Potential efficacy and mechanism of eight mild-natured and bitter-flavored TCMs based on gut microbiota: A review / 中草药·英文版

The mild-natured and bitter-flavored traditional Chinese medicines (MB-TCMs) are an important class of TCMs that have been widely used in clinical practice and recognized as safe long-term treatments for chronic diseases. However, as an important class of TCMs, the panorama of pharmacological effects and the mechanisms of MB-TCMs have not been systemically reviewed. Compelling studies have shown that gut microbiota can mediate the therapeutic activity of TCMs and help to elucidate the core principles of TCM medicinal theory. In this systematic review, we found that MB-TCMs commonly participated in the modulation of metabolic syndrome, intestinal inflammation, nervous system disease and cardiovascular system disease in association with promoting the growth of beneficial bacteria Bacteroides, Akkermansia, Lactobacillus, Bifidobacterium, Roseburia as well as inhibiting the proliferation of harmful bacteria Helicobacter, Enterococcus, Desulfovibrio and Escherichia-Shigella. These alterations, correspondingly, enhance the generation of protective metabolites, mainly including short-chain fatty acids (SCFAs), bile acid (BAs), 5-hydroxytryptamine (5-HT), indole and gamma-aminobutyric acid (GABA), and inhibit the generation of harmful metabolites, such as proinflammatory factors trimethylamine oxide (TAMO) and lipopolysaccharide (LPS), to further exert multiplicative effects for the maintenance of human health through several different signaling pathways. Altogether, this present review has attempted to comprehensively summarize the relationship between MB-TCMs and gut microbiota by establishing the TCMs-gut microbiota-metabolite-signaling pathway-diseases axis, which may provide new insight into the study of TCM medicinal theories and their clinical applications.

Activation of GABAergic neurons in the zona incerta accelerates anesthesia induction with sevoflurane and propofol without affecting anesthesia maintenance or awakening in mice / 南方医科大学学报

OBJECTIVE@#To explore the regulatory effects of GABAergic neurons in the zona incerta (ZI) on sevoflurane and propofol anesthesia.@*METHODS@#Forty-eight male C57BL/6J mice divided into 8 groups (n=6) were used in this study. In the study of sevoflurane anesthesia, chemogenetic experiment was performed in 2 groups of mice with injection of either adeno-associated virus carrying hM3Dq (hM3Dq group) or a virus carrying only mCherry (mCherry group). The optogenetic experiment was performed in another two groups of mice injected with an adeno-associated virus carrying ChR2 (ChR2 group) or GFP only (GFP group). The same experiments were also performed in mice for studying propofol anesthesia. Chemogenetics or optogenetics were used to induce the activation of GABAergic neurons in the ZI, and their regulatory effects on anesthesia induction and arousal with sevoflurane and propofol were observed; EEG monitoring was used to observe the changes in sevoflurane anesthesia maintenance after activation of the GABAergic neurons.@*RESULTS@#In sevoflurane anesthesia, the induction time of anesthesia was significantly shorter in hM3Dq group than in mCherry group (P < 0.05), and also shorter in ChR2 group than in GFP group (P < 0.01), but no significant difference was found in the awakening time between the two groups in either chemogenetic or optogenetic tests. Similar results were observed in chemogenetic and optogenetic experiments with propofol (P < 0.05 or 0.01). Photogenetic activation of the GABAergic neurons in the ZI did not cause significant changes in EEG spectrum during sevoflurane anesthesia maintenance.@*CONCLUSION@#Activation of the GABAergic neurons in the ZI promotes anesthesia induction of sevoflurane and propofol but does not affect anesthesia maintenance or awakening.

Progress of cyclic adenosine monophosphate responsive element binding protein in the pathogenesis of drug-resistant epilepsy / 中华神经科杂志

Recent studies have found that in the development of epilepsy, cyclic adenosine monophosphate response element binding protein (CREB) may cause recurrent epilepsy by inhibiting the expression of γ-aminobutyric acid, resulting in neuron damage and weakened effect of antiepileptic drug targets. Antiepileptic drugs can not control the extent or frequency of seizures, and then the patients are in a persistent state, hence the development of drug-resistant epilepsy. Therefore, the mechanism of CREB leading to drug-resistant epilepsy was reviewed in this paper, hoping to provide ideas for the treatment of drug-resistant epilepsy patients.

Effects of propofol on glutamatergic neuronal activity in paraventricular thalamus / 药学学报

This study explored the effects of propofol on the activity of glutamatergic neurons in the paraventricular thalamus (PVT) and the underlying mechanisms at the molecular level using whole-cell patch-clamp techniques. Acute brain slices containing the PVT were obtained from 8 weeks old C57BL/6J mice. The electrophysiological characteristics of PVT neurons were recorded in current-clamp mode, then single-cell sequencing was used to identify neuronal types. The firing frequencies before, during, and after propofol or intralipid application were recorded as FB, FD and FW; and the membrane potentials were recorded as MPB and MPD. Picrotoxin (PTX) was used to block inhibitory gamma-aminobutyric acid type A (GABAA) receptors during the application of propofol at 10 μmol·L-1. Then, GABAA receptor-mediated spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) were recorded, and the effects of 10 μmol·L-1 propofol were investigated. The animal experiments were approved by the Medical Animal Administrative Committee of Shanghai Medical College Fudan University. The results showed that there were no significant differences in FB, FD and FW during intralipid and 2 μmol·L-1 propofol application. With propofol at 5, 10 and 20 μmol·L-1, FD decreased significantly when compared with FB, and FW increased significantly as compared with FD (P < 0.01). The inhibition degree of the three concentration groups was significantly different (P < 0.01). In addition, with propofol at 20 μmol·L-1, MPD hyperpolarized significantly (P < 0.01). In the presence of PTX, 10 μmol·L-1 propofol could not suppress the firing frequency of PVT glutamatergic neurons. Propofol at 10 μmol·L-1 prolonged the decay time of sIPSCs (P < 0.01) and mIPSCs (P < 0.05), and increased the amplitude (P < 0.01) of mIPSCs of PVT glutamatergic neurons. Together, these results indicate that propofol can inhibit the activity of PVT glutamatergic neurons in a concentration-dependent and reversible manner, and the effect is likely to be mediated by postsynaptic GABAA receptors.

Research Progress of GABA Receptors in Alzheimer’s Disease / 中国生物化学与分子生物学报

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with the early symptom of A β plaque, tau hyperphosphorylation neuronal tangle formation in cells. At present, accumulated evidence shows that the changes of GABA receptors are closely related to AD. Some studies have shown that the expression level of each subunit of the GABA receptor changes in AD patients. Therefore, it is speculated that the changes of GABA subunits may be related to the pathogenesis of AD, but there is no better methods to improve AD by targeting GABA receptors. In order to further understand the relationship between the changes of GABA receptors and AD, this paper first reviewed the changes of GABA receptors in AD patients and animal models’ brains and found that there was differential expression in GABA(A) receptor subunits in AD patients. Then we summarized the changes of GABA receptor subunits in Alzheimer database. Based on the data, we found that a few GABA subunits had significant changes. The evidence shows that the change of GABA receptors alters the neural activity in the brain. Other studies have found that the treatment of mice with GABA receptor agonists and antagonists can improve the cognitive ability of mice. We hope that understanding the differential expression of GABA receptors in AD will provide a more accurate target for the treatment of AD.

Effect of hydroxysafflor yellow a on γ-aminobutyric acid and glutamic acid levels in the inferior colliculus of rats with tinnitus / 国际中医中药杂志

Objective:To evaluate the therapeutic effect of hydroxysafflor yellow A (HYA) on rats with tinnitus and investigate its influence on γ-aminobutyric acid (GABA) and glutamic acid (Glu) levels of inferior colliculus.Methods:The model of rats with tinnitus received an injection of sodium salicylate and "water-drinking suppression" was extablished, and then were divided into four groups with random number table method: normal group, model group, positive control (carbamazepine 5 mg/kg) and HYA (20 mg/kg) groups. Animals were intraperitoneally injected for 15 days. The recovery time of water-drinking suppression of all groups were recorded. The threshold value of auditory brainstem response (ABR) under the different frequency (4, 12, 20 and 28 kHz) in each rat was measured. The levels of GABA and Glu in inferior colliculus in rats with tinnitus were detected by LC-MS/MS.Results:Compared with the model group, the recovery time of water drinking suppression [(3.55±0.69)d vs.(1.83±0.58)d] in HYA group was significantly prolonged ( P<0.01). Compared with the model group, the threshold value of ABR under different frequency (4, 12, 20 and 28 kHz) were significantly reduced in HYA group ( P<0.01). The GABA levels [(2.25±0.26) μmol/g vs.(1.96±0.19)μmol/g] in inferior colliculus of tinnitus rats in HYA group was significantly increased ( P<0.05) while the Glu levels [(2.95±0.34)μmol/g vs.(3.71±0.39)μmol/g] were significantly decreased ( P<0.01). Conclusion:HYA treatment could relieve tinnitus symptoms induced by sodium salicylate, which might be related to the recovery of excitatory/inhibitory neurotransmitter balance.

Transcranial direct current stimulation for the relief of neuropathic pain in rats and the underlying mechanism / 中华物理医学与康复杂志

Objective:To observe any therapeutic effect of repeated transcranial direct current stimulation (tDCS) on rats modeling neuropathic pain and explore possible mechanisms.Methods:Forty adult male Sprague-Dawley rats were randomly divided into a normal group ( n=10), a sham operation group ( n=10), a treatment group ( n=10) and a sham treatment group ( n=10). A model of chronic constriction injury of the sciatic nerve was established in the latter two groups. Fourteen days after the modeling, the treatment group was given tDCS for 8 consecutive days, while the sham treatment group received sham stimulation, and the other 2 groups did not receive any intervention. Von Frey and hotplate tests were used to test the rats′ pain thresholds 1 day before, as well as 14 and 22 days after the surgery (i.e., 8 days after the end of the treatment). Spinal cord tissue samples were taken to detect the protein expressions of N-methyl-D-aspartic acid receptor 2B, gamma-aminobutyric acid receptor types A (GABA a-R) and B (GABA b-R) using western blotting. Results:On the 14th day after the operation the average 50% MWT and WTL values of the sham treatment and treatment groups had decreased significantly compared with the sham operation group. By the 22nd day the average 50% MWT and WTL values of the treatment group were significantly higher than those of the sham treatment group, but there was no significant change in the treatment group′s average WTL between the 21st and 22nd days. On the 22nd day after the operation the average NR2B-NMDA-R level of the sham treatment group were significantly higher than that of the sham operation group, while the average GABA a-R and GABA b-R levels were significantly lower. At the same time point the treatment group′s average NR2B-NMDA-R level had decreased significantly compared to the sham treatment group, while the average GABA a-R level had increased significantly. There was no significant difference in average GABA b-R level between the treatment group and the sham treatment group at that point. On the 22nd day there was also no significant difference in the average NR2B-NMDA-R level between the treatment group and the sham operation group. Conclusions:Repeated tDCS can effectively relieve neuropathic pain. The relief of hyperalgesia is more significant than that of mechanical allodynia. A possible mechanism may be the down-regulation of spinal NR2B-NMDA-R to normal levels and modest up-regulation of GABA a-R.

Effect of etomidate on the reuniens neuronal activity / 中南大学学报(医学版)

OBJECTIVES@#To explore the effect of etomidate on the neuronal activity of ventral thalamic reuniens nucleus and the underlying mechanisms.@*METHODS@#Whole-cell patch clamp method was used to explore the effect of etomidate on the activity of ventral thalamic reuniens neurons in the acute brain slices obtained from 4-5 weeks old C57BL/6J mice. The electrophysiological characteristics of ventral thalamic reuniens neurons were recorded in the current clamp mode, and then the effects of etomidate (0.5, 2.0, 8.0 μmol/L etomidate groups) and intralipid (intralipid group) on the discharge frequency and membrane potential of ventral thalamic reuniens neurons were recorded. During the experiment, the ventral thalamic reuniens neuron firing rates (RNFRs) were recorded as F@*RESULTS@#In the intralipid group, there was no significant difference among the F@*CONCLUSIONS@#Etomidate can inhibit the activity of ventral thalamic reuniens neurons in concentration-dependent manner, and which is reversible. Etomidate with sub-anesthetic concentration inhibits the activity of ventral thalamic reuniens neurons via targeting the GABA

The mechanism of Shuyu capsules in treating premenstrual dysphoric disorder caused by liver qi depression based on microdialysis technology from the aspect of Glu-GABA metabolic pathway / 国际中医中药杂志

Objective:To explore the mechanism of premenstrual dysphoric disorder (PMDD) caused by liver-qi depression from the aspect of Glu-GABA metabolic pathways.Methods:Thirty-six rats with similar open field scores and regular estrus cycles were divided into blank group, model group, fluoxetine group, Shuyu capsule group, saikosaponin group and inhibitor group according to the random number table method, with 6 rats in each group. Stereotactic hippocampus surgery was performed during the first estrous cycle reception period after the estrus cycle was determined. In the non-receiving period of the third and fourth estrus cycles, the restraint model was constructed, and from the first day of the modeling, rats of the fluoxetine group were given fluoxetine capsules 2.67 mg/kg, while rats of the Shuyu capsule group and saikosaponin group were given Shuyu capsules 0.408 g/kg and saikosaponin 0.72 mg/kg once a day for 5 consecutive days. Rats in the inhibitor group were injected with 20 μl L-malic acid with 5 mmol/L concentration, which is an inhibitor of glutamate decarboxylase (GAD), in the hippocampus on the last day of modeling. After the administration, weighed the rats and carried out open field experiments. During the second and fivth estrus cycles of rats, the extracellular fluid of the hippocampus was collected by microdialysis technology, and the content of Glu and GABA in the dialysate was detected by HPLC-FLD. Results:After 5 days of administration, compared with the model group, the body weight of rats in the Shuyu capsule group, the inhibitor group and the fluoxetine group increased ( P<0.05), and the total score of the open field experiment decreased ( P<0.05); compared with the model group, during the receiving period of the five estrus cycle, the Glu level of the Shuyu capsule group and the inhibitor group decreased ( P<0.05); In the non-receiving period of the fifth estrus cycle, the Shuyu capsule group, Glu level of the fluoxetine group and the saikosaponin group increased, GABA level of Shuyu capsule group, inhibitor group and fluoxetine group decreased ( P<0.05), Glu/GABA level of Shuyu capsule group, fluoxetine group and inhibitor group (1.49 ± 0.13, 1.32 ± 0.33, 3.92 ± 0.79 vs. 0.35 ± 0.48) was higher than that of the model group ( P<0.05). Conclusion:The therapeutic mechanism of Shuyu capsule in the treatment of PMDD caused by liver Qi depression rats may be ascribed to inhibiting GAD from Glu-GABA metabolic pathway.

Astrocytic GABA Receptors in Mouse Hippocampus Control Responses to Behavioral Challenges through Astrocytic BDNF / 神经科学通报·英文版

Major depressive disorder (MDD) is a common mood disorder that affects almost 20% of the global population. In addition, much evidence has implicated altered function of the gamma-aminobutyric acid (GABAergic) system in the pathophysiology of depression. Recent research has indicated that GABA receptors (GABARs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD. However, which cell types with GABARs are involved in this process is unknown. As hippocampal dysfunction is implicated in MDD, we knocked down GABARs in the hippocampus and found that knocking down these receptors in astrocytes, but not in GABAergic or pyramidal neurons, caused a decrease in immobility in the forced swimming test (FST) without affecting other anxiety- and depression-related behaviors. We also generated astrocyte-specific GABAR-knockout mice and found decreased immobility in the FST in these mice. Furthermore, the conditional knockout of GABARs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes, which controlled the decrease in immobility in the FST. Taken together, our findings contribute to the current understanding of which cell types expressing GABARs modulate antidepressant activity in the FST, and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.

Effect of An-pressing manipulation on post-stroke muscle spasticity in rats and its mechanism study / 针灸推拿医学（英文版）

Objective: To explore the mechanism of An-pressing manipulation in improving post-stroke muscle spasticity, by observing the changes of γ-aminobutyric acid (GABA) and glycine (Gly) in plasma and gray matter of L1-L3 spinal cord anterior horn in post-stroke rats with muscle spasticity after An-pressing manipulation intervention. Methods: Ten of 80 adult male Sprague-Dawley (SD) rats were randomly selected as the blank group, and the remaining 70 were used for modeling. The middle cerebral artery occlusion (MCAO) rat model was established by insertion suture occlusion method in the left external carotid artery. Thirty rats with a Longa neurological score of 2-3 points and a modified Ashworth spasticity scale score of 1-, 1+, or 2 were included in the experiment. Using the random number table method, the 30 successfully modeled rats were randomly divided into a model group, an An-pressing tendon group and an An-pressing muscle belly group. Two days after modeling, rats in the An-pressing tendon group and An-pressing muscle belly group received An-pressing manipulation on the tendon and belly of quadriceps femoris muscle respectively, with the pressure of (350±50) g and the frequency of 5 s/time, 15 min per session, once a day for 5 continuous days. After the 5th treatment, the tension of the rat quadriceps femoris muscle was evaluated using the modified Ashworth spasticity scale. The Gly levels in rat plasma and L1-L3 segments of spinal cord were determined by enzyme-linked immunosorbent assay (ELISA). The GABA levels in rat plasma and L1-L3 segments of spinal cord were measured by high performance liquid chromatography (HPLC). Results: The decrease in rat muscle tension scored by the modified Ashworth spasticity scale in the An-pressing tendon group was more significant than that in the An-pressing muscle belly group (P<0.01); the increases in Gly and GABA levels in the rat plasma and L1-L3 segments of spinal cord were more significant in the An-pressing tendon group than those in the An-pressing muscle belly group (all P<0.01). Conclusion: Based on the theory of 'anti-stretch reflex' of tendon organs, the use of An-pressing manipulation to induce the 'anti-stretch reflex' by stimulating the tendon organs can improve the muscle spasticity of rats, which is better than An-pressing the muscle belly. Increased levels of Gly and GABA in rat plasma and L1-L3 segments of spinalcord may be one mechanism of An-pressing manipulation to improve muscle spasticity by stimulating tendon organs.

Anti-γ-aminobutyric acid type A receptor encephalitis: a new type of autoimmune encephalitis with prominent epilepsy / 中华神经科杂志

Objective To firstly report the clinical features,diagnosis and treatment response of patients with anti-γ-aminobutyric acid type A receptor (GABAAR) encephalitis in China,thus raising neurologists' awareness of this emerging type of autoimmune encephalitis.Methods Specific anti-GABAAR autoantibodies in the serum and cerebrospinal fluid (CSF) of patients with suspected autoimmune encephalitis but negative for commercial available antibody tests were detected by live cell-based assay (CBA).The clinical features,laboratory examinations and treatment of two cases of autoimmune encephalitis with anti-GABAAR autoantibodies were analyzed,who admitted to Huashan Hospital,Fudan University between 2013 and 2014.Results By using live CBA,serum and CSF of the two patients diagnosed with possible autoimmune encephalitis both contained autoantibodies targeted to the GABAAR.These two patients had onset symptom of seizure or refractory seizures.Memory impairment,psychiatric symptoms and decreased consciousness were also presented.One patient was combined with mass in anterior superior mediastinum.Both patients had multifocal cortical and subcortical T2 /fluid attenuated inversion recovery-weighted images hyperintensity signal on brain magnetic resonance imaging.The two patients had poor response to antiepileptic drugs,but showed noticeable recovery with sufficient immunotherapeutic treatments.Conclusions Anti-GABAAR encephalitis is characterized by prominent epilepsy and multifocal abnormalities on brain magnetic resonance imaging.Autoantibodies specifically against GABAAR could be detected by CBA in this group of patients.Early diagnosis and immunotherapy are critical to improve clinical symptoms and outcomes of the disease.

The antinociceptive effect of artemisinin on the inflammatory pain and role of GABAergic and opioidergic systems

BACKGROUND: Pain is a complex mechanism which involves different systems, including the opioidergic and GABAergic systems. Due to the side effects of chemical analgesic agents, attention toward natural agents have been increased. Artemisinin is an herbal compound with widespread modern and traditional therapeutic indications, which its interaction with the GABAergic system and antinoniceptive effects on neuropathic pain have shown. Therefore, this study was designed to evaluate the antinociceptive effects of artemisinin during inflammatory pain and interaction with the GABAergic and opioidergic systems by using a writhing response test. METHODS: On the whole, 198 adult male albino mice were used in 4 experiments, including 9 groups (n = 6) each with three replicates, by intraperitoneal (i.p.) administration of artemisinin (2.5, 5, and 10 mg/kg), naloxone (2 mg/kg), bicuculline (2 mg/kg), saclofen (2 mg/kg), indomethacin (5 mg/kg), and ethanol (10 mL/kg). Writhing test responses were induced by i.p. injection of 10 mL/kg of 0.6% acetic acid, and the percentage of writhing inhibition was recorded. RESULTS: Results showed significant dose dependent anti-nociceptive effects from artemisinin which, at a 10 mg/kg dose, was statistically similar to indomethacin. Neither saclofen nor naloxone had antinociceptive effects and did not antagonize antinociceptive effects of artemisinin, whereas bicuculline significantly inhibited the antinocicptive effect of artemisinin. CONCLUSIONS: It seems that antinocicptive effects of artemisinin are mediated by GABAA receptors.

Expression of gamma-aminobutyric acid type A receptor beta3 subunit in murine cleft palate induced by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin / 中华口腔医学杂志

Objective@#To investigate the expression of gamma-aminobutyric acid type A receptor beta3 subunit (GABRB3) on cleft palate in C57BL/6J mice induced by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD).@*Methods@#Sixty C57BL/6J pregnant mice on gestation day (GD) 10.5 were divided into two groups: one group was administered through gastric tubes one dose of 28 μg/kg TCDD (experimental group) and the other group was administered through gastric tubes one dose of 5.6 ml/kg corn oil (control group). Embryos were removed by cesarean section from pregnant mice during the palatal formation stage (GD 13.5-17.5) and the palatal tissue studied in morphological and histological observation. The relative mRNA and protein expression of GABRB3 was measured by real-time quantitative PCR and Western blotting. Localization of GABRB3 protein was measured by immunohistochemistry or immunofluorescence.@*Results@#The incidence of cleft palate at GD17.5 was 100% in experimental group and there was no cleft palate occurred in the control group (0); elevation of palatine processes in experimental group was completed on GD15.5 which was clearly delayed by a day compared with that in control group. On GD14.5-GD17.5, the mRNA expression (0.561±0.073, 0.728±0.104, 0.782±0.137, 0.686±0.145) and protein expression (0.288±0.013, 0.404±0.017, 0.399±0.012, 0.307±0.010) in the experimental group were significantly lower than the control group mRNA expression (0.818±0.088, 0.865±0.086, 1.021±0.054, 1.163±0.179) and protein expression (0.481±0.017, 0.456±0.009, 0.474±0.016, 0.529±0.015)(P<0.05). Immunohistochemistry and immunofluorescence showed that GABRB3 was mainly expressed in the mesenchymal cells and medial edge epithelium.@*Conclusions@#TCDD delayed palatal shelf elevation and eventually led to cleft palate may be associated with a decrease in GABRB3. GABRB3 may play an important role in the elevation and fusion phases of the palate development.

Effect of 17β estradiol on propofol-induced long-term cognitive dysfunction in developing rats: the relationship with hippocampal Glu∕GABA / 中华麻醉学杂志

Objective To evaluate the effect of 17βestradiol on propofol-induced long-term cogni-tive dysfunction in developing rats and the relationship with hippocampal glutamate ( Glu )∕γ-aminobutyric acid (GABA). Methods Sixty healthy male Sprague-Dawley rats, aged 7 days, weighing 11-18 g, were divided into 5 groups ( n=12 each) using a random number table method: dimethyl sulfoxide ( DM-SO) group, fat emulsion group (group F), 17β estradiol group (group E), propofol group (group P) and propofol plus 17β estradiol group ( group P+E) . 17β estradiol 600 μg∕kg was subcutaneously injected in group E, and the equal volume of DMSO was given instead in group DMSO. Propofol 75 mg∕kg was in-traperitoneally injected in group P, and the equal volume of fat emulsion was given instead in group F. 17βestradiol 600μg∕kg was subcutaneously injected and 30 min later propofol 75 mg∕kg was intraperitoneally in-jected in group P+E. Injection was performed once every 24 h for 7 consecutive days in each group. Morris water maze test was performed at 60 days of age. The rats were sacrificed after the end of Morris water maze test and hippocampi were removed for determination of Glu content ( by ultraviolet colorimetry method) andGABA content (using enzyme-linked immunosorbent assay) in hippocampal tissues. Glu∕GABA ratio was calculated. Results There was no significant difference in the escape latency, the number of crossing the original platform, percentage of time spent in target quadrant, Glu content or Glu∕GABA ratio between group DMSO, group F and group E (P>0. 05). There was no significant difference in GABA content a-mong the five groups ( P>0. 05) . Compared with group F, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, and the percentage of time spent in target quad-rant, Glu content and Glu∕GABA ratio were decreased in group P (P<0. 05). Compared with group P, the escape latency was significantly shortened, the number of crossing the original platform was increased, and the percentage of time spent in target quadrant, Glu content and Glu∕GABA ratio were increased in group P+E ( P<0. 05) . Conclusion 17β estradiol can improve propofol-induced long-term cognitive dysfunction and the mechanism may be related to maintaining hippocampal Glu∕GABA balance in developing rats.

GABA Receptor Activity Suppresses the Transition from Inter-ictal to Ictal Epileptiform Discharges in Juvenile Mouse Hippocampus / 神经科学通报·英文版

Exploring the transition from inter-ictal to ictal epileptiform discharges (IDs) and how GABA receptor-mediated action affects the onset of IDs will enrich our understanding of epileptogenesis and epilepsy treatment. We used Mg-free artificial cerebrospinal fluid (ACSF) to induce epileptiform discharges in juvenile mouse hippocampal slices and used a micro-electrode array to record the discharges. After the slices were exposed to Mg-free ACSF for 10 min-20 min, synchronous recurrent seizure-like events were recorded across the slices, and each event evolved from inter-ictal epileptiform discharges (IIDs) to pre-ictal epileptiform discharges (PIDs), and then to IDs. During the transition from IIDs to PIDs, the duration of discharges increased and the inter-discharge interval decreased. After adding 3 μmol/L of the GABA receptor agonist muscimol, PIDs and IDs disappeared, and IIDs remained. Further, the application of 10 μmol/L muscimol abolished all the epileptiform discharges. When the GABA receptor antagonist bicuculline was applied at 10 μmol/L, IIDs and PIDs disappeared, and IDs remained at decreased intervals. These results indicated that there are dynamic changes in the hippocampal network preceding the onset of IDs, and GABA receptor activity suppresses the transition from IIDs to IDs in juvenile mouse hippocampus.

Fatty Acid Increases cAMP-dependent Lactate and MAO-B-dependent GABA Production in Mouse Astrocytes by Activating a G(αs) Protein-coupled Receptor

Medium-chain fatty acids (MCFAs) are mostly generated from dietary triglycerides and can penetrate the blood-brain barrier. Astrocytes in the brain use MCFAs as an alternative energy source. In addition, MCFAs have various regulatory and signaling functions in astrocytes. However, it is unclear how astrocytes sense and take up MCFAs. This study demonstrates that decanoic acid (DA; C10), a saturated MCFA and a ligand of G(αs) protein-coupled receptors (G(αs)-GPCRs), is a signaling molecule in energy metabolism in primary astrocytes. cAMP synthesis and lactate release were increased via a putative G(αs)-GPCR and transmembrane adenylyl cyclase upon short-term treatment with DA. By contrast, monoamine oxidase B-dependent gamma-aminobutyric acid (GABA) synthesis was increased in primary cortical and hypothalamic astrocytes upon long-term treatment with DA. Thus, astrocytes respond to DA by synthesizing cAMP and releasing lactate upon short-term treatment, and by synthesizing and releasing GABA upon long-term treatment, similar to reactive astrocytes. Our data suggest that astrocytes in the brain play crucial roles in lipid-sensing via GPCRs and modulate neuronal metabolism or activity by releasing lactate via astrocyte-neuron lactate shuttle or GABA to influence neighboring neurons.

Safety and Efficacy of Gamma-Aminobutyric Acid from Fermented Rice Germ in Patients with Insomnia Symptoms: A Randomized, Double-Blind Trial

BACKGROUND AND PURPOSE: This study aimed to determine the subjective and objective improvements in sleep quality after treatment with gamma-aminobutyric acid (GABA; 300 mg daily) extracted from unpolished rice germ. METHODS: This study was a prospective, randomized, double-blind, and placebo-controlled trial. In total, 40 patients who complained of insomnia symptoms were enrolled and randomly assigned to the GABA treatment group (n=30) or the placebo group (n=10). Polysomnography was performed, and sleep questionnaires were administered before treatment and after 4 weeks of treatment. RESULTS: After 4 weeks of treatment the sleep latency had decreased [13.4±15.7 min at pretreatment vs. 5.7±6.2 min at posttreatment (mean±SD), p=0.001] and the sleep efficacy had increased (79.4±12.9% vs. 86.1±10.5%, p=0.018) only in the GABA treatment group. Adverse events occurred in four subjects (10%). CONCLUSIONS: This study shows that treatment with unpolished-rice-germ-derived GABA improved not only the subjective sleep quality but also the objective sleep efficacy without severe adverse events.

Astrocytic proBDNF and Tonic GABA Distinguish Active versus Reactive Astrocytes in Hippocampus

Astrocytes are the most abundant cell type in the brain and they make close contacts with neurons and blood vessels. They respond dynamically to various environmental stimuli and change their morphological and functional properties. Both physiological and pathological stimuli can induce versatile changes in astrocytes, as this phenomenon is referred to as ‘astrocytic plasticity’. However, the molecular and cellular mechanisms of astrocytic plasticity in response to various stimuli remain elusive, except for the presence of hypertrophy, a conspicuous structural change which is frequently observed in activated or reactive astrocytes. Here, we investigated differential characteristics of astrocytic plasticity in a stimulus-dependent manner. Strikingly, a stab wound brain injury lead to hypertrophy of astrocytes accompanied by increased GABA expression and tonic GABA release in mouse CA1 hippocampus. In contrast, the mice experiencing enriched environment exhibited astrocytic hypertrophy with enhanced proBDNF immunoreactivity but without GABA signal. Based on the results, we define proBDNF-positive/GABA-negative hypertrophic astrocytes as ‘active’ astrocytes and GABA-positive hypertrophic astrocytes as ‘reactive’ astrocytes, respectively. We propose for the first time that astrocytic proBDNF can be a bona fide molecular marker of the active astrocytes, which are distinct from the reactive astrocytes which show hypertrophy but with aberrant GABA.

Long-term prenatal stress increases susceptibility of N-methyl-D-aspartic acid-induced spasms in infant rats / 소아과

PURPOSE: Infantile spasms, also known as West syndrome, is an age-specific epileptic seizure. Most patients with this condition also exhibit delayed development. This study aimed to determine the effect of long-term prenatal stress on susceptibility to infantile spasms. METHODS: We subjected pregnant rats to acute or chronic immobilization stress. Resulting offspring received N-methyl-D-aspartic acid (15 mg/kg, intraperitoneally) on postnatal day 15, and their behaviors were observed 75 minutes after injection. The expression of KCC2 and GAD67 was also determined using immunohistochemistry. RESULTS: Exposure to long-term prenatal stress increased the frequency of spasms and decreased the latency to onset of spasms compared with offspring exposed to short-term prenatal stress. Expression of KCC2 and GAD67 also decreased in the group exposed to long-term prenatal stress compared with the group exposed to short-term prenatal stress. CONCLUSION: Our study suggests that exposure to long-term prenatal stress results in increased susceptibility to seizures.