Abstract : In drug discovery or preclinical stages of development, potency parameters such as IC50, Ki, or Kd in vitro have been routinely used to predict the parameters of efficacious exposure (AUC, Cmin, etc.) in humans. However, to our knowledge, the fundamental assumption that the potency in vitro is correlated with the efficacious concentration in vivo in humans has not been investigated extensively. Thus, the present review examined this assumption by comparing a wide range of published pharmacokinetic (PK) and potency data. If the drug potency in vitro and its in vivo effectiveness in humans are well correlated, the steady-state average unbound concentrations in humans [Cu_ss.avg = fu·F·Dose/(CL· τ) = fu·AUCss/τ] after treatment with approved dosage regimens should be higher than, or at least comparable to, the potency parameters assessed in vitro. We reviewed the ratios of Cu_ss.avg/potency in vitro for a total of 54 drug entities (13 major therapeutic classes) using the dosage, PK, and in vitro potency reported in the published literature. For 54 drugs, the Cu_ss.avg/in vitro potency ratios were < 1 for 38 (69%) and < 0.1 for 22 (34%) drugs. When the ratios were plotted against fu (unbound fraction), “ratio < 1” was predominant for drugs with high protein binding (90% of drugs with fu ≤ 5%; i.e., 28 of 31 drugs). Thus, predicting the in vivo efficacious unbound concentrations in humans using only in vitro potency data and fu should be avoided, especially for molecules with high protein binding.
Abstract : Confirming the direct link between neural circuit activity and animal behavior has been a principal aim of neuroscience. The genetically encoded calcium indicator (GECI), which binds to calcium ions and emits fluorescence visualizing intracellular calcium concentration, enables detection of in vivo neuronal firing activity. Various GECIs have been developed and can be chosen for diverse purposes. These GECI-based signals can be acquired by several tools including two-photon microscopy and microendoscopy for precise or wide imaging at cellular to synaptic levels. In addition, the images from GECI signals can be analyzed with open source codes including constrained non-negative matrix factorization for endoscopy data (CNMF_E) and miniscope 1-photon-based calcium imaging signal extraction pipeline (MIN1PIPE), and considering parameters of the imaged brain regions (e.g., diameter or shape of soma or the resolution of recorded images), the real-time activity of each cell can be acquired and linked with animal behaviors. As a result, GECI signal analysis can be a powerful tool for revealing the functions of neuronal circuits related to specific behaviors.
Abstract : Allergic asthma, is a common chronic inflammatory disease of the airway presenting with airway hyperresponsiveness and airway remodelling. T helper cells-derived cytokines are critically associated with asthma pathogenesis. Janus kinase-signal transduction and activation of transcription (JAK/STAT) signaling is found to be involved in asthma. Magnolol is a plant-derived bioactive compound with several pharmacological effects. The study aimed to assess the effects of magnolol in ovalbumin (OVA)-induced asthmatic model. BALB/c mice were sensitized and challenged with OVA. Magnolol (12.5, 25, or 50 mg/kg body weight) was administered to separate groups of animals. Dexamethasone was used as the positive control. Cellular infiltration into the bronchoalveolar lavage fluid (BALF) were reduced on magnolol treatment. The levels of Th2 and Th17 cytokines were reduced with noticeably raised levels of interferon gamma. Lung function was improved effectively along with restoration of bronchial tissue architecture. OVA-specific immunoglobulin E levels in serum and BALF were decreased by magnolol. Magnolol reduced Th17 cell population and effectively modulated the JAK-STAT and Notch 1 signaling. The results suggest the promising use of magnolol in therapy for allergic asthma.
Kyoung Wan Kwon, Yoonjin Nam, Won Seok Choi et al.
Abstract : Hydrogen sulfide is well-known to exhibit anti-inflammatory and cytoprotective activities, and also has protective effects in the liver. This study aimed to examine the protective effect of hydrogen sulfide in rats with hepatic encephalopathy, which was induced by mild bile duct ligation. In this rat model, bile ducts were mildly ligated for 26 days. Rats were treated for the final 5 days with sodium hydrosulfide (NaHS). NaHS (25 μmol/kg), 0.5% sodium carboxymethyl cellulose, or silymarin (100 mg/kg) was administered intraperitoneally once per day for 5 consecutive days. Mild bile duct ligation caused hepatotoxicity and inflammation in rats. Intraperitoneal NaHS administration reduced levels of aspartate aminotransferase and alanine aminotransferase, which are indicators of liver disease, compared to levels in the control mild bile duct ligation group. Levels of ammonia, a major causative factor of hepatic encephalopathy, were also significantly decreased. Malondialdehyde, myeloperoxidase, catalase, and tumor necrosis factor-α levels were measured to confirm antioxidative and anti-inflammatory effects. N-Methyl-D-aspartic acid (NMDA) receptors with neurotoxic activity were assessed for subunit NMDA receptor subtype 2B. Based on these data, NaHS is suggested to exhibit hepatoprotective effects and guard against neurotoxicity through antioxidant and anti-inflammatory actions.
Hoang Thi Thanh Nguyen, Dong Hyu Cho, Seon Hui Jang et al.
Abstract : The lamina II, also called the substantia gelatinosa (SG), of the trigeminal subnucleus caudalis (Vc), is thought to play an essential role in the control of orofacial nociception. Glycine and serotonin (5-hydroxytryptamine, 5-HT) are the important neurotransmitters that have the individual parts on the modulation of nociceptive transmission. However, the electrophysiological effects of 5-HT on the glycine receptors on SG neurons of the Vc have not been well studied yet. For this reason, we applied the whole-cell patch clamp technique to explore the interaction of intracellular signal transduction between 5-HT and the glycine receptors on SG neurons of the Vc in mice. In nine of 13 neurons tested (69.2%), pretreatment with 5-HT potentiated glycine-induced current (IGly). Firstly, we examined with a 5-HT1 receptor agonist (8-OH-DPAT, 5-HT1/7 agonist, co-applied with SB-269970, 5-HT7 antagonist) and antagonist (WAY-100635), but 5-HT1 receptor agonist did not increase IGly and in the presence of 5-HT1 antagonist, the potentiation of 5-HT on IGly still happened. However, an agonist (α-methyl-5-HT) and antagonist (ketanserin) of the 5-HT2 receptor mimicked and inhibited the enhancing effect of 5-HT on IGly in the SG neurons, respectively. We also verified the role of the 5-HT7 receptor by using a 5-HT7 antagonist (SB-269970) but it also did not block the enhancement of 5-HT on IGly. Our study demonstrated that 5-HT facilitated IGly in the SG neurons of the Vc through the 5-HT2 receptor. The interaction between 5-HT and glycine appears to have a significant role in modulating the transmission of the nociceptive pathway.
Kyung-Ok Cho, Joo Youn Kim, Kyoung Hoon Jeong et al.
Abstract : Vascular endothelial growth factor (VEGF)-C and its receptor, vascular endothelial growth factor receptor (VEGFR)-3, are responsible for lymphangiogenesis in both embryos and adults. In epilepsy, the expression of VEGF-C and VEGFR-3 was significantly upregulated in the human brains affected with temporal lobe epilepsy. Moreover, pharmacologic inhibition of VEGF receptors after acute seizures could suppress the generation of spontaneous recurrent seizures, suggesting a critical role of VEGF-related signaling in epilepsy. Therefore, in the present study, the spatiotemporal expression of VEGF-C and VEGFR-3 against pilocarpine-induced status epilepticus (SE) was investigated in C57BL/6N mice using immunohistochemistry. At 1 day after SE, hippocampal astrocytes and microglia were activated. Pyramidal neuronal death was observed at 4 days after SE. In the subpyramidal zone, VEGF-C expression gradually increased and peaked at 7 days after SE, while VEGFR-3 was significantly upregulated at 4 days after SE and began to decrease at 7 days after SE. Most VEGF-C/VEGFR-3-expressing cells were pyramidal neurons, but VEGF-C was also observed in some astrocytes in sham-manipulated animals. However, at 4 days and 7 days after SE, both VEGFR-3 and VEGF-C immunoreactivities were observed mainly in astrocytes and in some microglia of the stratum radiatum and lacunosum-moleculare of the hippocampus, respectively. These data indicate that VEGF-C and VEGFR-3 can be upregulated in hippocampal astrocytes and microglia after pilocarpine-induced SE, providing basic information about VEGF-C and VEGFR-3 expression patterns following acute seizures.