mice treated with HDM extracts ingestion had decreased eosinophilic airway inflammation, suppressed HDM-specific Th2 cell responses in the mediastinal lymph nodes, and attenuated serum HDM-specific IgE levels. CONCLUSIONS: Oral immunotherapy with HDM extracts ingestion was demonstrated to have a partial therapeutic effect in the murine model of allergic asthma. This study may serve as the basis for the further development of oral immunotherapy with HDM extracts in allergic asthma.

Fermi surfaces in Kondo insulators.

We report magnetic quantum oscillations measured using torque magnetisation in the Kondo insulator YbB12 and discuss the potential origin of the underlying Fermi surface. Observed quantum oscillations as well as complementary quantities such as a finite linear specific heat capacity in YbB12 exhibit similarities with the Kondo insulator SmB6, yet also crucial differences. Small heavy Fermi sections are observed in YbB12 with similarities to the neighbouring heavy fermion semimetallic Fermi surface, in contrast to large light Fermi surface sections in SmB6 which are more similar to the conduction electron Fermi surface. A rich spectrum of theoretical models is suggested to explain the origin across different Kondo insulating families of a bulk Fermi surface potentially from novel itinerant quasiparticles that couple to magnetic fields, yet do not couple to weak DC electric fields.

Differences in IL-8 in serum and exhaled breath condensate from patients with exacerbated COPD or asthma attacks.

BACKGROUND/PURPOSE: The collection of exhaled breath condensate (EBC) is a noninvasive method that can be used to monitor the inflammatory status of patients with chronic airway diseases. We aimed to study differences in cytokine expression between patients with exacerbations of chronic obstructive pulmonary disease (COPD) and patients with asthma attacks. METHODS: Using a custom-made device and methods based on American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations, EBC samples were collected from nine COPD patients, 12 asthma patients and 10 healthy individuals. Cytokine concentrations in serum and EBC were measured via commercial ELISA kits. RESULTS: Of four cytokines measured in EBC [interleukin-8 (IL-8), IL-17, IL-4 and tumor necrosis factor-α (TNF-α)], only IL-8 was significantly higher in COPD than in asthma patients (5.27 ± 0.18 vs. 4.36 ± 0.34 pg/mL, p = 0.001). Moreover, COPD patients had higher serum IL-8 than asthma patients (10.57 ± 0.55 vs. 5.15 ± 0.24 pg/mL, p < 0.001). No significant correlation between serum and EBC cytokine concentrations was observed in each subgroup of patients. CONCLUSION: Compared with patients with asthma attacks, patients with exacerbated COPD had increased IL-8 expression in both serum and EBC. These results suggest that IL-8 may be more important in airway and systemic inflammation in COPD exacerbations than in asthma attacks.

Recombinant Derp5 allergen with αS1-casein signal peptide secreted in murine milk protects against dust mite allergen-induced airway inflammation.

Recent advances in recombinant technology make transgenic animals that produce pharmaceutical proteins in their milk more feasible. The group 5 allergen isolated from Dermatophagoides pteronyssinus (Derp5) is one of the most important dust mite allergens in humans. The aims of this study were to develop transgenic mice that could secrete recombinant Derp5-containing milk and to demonstrate that ingesting recombinant milk protects against allergic airway inflammation. Two transgenes were constructed separately. The α-LA-Derp5f transgene consisted of the bovine α-lactalbumin (α-LA) promoter and full-length Derp5 cDNA. The α-LA-CN-Derp5t transgene included the α-LA promoter, a leader sequence of αS1-casein (CN), and signal peptide-truncated Derp5 cDNA. Both species of transgenic mice were confirmed to have successful transgene integration and stable germline transmission. Western blot analysis of the milk obtained from the offspring of transgenic mice demonstrated that recombinant Derp5 was secreted successfully in the milk of αLA-CN-Derp5t transgenic mice but not in that of αLA-Derp5f transgenic mice. This study provides new evidence that transgenic mice can secrete recombinant Derp5 efficiently in milk by adding a signal peptide of αS1-casein. The antigenic activity of recombinant Derp5 milk was demonstrated to have a protective effect against allergic airway inflammation in a murine model in which the ingestion of recombinant Derp5-containing milk was used as pretreatment.

Electroacupuncture at ST36-ST37 and at ear ameliorates hippocampal mossy fiber sprouting in kainic acid-induced epileptic seizure rats.

Our previous study showed that mossy fiber sprouting can occur in the hippocampus region in rats 6 wk after kainic acid-induced epileptic seizure, and this mossy fiber sprouting can facilitate epileptogenesis. Transcutaneous auricular vagal nerve stimulation (VNS), which is similar to cervical VNS, can reduce the occurrence of epileptic seizure in intractable epilepsy patients. Greater parasympathetic nerve activity can be caused by 2 Hz electroacupuncture (EA). Therefore, we investigated the effect of 2 Hz EA at ST-36-ST37 and at the ear on mossy fiber sprouting in kainic-treated Sprague-Dawley rats. The results indicated that applying 2 Hz EA at ST36-ST37 and at the ear for 3 d per week over 6 consecutive weeks can ameliorate mossy fiber sprouting in the hippocampus region of rats. These results indicated that applying 2 Hz EA at ST36-ST37 and at the ear might be beneficial for the treatment and prevention of epilepsy in humans.

Effect of electroacupuncture on rats with chronic constriction injury-induced neuropathic pain.

We adopt the chronic constriction injury (CCI) model to induce neuropathic pain to Spragrue-Dawley (SD) rats by ligating the right sciatic nerve of using four 4-0 chromic gut sutures and subsequently applying 2 and 15 Hz electroacupuncture (EA), respectively, to the right (ipsilateral) Zusanli (St-36) and Shangjuxu (St-37) acupoints. The results of this study are summarized as follows: (1) the differences in withdrawal latencies for the radiant heat test and total lift leg counts for the cold plate test (4°C) of the control (i.e., non-EA) and sham groups were greater than those of the 2 Hz EA (2EA) and 15 Hz EA (15EA) groups; (2) the von Frey test filament gram counts of the control and sham groups were less than those of the 2EA and 15EA groups on the 6th, 7th, 8th, 11th, 12th, and 13th day following ligation; and (3) the 2EA and 15EA groups exhibited reduced cerebral transient receptor potential vanilloid type 4 (TRPV4) expressions, although we did not observe a similar effect for cerebral TRPV1 or spinal TRPV4/TRPV1 expressions. These findings show that 2 and 15 Hz EA can reduce CCI-induced neuropathic pain, which indicates that various spinal segmental and gate effects have a crucial function in pain reduction. The relationship between EA and TRPV4/TRPV1 expression requires further study.

Activation of IFN-γ/STAT/IRF-1 in hepatic responses to Klebsiella pneumoniae infection.

BACKGROUND: Klebsiella pneumoniae-caused liver abscess (KLA) has become a health problem in Taiwan and is continually reported in other countries. Diabetes mellitus, the most common metabolic disorder, underlies half of the KLA patients in Taiwan. The clinical impact of KLA has been well-documented. Nevertheless, the molecular basis regarding how K. pneumoniae causes liver infection, particularly in diabetic individuals, remains unclear. METHODOLOGY/PRINCIPLE FINDINGS: Auto-bioluminescence-expressing K. pneumoniae was inoculated into diabetic mice and age-match naïve control. With the use of in vivo imaging system, translocation of the bioluminescence-expressing K. pneumoniae from intestine to extraintestinal organs, mainly the liver, was noted in 80% of the diabetic mice, whereas the same bacteria causes extraintestinal infections in only 31% of naïve mice. Besides increased morbidity, the severity of hepatic tissue injury was also enhanced in the K. pneumoniae-infected diabetic mice. Upon K. pneumoniae infection, IFN-γ production was significantly evoked in the liver. To mediate IFN-γ signal, STAT (signal transducers and activators of transcription) 1 and 3 were activated in hepatocytes, and so was the expression of IRF (interferon regulatory factor)-1. Moreover, accumulation of neutrophils which was triggered by prolonged production of IL-1ß and MIP-2, and significant increases in the level of active caspase 3 and phospho-eIF2α, were exclusively revealed in the K. pneumoniae-infected diabetic mice. CONCLUSION: The activation of IFN-γ/STAT/IRF-1 signaling demonstrated by this work emphasizes the role of IFN-γ for mediating the hepatic response to K. pneumoniae infection.

Ingestion of milk containing the Dp2 peptide, a dust mite allergen, protects mice from allergic airway inflammation and hyper-responsiveness.

BACKGROUND: Allergen-specific immunotherapy has been demonstrated to have potential for the treatment of allergic diseases. Transgenic animals are currently the best available bioreactors to produce recombinant proteins, which can be secreted in milk. It has not been clearly demonstrated whether milk from transgenic animals expressing recombinant allergens has immunomodulatory effects on allergic asthma. METHODS: We aimed to determine whether the oral administration of milk containing a mite allergen can down-regulate allergen-specific airway inflammation. Transgenic CD-1 mice that express a recombinant group 2 allergen from Dermatophagoides pteronyssinus (Dp2) in their milk were generated using an embryonic gene-microinjection technique. Mouse pups were fed transgenic Dp2-containing milk or wild-type milk. Subsequently, these mice were sensitized and challenged with Dp2 to induce allergic airway inflammation. RESULTS: Upon sensitization and challenge, mice fed transgenic Dp2 milk had decreased T-helper 2 (Th2) and increased T-helper 1 (Th1) responses in the airway compared with mice fed wild-type milk. Moreover, pre-treatment with transgenic Dp2 milk attenuated airway inflammation and decreased airway hyper-responsiveness. CONCLUSIONS: This study provides new evidence that oral administration of transgenic milk containing the Dp2 allergen down-regulated and moderately protected against allergic airway inflammation. Milk from transgenic animals expressing allergens may have potential use in the prevention of allergic asthma.

Tail loss compromises immunity in the many-lined skink, Eutropis multifasciata.

Tail autotomy incurs energetic costs, and thus, a trade-off in resource allocation may lead to compromised immunity in lizards. We tested the hypothesis that tailless lizards will favor constitutive innate immunity responses over an energetically costly inflammatory response. The influence of fasting and colorful ornamentation was also investigated. We experimentally induced tail autotomy in the lizard Eutropis multifasciata and found that inflammation was suppressed by tail loss, but not further affected by fasting; the suppressive effect of colorful ornamentation was manifested only in males, but not in females. Constitutive innate immunity was not affected by any of these factors. As expected, only costly inflammation was compromised, and a less expensive constitutive innate immunity might be favored as a competent first-line defense during energetically demanding periods. After considering conventional trade-offs among tail regeneration and reproduction, further extending these studies to incorporate disease risk and how this influences escape responses to predators and future reproduction would make worthwhile studies.

Methadone concentrations in blood, plasma, and oral fluid determined by isotope-dilution gas chromatography-mass spectrometry.

Methadone (MTD) is widely used for detoxification of heroin addicts and also in pain management programs. Information about the distribution of methadone between blood, plasma, and alternative specimens, such as oral fluid (OF), is needed in clinical, forensic, and traffic medicine when analytical results are interpreted. We determined MTD and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in blood, plasma, blood cells, and OF by gas chromatography-mass spectrometry (GC-MS) after adding deuterium-labeled internal standards. The analytical limits of quantitation for MTD and EDDP by this method were 20 and 3 ng/mL, respectively. The amounts of MTD and EDDP were higher in plasma (80.4 % and 76.5 %) compared with blood cells (19.6 % and 23.5 %) and we found that repeated washing of blood cells with phosphate-buffered saline increased the amounts in plasma (93.6 % and 88.6 %). Mean plasma/blood concentration ratios of MTD and EDDP in spiked samples (N = 5) were 1.27 and 1.21, respectively. In clinical samples from patients (N = 46), the concentrations of MTD in plasma and whole blood were highly correlated (r = 0.92, p < 0.001) and mean (median) plasma/blood distribution ratios were 1.43 (1.41). The correlations between MTD in OF and plasma (r = 0.46) and OF and blood (r = 0.52) were also statistically significant (p < 0.001) and the mean OF/plasma and OF/blood distribution ratios were 0.55 and 0.77, respectively. The MTD concentration in OF decreased as salivary pH increased (more basic). These results will prove useful in clinical and forensic medicine when MTD concentrations in alternative specimens are compared and contrasted.

2 Hz electro-acupuncture at yinlingquan (SP9) and ququan (LR8) acupoints induces changes in blood flow in the liver and spleen.

According to the principles of traditional Chinese medicine, channels and collaterals within the body provide pathways through which qi and blood travel, and each channel or collateral is linked with a specific organ. The Yinlingquan (spleen 9, SP9) and Ququan (liver 8, LR8) acupoints represent the sea points of the spleen and liver meridians, respectively, from which qi and blood flow into their specific visceral organs. The purpose of this study was to investigate the changes in blood flow/perfusion in the liver and spleen resulting from the application of 2 Hz electro-acupuncture (EA) to the Yinlingquan (SP9) or Ququan (LR8) acupoints. A total of 18 Spragrue-Dawley rats were randomly divided into three groups of six rats each as follows: sham group receiving sham EA; Yinlingquan (SP9) group receiving 2 Hz EA, applied at bilateral Yinlingquan (SP9) acupoints; and Ququan (LR8) groups receiving 2 Hz EA, applied at bilateral Ququan (LR8) acupoints. The mean blood flow/perfusion of the spleen and liver was recorded using a laser Doppler blood flow monitor prior to EA (representing the baseline), during EA, and post-EA. Each measurement period lasted ten minutes. Nitric oxide levels were also measured from the right femoral arterial blood, following the conclusion of each series of blood flow/perfusion recordings. The results indicate that the sham EA did not increase the mean blood flow/perfusion in the liver or spleen; 2 Hz EA at bilateral Yinlingquan (SP9) acupoints increased the mean blood flow/perfusion in the spleen, but not in the liver. In contrast, 2 Hz EA at bilateral Ququan (LR8) acupoints increased the mean blood flow/perfusion in the liver, but not in the spleen. Nitric oxide levels showed no significant difference between any of the groups at any stage of the measurements. According to the results, we conclude that EA at the Yinlingquan (SP9) and Ququan (LR8) acupoints can increase the blood flow in the spleen and liver, respectively.

Neuroprotective Effect of Uncaria rhynchophylla in Kainic Acid-Induced Epileptic Seizures by Modulating Hippocampal Mossy Fiber Sprouting, Neuron Survival, Astrocyte Proliferation, and S100B Expression.

Uncaria rhynchophylla (UR), which is a traditional Chinese medicine, has anticonvulsive effect in our previous studies, and the cellular mechanisms behind this are still little known. Because of this, we wanted to determine the importance of the role of UR on kainic acid- (KA-) induced epilepsy. Oral UR for 6 weeks can successfully attenuate the onset of epileptic seizure in animal tests. Hippocampal mossy fiber sprouting dramatically decreased, while neuronal survival increased with UR treatment in hippocampal CA1 and CA3 areas. Furthermore, oral UR for 6 weeks significantly attenuated the overexpression of astrocyte proliferation and S100B proteins but not γ-aminobutyric acid A (GABA(A)) receptors. These results indicate that oral UR for 6 weeks can successfully attenuate mossy fiber sprouting, astrocyte proliferation, and S100B protein overexpression and increase neuronal survival in KA-induced epileptic rat hippocampus.