PURPOSE: To improve the treatment efficiency of optic nerve diseases by delivering therapeutic materials to the optic nerve directly. METHODS: We tried to optimize liposomal composition to deliver a payload to the optic nerve efficiently when it is injected intravitreally. After loading dexamethasone into this liposome, we tested the therapeutic effect of liposomes in this treatment using a murine model of ischemic optic neuropathy. RESULTS: Our optimized liposome can deliver its payload to the optic nerve more efficiently than other tested compositions. Moreover, dexamethasone-loaded liposomes had a significant therapeutic effect in a murine model of ischemic optic neuropathy. CONCLUSIONS: Here, we demonstrate the optimal composition of liposomes that could efficiently deliver intravitreally injected exogenous compounds to the optic nerve. We expect that the intravitreal injection of liposomes with the suggested composition would improve the delivery efficacy of therapeutic compounds to the optic nerve.
Dexamethasone ; Intravitreal Injections* ; Liposomes* ; Optic Nerve Diseases ; Optic Nerve* ; Optic Neuropathy, Ischemic

PURPOSE: Children with asthma frequently have allergic rhinitis (AR) as a comorbidity. Asthmatic children with AR have a higher exhaled nitric oxide (eNO) level and bronchial hyperresponsiveness (BHR) than those without. The purpose of this study is to investigate the difference in lung function, eNO, and BHR between atopic asthma with and without AR, and the association of eNO and BHR with atopic intensity in total asthmatics. METHODS: We recruited 69 atopic asthmatic children with AR, 19 atopic asthmatic children without AR, 38 children with AR, and 43 nonatopic controls. We measured forced expiratory volume in one second (FEV1) and forced expiratory flow at 25% to 75% of forced vital capacity (FEF(25%-75%)), dose response slope (DRS) of bronchial challenge with methacholine and adenosine 5'-monophosphate (AMP), the levels of eNO, and the ratio of sum of allergen wheal diameter to histamine using skin prick tests. RESULTS: Atopic asthmatic children with AR had a higher eNO level compared to those without AR (P<0.05). However, there was no difference in FEV1 %predicted, FEF(25%-75%) %predicted, methacholine DRS, and AMP DRS between asthmatic children with and without AR. In total asthmatics, methacholine DRS and AMP DRS significantly correlated with eNO levels (r=0.338, P<0.001; r=0.365, P<0.001), but not with total IgE levels. However, eNO significantly correlated with total IgE levels (r=0.479, P<0.001). CONCLUSION: These results suggest that AR may enhance airway inflammation but may not lead to enhanced BHR in children with asthma.
Adenosine ; Asthma ; Bronchial Hyperreactivity ; Child* ; Comorbidity ; Forced Expiratory Volume ; Histamine ; Humans ; Immunoglobulin E ; Inflammation ; Lung ; Methacholine Chloride ; Nitric Oxide* ; Rhinitis* ; Skin ; Vital Capacity

The neuronal activity-dependent change in the manner in which light is absorbed or scattered in brain tissue is called the intrinsic optical signal (IOS), and provides label-free, minimally invasive, and high spatial (~100 µm) resolution imaging for visualizing neuronal activity patterns. IOS imaging in isolated brain slices measured at an infrared wavelength (>700 nm) has recently been attributed to the changes in light scattering and transmittance due to aquaporin-4 (AQP4)-dependent astrocytic swelling. The complexity of functional interactions between neurons and astrocytes, however, has prevented the elucidation of the series of molecular mechanisms leading to the generation of IOS. Here, we pharmacologically dissected the IOS in the acutely prepared brain slices of the stratum radiatum of the hippocampus, induced by 1 s/20 Hz electrical stimulation of Schaffer-collateral pathway with simultaneous measurement of the activity of the neuronal population by field potential recordings. We found that 55% of IOSs peak upon stimulation and originate from postsynaptic AMPA and NMDA receptors. The remaining originated from presynaptic action potentials and vesicle fusion. Mechanistically, the elevated extracellular glutamate and K⁺ during synaptic transmission were taken up by astrocytes via a glutamate transporter and quinine-sensitive K2P channel, followed by an influx of water via AQP-4. We also found that the decay of IOS is mediated by the DCPIB- and NPPB-sensitive anion channels in astrocytes. Altogether, our results demonstrate that the functional coupling between synaptic activity and astrocytic transient volume change during excitatory synaptic transmission is the major source of IOS.
Action Potentials ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid ; Amino Acid Transport System X-AG ; Astrocytes ; Brain ; Electric Stimulation ; Glutamic Acid ; Hippocampus ; Jupiter ; Neurons ; Receptors, N-Methyl-D-Aspartate ; Synaptic Transmission ; Water

In the brain, a reduction in extracellular osmolality causes water-influx and swelling, which subsequently triggers Cl⁻- and osmolytes-efflux via volume-regulated anion channel (VRAC). Although LRRC8 family has been recently proposed as the pore-forming VRAC which is activated by low cytoplasmic ionic strength but not by swelling, the molecular identity of the pore-forming swelling-dependent VRAC (VRAC(swell)) remains unclear. Here we identify and characterize Tweety-homologs (TTYH1, TTYH2, TTYH3) as the major VRAC(swell) in astrocytes. Gene-silencing of all Ttyh1/2/3 eliminated hypo-osmotic-solution-induced Cl⁻ conductance (I(Cl,swell)) in cultured and hippocampal astrocytes. When heterologously expressed in HEK293T or CHO-K1 cells, each TTYH isoform showed a significant I(Cl,swell) with similar aquaporin-4 dependency, pharmacological properties and glutamate permeability as I(Cl,swell) observed in native astrocytes. Mutagenesis-based structure-activity analysis revealed that positively charged arginine residue at 165 in TTYH1 and 164 in TTYH2 is critical for the formation of the channel-pore. Our results demonstrate that TTYH family confers the bona fide VRAC(swell) in the brain.
Arginine ; Astrocytes ; Brain ; Cytoplasm ; Glutamic Acid ; Humans ; Osmolar Concentration ; Permeability