NMDA receptors sustain but do not initiate neuronal depolarization in spreading depolarization.

Spreading depolarization (SD) represents a neurological process characterized by a massive, self-sustaining wave of brain cell depolarization. Understanding its mechanism is important for treating ischemic or hemorrhagic stroke and migraine with aura. Many believed that ion fluxes through NMDA receptors (NMDARs) are responsible for neuronal transmembrane currents of SD. However, the explicit role of NMDARs remains ambiguous. This is in part due to the limitation of traditional pharmacological approaches in resolving the contribution of NMDARs in different intercellular and intracellular processes of SD. Here, we applied single-cell blockade and genetic deletion methods to remove functional NMDARs from individual hippocampal CA1 neurons in order to examine the role of NMDARs in the depolarization mechanism without affecting the propagation of SD. We analyzed neuronal membrane potential changes to demonstrate that NMDARs are not required for initiating the depolarization. Consistently, neuronal input resistance (RN) revealed a sharp decline at the start of SD, which was unaffected by blocking NMDARs. Instead, the recovery of both membrane potential and RN during the late phase of SD was facilitated by inhibition of NMDARs, indicating that NMDARs are responsible for sustaining the depolarization. Our results strongly indicate that NMDAR activation is not a determinant of the initiation of depolarization but is important for sustaining transmembrane ion fluxes during SD.

A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors.

Hyperekplexia, an inherited neuronal disorder characterized by exaggerated startle responses with unexpected sensory stimuli, is caused by dysfunction of glycinergic inhibitory transmission. From analysis of newly identified human hyperekplexia mutations in the glycine receptor (GlyR) α1 subunit, we found that an alanine-to-proline missense mutation (A384P) resulted in substantially higher desensitization level and lower agonist sensitivity of homomeric α1 GlyRs when expressed in HEK cells. The incorporation of the ß subunit fully reversed the reduction in agonist sensitivity and partially reversed the desensitization of α1A384P The heteromeric α1A384Pß GlyRs showed enhanced desensitization but unchanged agonist-induced maximum responses, surface expression, main channel conductance, and voltage dependence compared with that of the wild-type α1ß (α1WTß) GlyRs. Coexpression of the R392H and A384P mutant α1 subunits, which mimic the expression of the compound heterozygous mutation in a hyperekplexia patient, resulted in channel properties similar to those with α1A384P subunit expression alone. In comparison, another human hyperekplexia mutation α1P250T, which was previously reported to enhance desensitization, caused a strong reduction in maximum currents in addition to the altered desensitization. These results were further confirmed by overexpression of α1P250T or α1A384P subunits in cultured neurons isolated from SD rats of either sex. Moreover, the IPSC-like responses of cells expressing α1A384Pß induced by repeated glycine pulses showed a stronger frequency-dependent reduction than those expressing α1WTß. Together, our findings demonstrate that A384 is associated with the desensitization site of the α1 subunit and its proline mutation produced enhanced desensitization of GlyRs, which contributes to the pathogenesis of human hyperekplexia.SIGNIFICANCE STATEMENT Human startle disease is caused by impaired synaptic inhibition in the brainstem and spinal cord, which is due to either direct loss of GlyR channel function or reduced number of synaptic GlyRs. Considering that fast decay kinetics of GlyR-mediated inhibitory synaptic responses, the question was raised whether altered desensitization of GlyRs will cause dysfunction of glycine transmission and disease phenotypes. Here, we found that the α1 subunit mutation A384P, identified from startle disease patients, results in enhanced desensitization and leads to rapidly decreasing responses in the mutant GlyRs when they are activated repeatedly by the synaptic-like simulation. These observations suggest that the enhanced desensitization of postsynaptic GlyRs could be the primary pathogenic mechanism of human startle disease.

Spreading Depression Promotes Astrocytic Calcium Oscillations and Enhances Gliotransmission to Hippocampal Neurons.

Spreading depression (SD) is a pathophysiological phenomenon characterized by propagating waves of profound neuronal and glial depolarization in central nervous system gray matter. Although SD is primarily mediated by neurons with a subsequent astrocytic response, it remains unclear how astrocytic activity is modulated after SD and how altered astrocyte signaling contribute to neuronal excitability. Here, we report that after the concurrent Ca2+ wave, SD enhanced astrocytic activity by promoting a secondary period of Ca2+ oscillations. SD-induced Ca2+ oscillations did not require the activation of metabotropic glutamate receptors or purinergic receptors; instead, they were mediated by the activation of GABAB receptors and 1,4,5-trisphosphate (IP3) receptors. Furthermore, SD increased the number of NMDA receptor-mediated slow inward currents (SICs) in CA1 pyramidal neurons. The frequency of SD-induced SICs was reduced by blockade of GABAB receptors or by limiting Ca2+ efflux from the ER. Selective inhibition of astrocytic Ca2+ signals by dialysis of BAPTA into astrocytes or by knocking out the astrocytic type of IP3 receptors suppressed SICs after SD. These results demonstrated a causative link between the SD-induced Ca2+ oscillations and the enhanced glutamatergic astrocyte-neuron signaling. Therefore, we conclude that SD enhances the astrocyte Ca2+ signals and further promotes gliotransmission and neuronal excitability.

The GLRA1 missense mutation W170S associates lack of Zn2+ potentiation with human hyperekplexia.

Hyperekplexia is a neurological disorder associated primarily with mutations in the α1 subunit of glycine receptors (GlyRs) that lead to dysfunction of glycinergic inhibitory transmission. To date, most of the identified mutations result in disruption of surface expression or altered channel properties of α1-containing GlyRs. Little evidence has emerged to support an involvement of allosteric GlyR modulation in human hyperekplexia. Here, we report that recombinant human GlyRs containing α1 or α1ß subunits with a missense mutation in the α1 subunit (W170S), previously identified from familial hyperekplexia, caused remarkably reduced potentiation and enhanced inhibition by Zn(2+). Interestingly, mutant α1(W170S)ß GlyRs displayed no significant changes in potency or maximum response to glycine, taurine, or ß-alanine. By temporally separating the potentiating and the inhibitory effects of Zn(2+), we found that the enhancement of Zn(2+) inhibition resulted from a loss of Zn(2+)-mediated potentiation. The W170S mutation on the background of H107N, which was previously reported to selectively disrupt Zn(2+) inhibition, showed remarkable attenuation of Zn(2+)-mediated potentiation and thus indicated that W170 is an important residue for the Zn(2+)-mediated GlyR potentiation. Moreover, overexpressing the α1(W170S) subunit in cultured rat neurons confirmed the results from heterologous expression. Together, our results reveal a new zinc potentiation site on α1 GlyRs and a strong link between Zn(2+) modulation and human disease.

Conjunctive encoding of exploratory intentions and spatial information in the hippocampus.

The hippocampus creates a cognitive map of the external environment by encoding spatial and self-motion-related information. However, it is unclear whether hippocampal neurons could also incorporate internal cognitive states reflecting an animal's exploratory intention, which is not driven by rewards or unexpected sensory stimuli. In this study, a subgroup of CA1 neurons was found to encode both spatial information and animals' investigatory intentions in male mice. These neurons became active before the initiation of exploration behaviors at specific locations and were nearly silent when the same fields were traversed without exploration. Interestingly, this neuronal activity could not be explained by object features, rewards, or mismatches in environmental cues. Inhibition of the lateral entorhinal cortex decreased the activity of these cells during exploration. Our findings demonstrate that hippocampal neurons may bridge external and internal signals, indicating a potential connection between spatial representation and intentional states in the construction of internal navigation systems.

What nature has to offer: Opportunities for immuno-oncology.

Recent rapid development of cancer therapy has come about with the paradigm shift from the traditional goal of targeting cancer cells themselves, to reprograming the immune tumor microenvironment. Accumulating evidence shows that compounds that target epigenetic regulation, called epidrugs, play a crucial role in mediating the immunogenicity of cancer cells and in reshaping antitumor immunity. A large body of literature has recognized natural compounds as epigenetic modulators for their immunomodulatory effects and anticancer potential. Unifying our understanding of the role of these biologically active compounds in immuno-oncology may open new avenues for more effective cancer therapies. In this review, we explore how natural compounds modulate the epigenetic machinery to shape antitumor immune response, highlighting the promise offered by the Mother Nature that could be exploited therapeutically to improve outcomes for cancer patients.

In Silico and In Vitro Screening of Serine Racemase Agonist and In Vivo Efficacy on Alzheimer's Disease Drosophila melanogaster.

The NMDA receptor hypofunction has been implicated in schizophrenia, memory impairment, and Alzheimer's disease. Modulating the abundance of D-serine, a co-agonist of the NMDA receptor, is a strategy to treat symptoms of the NMDA receptor hypofunction. In contrast to D-amino acid oxidase (DAAO) inhibitors, which aim at decreasing the loss of D-serine, this study tried to identify serine racemase (SRR) agonists, which boost the conversion of L-serine to D-serine. We used holo and apo structures of human SRR for the molecular docking against the National Cancer Institute (NCI) and ZINC compound databases and validated their efficacy by in vitro SRR activity assay. We identified NSC294149 (2-amino-3-(3-nitroimidazo[1,2-a]pyridin-2-yl)sulfanylpropanoic acid) as a potential SRR agonist and confirmed its amelioration of the hazard ratio of survival of the AD model of fruit fly (Drosophila melanogaster). These results suggest that the SRR agonist could be a drug design target against the NMDA receptor hypofunction symptoms.

Vascular responses of penetrating vessels during cortical spreading depolarization with ultrasound dynamic ultrafast Doppler imaging.

The dynamic vascular responses during cortical spreading depolarization (CSD) are causally related to pathophysiological consequences in numerous neurovascular conditions, including ischemia, traumatic brain injury, cerebral hemorrhage, and migraine. Monitoring of the hemodynamic responses of cerebral penetrating vessels during CSD is motivated to understand the mechanism of CSD and related neurological disorders. Six SD rats were used, and craniotomy surgery was performed before imaging. CSDs were induced by topical KCl application. Ultrasound dynamic ultrafast Doppler was used to access hemodynamic changes, including cerebral blood volume (CBV) and flow velocity during CSD, and further analyzed those in a single penetrating arteriole or venule. The CSD-induced hemodynamic changes with typical duration and propagation speed were detected by ultrafast Doppler in the cerebral cortex ipsilateral to the induction site. The hemodynamics typically showed triphasic changes, including initial hypoperfusion and prominent hyperperfusion peak, followed by a long-period depression in CBV. Moreover, different hemodynamics between individual penetrating arterioles and venules were proposed by quantification of CBV and flow velocity. The negative correlation between the basal CBV and CSD-induced change was also reported in penetrating vessels. These results indicate specific vascular dynamics of cerebral penetrating vessels and possibly different contributions of penetrating arterioles and venules to the CSD-related pathological vascular consequences. We proposed using ultrasound dynamic ultrafast Doppler imaging to investigate CSD-induced cerebral vascular responses. With this imaging platform, it has the potential to monitor the hemodynamics of cortical penetrating vessels during brain injuries to understand the mechanism of CSD in advance.

A critical role for myosin IIb in dendritic spine morphology and synaptic function.

Dendritic spines show rapid motility and plastic morphology, which may mediate information storage in the brain. It is presently believed that polymerization/depolymerization of actin is the primary determinant of spine motility and morphogenesis. Here, we show that myosin IIB, a molecular motor that binds and contracts actin filaments, is essential for normal spine morphology and dynamics and represents a distinct biophysical pathway to control spine size and shape. Myosin IIB is enriched in the postsynaptic density (PSD) of neurons. Pharmacologic or genetic inhibition of myosin IIB alters protrusive motility of spines, destabilizes their classical mushroom-head morphology, and impairs excitatory synaptic transmission. Thus, the structure and function of spines is regulated by an actin-based motor in addition to the polymerization state of actin.

The Protective Role of Peroxisome Proliferator-Activated Receptor-Gamma in Seizure and Neuronal Excitotoxicity.

The peroxisome proliferator-activated receptor (PPAR) family, type II nucleus receptors have been successfully tested for their neuroprotective potential in certain central nervous system diseases. The aim of the present study was to determine if modulation by PPAR-γ could attenuate pilocarpine-induced seizures and decrease neuronal excitability. Adult male C57BL/6 mice were divided into two groups: one group received pretreatment with pioglitazone and the other received dimethyl sulfoxide (DMSO) for a period of 2 weeks. Status epilepticus was then induced in both groups by lithium-pilocarpine, after which seizure susceptibility, severity, and mortality were evaluated. Hippocampal histopathology was carried out on all mice at 24 h post-status epilepticus as well as blood-brain barrier (BBB) damage analysis. With the aid of patch clamp technology, the hippocampal neuronal excitability from mice with PPAR-γ 50% expression (PpargC/C) and PPAR-γ 25% expression (PpargC/-), as well as the effect of pioglitazone on the sodium currents in hippocampal neurons, were evaluated. It was found that pioglitazone, a PPAR-γ agonist, could attenuate pilocarpine-induced seizure severity in mice. Pathological examination showed that pioglitazone significantly attenuated pilocarpine-induced status epilepticus-related hippocampal neuronal loss and BBB damage. Further characterization of neuronal excitability revealed higher excitability in the brain slices from mice with PpargC/- expression, compared with the PpargC/C group. It was also found that pioglitazone could decrease sodium currents in hippocampal neurons. In conclusion, PPAR-γ deficiency aggravated neuronal excitability and excitotoxicity. PPAR-γ attenuated pilocarpine-induced seizure severity, neuronal loss, BBB damage, and sodium currents in hippocampal neurons. Modulation of PPAR-γ could be a potential novel treatment for epileptic seizures.

NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo.

Well-documented experimental evidence from both in vitro and in vivo models of stroke strongly supports the critical involvement of NMDA receptor-mediated excitotoxicity in neuronal damage after stroke. Despite this, the results of clinical trials testing NMDA receptor antagonists as neuroprotectants after stroke and brain trauma have been discouraging. Here, we report that in mature cortical cultures, activation of either synaptic or extrasynaptic NR2B-containing NMDA receptors results in excitotoxicity, increasing neuronal apoptosis. In contrast, activation of either synaptic or extrasynaptic NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action against both NMDA receptor-mediated and non-NMDA receptor-mediated neuronal damage. A similar opposing action of NR2B and NR2A in mediating cell death and cell survival was also observed in an in vivo rat model of focal ischemic stroke. Moreover, we found that blocking NR2B-mediated cell death was effective in reducing infarct volume only when the receptor antagonist was given before the onset of stroke and not 4.5 h after stroke. In great contrast, activation of NR2A-mediated cell survival signaling with administration of either glycine alone or in the presence of NR2B antagonist significantly attenuated ischemic brain damage even when delivered 4.5 h after stroke onset. Together, the present work provides a molecular basis for the dual roles of NMDA receptors in promoting neuronal survival and mediating neuronal damage and suggests that selective enhancement of NR2A-containing NMDA receptor activation with glycine may constitute a promising therapy for stroke.

Role of AMPA receptor trafficking in NMDA receptor-dependent synaptic plasticity in the rat lateral amygdala.

Stimulated exocytosis and endocytosis of post-synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of glutamate receptors (AMPARs) have been proposed as primary mechanisms for the expression of hippocampal CA1 long-term potentiation (LTP) and long-term depression (LTD), respectively. LTP and LTD, the two most well characterized forms of synaptic plasticity, are thought to be important for learning and memory in behaving animals. Both LTP and LTD can also be induced in the lateral amygdala (LA), a critical structure involved in fear conditioning. However, the role of AMPAR trafficking in the expression of either LTP or LTD in this structure remains unclear. In this study, we show that NMDA receptor-dependent LTP and LTD can be reliably induced at the synapses of the auditory thalamic inputs to the LA in brain slices. The expression of LTP was prevented by post-synaptic blockade of vesicle-mediated exocytosis with application of a light chain of Clostridium tetanus neurotoxin and was associated with increased cell-surface AMPAR expression. In contrast, the expression of LTD was prevented by post-synaptic application of a glutamate receptor 2-derived interference peptide, which specifically blocks the stimulated clathrin-dependent endocytosis of AMPARs, and was correlated with a reduction in plasma membrane-surface expression of AMPARs. These results strongly suggest that regulated trafficking of post-synaptic AMPARs is also involved in the expression of LTP and LTD in the LA.

Astrocytic Regulation of Glutamate Transmission in Schizophrenia.

According to the glutamate hypothesis of schizophrenia, the abnormality of glutamate transmission induced by hypofunction of NMDA receptors (NMDARs) is causally associated with the positive and negative symptoms of schizophrenia. However, the underlying mechanisms responsible for the changes in glutamate transmission in schizophrenia are not fully understood. Astrocytes, the major regulatory glia in the brain, modulate not only glutamate metabolism but also glutamate transmission. Here we review the recent progress in understanding the role of astrocytes in schizophrenia. We focus on the astrocytic mechanisms of (i) glutamate synthesis via the glutamate-glutamine cycle, (ii) glutamate clearance by excitatory amino acid transporters (EAATs), (iii) D-serine release to activate NMDARs, and (iv) glutamatergic target engagement biomarkers. Abnormality in these processes is highly correlated with schizophrenia phenotypes. These findings will shed light upon further investigation of pathogenesis as well as improvement of biomarkers and therapies for schizophrenia.

Effects of anti-epileptic drugs on spreading depolarization-induced epileptiform activity in mouse hippocampal slices.

Epilepsy and spreading depolarization (SD) are both episodic brain disorders and often exist together in the same individual. In CA1 pyramidal neurons of mouse hippocampal slices, induction of SD evoked epileptiform activities, including the ictal-like bursts, which occurred during the repolarizing phase of SD, and the subsequent generation of paroxysmal depolarization shifts (PDSs), which are characterized by mild depolarization plateau with overriding spikes. The duration of the ictal-like activity was correlated with both the recovery time and the depolarization potential of SD, whereas the parameters of PDSs were not significantly correlated with the parameters of SD. Moreover, we systematically evaluated the effects of multiple anti-epileptic drugs (AEDs) on SD-induced epileptiform activity. Among the drugs that are known to inhibit voltage-gated sodium channels, carbamazepine, phenytoin, valproate, lamotrigine, and zonisamide reduced the frequency of PDSs and the overriding firing bursts in 20-25 min after the induction of SD. The GABA uptake inhibitor tiagabine exhibited moderate effects and partially limited the incidence of PDSs after SD. AEDs including gabapentin, levetiracetam, ethosuximide, felbamate, and vigabatrin, had no significant effect on SD-induced epileptic activity. Taken together, these results demonstrate the effects of AEDs on SD and the related epileptiform activity at the cellular level.

Luteolin Attenuates Airway Mucus Overproduction via Inhibition of the GABAergic System.

Airway mucus overproduction is one of the most common symptoms of asthma that causes severe clinical outcomes in patients. Despite the effectiveness of general asthma therapies, specific treatments that prevent mucus overproduction in asthma patients remain lacking. Recent studies have found that activation of GABAA receptors (GABAAR) is important for promoting mucus oversecretion in lung airway epithelia. Here, we report that luteolin, a natural flavonoid compound, suppresses mucus overproduction by functionally inhibiting the GABAergic system. This hypothesis was investigated by testing the effects of luteolin on goblet cell hyperplasia, excessive mucus secretion, and GABAergic transmission using histological and electrophysiological approaches. Our results showed that 10 mg/kg luteolin significantly decreased the number of goblet cells in the lung tissue and inhibited mucus overproduction in an in vivo asthma model induced by ovalbumin (OVA) in mice. Patch-clamp recordings showed that luteolin inhibited GABAAR-mediated currents in A549 cells. Furthermore, the inhibitory effects of luteolin on OVA-induced goblet cell hyperplasia and mucus overproduction were occluded by the GABAAR antagonist picrotoxin. In conclusion, our observations indicate that luteolin effectively attenuates mucus overproduction at least partially by inhibiting GABAARs, suggesting the potential for therapeutic administration of luteolin in the treatment of mucus overproduction in asthma patients.

Luteolin inhibits GABAA receptors in HEK cells and brain slices.

Modulation of the A type γ-aminobutyric acid receptors (GABAAR) is one of the major drug targets for neurological and psychological diseases. The natural flavonoid compound luteolin (2-(3,4-Dihydroxyphenyl)- 5,7-dihydroxy-4-chromenone) has been reported to have antidepressant, antinociceptive, and anxiolytic-like effects, which possibly involve the mechanisms of modulating GABA signaling. However, as yet detailed studies of the pharmacological effects of luteolin are still lacking, we investigated the effects of luteolin on recombinant and endogenous GABAAR-mediated current responses by electrophysiological approaches. Our results showed that luteolin inhibited GABA-mediated currents and slowed the activation kinetics of recombinant α1ß2, α1ß2γ2, α5ß2, and α5ß2γ2 receptors with different degrees of potency and efficacy. The modulatory effect of luteolin was likely dependent on the subunit composition of the receptor complex: the αß receptors were more sensitive than the αßγ receptors. In hippocampal pyramidal neurons, luteolin significantly reduced the amplitude and slowed the rise time of miniature inhibitory postsynaptic currents (mIPSCs). However, GABAAR-mediated tonic currents were not significantly influenced by luteolin. These data suggested that luteolin has negative modulatory effects on both recombinant and endogenous GABAARs and inhibits phasic rather than tonic inhibition in hippocampus.

Anti-nociceptive effect induced by intrathecal injection of ATPA, an effect enhanced and prolonged by concanavalin A.

The present study investigated the effect of intrathecal injection of (RS)-2-alpha-amino-3-(3-hydroxy-5-tbutylisoxazol-4-yl) propanoic acid (ATPA), a selective agonist to kainate receptor, on nociception in rats. Intrathecal administration of 1, 4 and 10 nmol of ATPA induced dose-dependent increases in the hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in rats. Pretreatment with intrathecal injection of 300 microg of concanavalin A (ConA) to block the desensitization of kainate receptors enhanced and prolonged the anti-nociceptive effect induced by intrathecal injection of ATPA. The results suggest that the pre-synaptic kainate receptor in the primary afferent terminals is involved in the transmission of nociceptive information in dorsal horn of the spinal cord in rats. Furthermore, blocking the desensitization of kainate receptor enhanced and prolonged the ATPA-induced anti-nociceptive effects.

Anti-nociceptive effects of diazepam binding inhibitor in the central nervous system of rats.

The present study investigated the effect of diazepam binding inhibitor (DBI) on nociception in the central nervous system of rats. There were dose-dependent increases in hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation after intrathecal injection of 1, 5 or 10 microg of DBI in rats, indicating a DBI-induced anti-nociceptive effect at the spinal levels of rats. Furthermore, it was found that there were no significant influences of intrathecal co-administration of gamma-aminobutyric acid (GABA) on the intrathecal DBI-induced increases in HWLs of rats. Intracerebroventricular administration of 1, 10 or 20 microg of DBI also induced dose-dependent increases in HWL to thermal and mechanical stimulation in rats, suggesting an anti-nociceptive effect of DBI in the brain. Moreover, there were no significant influences of intracerebroventricular co-administration of 2 microg of GABA on the intracerebroventricular DBI-induced increases in HWL of rats. The results of the present study demonstrated that DBI played anti-nociceptive effects in the central nervous system of rats.

The effect of sesamin on airway fibrosis in vitro and in vivo.

Airway fibrosis, which is a crucial pathological condition occurring in various types of pulmonary disorders, is characterized by accumulation and activation of fibroblast cells, deposition of extracellular matrix (ECM) proteins, and increase of airway basement membrane. Transforming growth factor beta 1 (TGF-ß1) is the principal profibrogenic cytokine that is responsible for fibrotic responses. In the present study, we aimed to investigate the antifibrotic effects of the natural polyphenolic compound, sesamin, on TGF-ß1-induced fibroblast proliferation and activation, epithelial-mesenchymal transition (EMT), and ovalbumin (OVA)-induced airway fibrosis in vivo. We found that sesamin attenuated TGF-ß1-induced proliferation of cultured lung fibroblasts. Sesamin inhibited TGF-ß1-stimulated expression of alpha smooth muscle actin (α-SMA), suggesting that sesamin plays an inhibitory role in fibroblast activation. Sesamin blocked upregulation of the mesenchymal markers (fibronectin and vimentin) and downregulation of the epithelial marker (E-cadherin), indicating an inhibitory effect on TGF-ß1-induced EMT in A549 cells. TGF-ß1-induced Smad3 phosphorylation was also significantly reduced by sesamin in both cultured fibroblast and A549 cells. In the airway fibrosis induced by OVA in mice, sesamin inhibited the accumulation of α-SMA-positive cells and expression of collagen I in the airway. Histological studies revealed that sesamin protected against subepithelial fibrosis by reducing myofibroblast activation and collagen accumulation in the ECM. OVA-induced thickening of basement membrane was significantly alleviated in animals receiving sesamin treatments. These results suggest a therapeutic potential of sesamin as an antifibrotic agent.

Protective effects of the polyphenol sesamin on allergen-induced T(H)2 responses and airway inflammation in mice.

Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and ß-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti-oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR). Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA)-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4), IL-5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IκB-α and nuclear expression levels of NF-κB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice.