Claustrum modulates behavioral sensitivity and EEG activity of propofol anesthesia.

AIMS: The claustrum has long been regarded as a vital center for conscious control. Electrical stimulation or damage to the claustrum can result in decreased awareness or loss of consciousness, suggesting that the claustrum may be a target for the action of general anesthetics. This study aimed to determine the role of the claustrum in propofol anesthesia. METHODS: We first applied a fiber photometry calcium signal recording system to record the claustral neuronal activity during the entire process of propofol anesthesia. Chemogenetic activation of claustral neurones was then performed to verify their role in anesthesia. Finally, muscimol (GABAa receptor agonist) and gabazine (GABAa receptor antagonist) were microinjected into the claustrum to determine whether their GABAa receptors were involved in modulating propofol anesthesia. EEG and behavioral indicators, such as anesthetic sensitivity and efficacy, were recorded and analyzed. RESULTS: An evident anesthesia-related change in claustrum neuronal activity was suppressed during propofol-induced unconsciousness and restored following recovery from anesthesia. Chemogenetic activation of claustrum neurons results in attenuated propofol sensitivity, a shorter anesthesia duration, and an EEG shift toward wakefulness. Manipulation of GABAa receptors in the claustrum showed bidirectional control of propofol sensitivity, as activation decreases anesthesia efficiency while inactivation augments it. Additionally, inhibiting claustrum GABAa receptors increases cortical EEG slow waves. CONCLUSIONS: Claustrum neurones and their GABAa receptors are implicated in the modulation of propofol anesthesia in both behavioral and EEG assessments. Our findings create scope to reveal the brain targets of anesthetic action further and add to the existing evidence on the consciousness-modulating role of the claustrum.

Effect of basal forebrain somatostatin and parvalbumin neurons in propofol and isoflurane anesthesia.

AIMS: The basal forebrain (BF) plays an essential role in wakefulness and cognition. Two subtypes of BF gamma-aminobutyric acid (GABA) neurons, including somatostatin-expressing (GABASOM ) and parvalbumin-positive (GABAParv ) neurons, function differently in mediating the natural sleep-wake cycle. Since the loss of consciousness induced by general anesthesia and the natural sleep-wake cycle probably share similar mechanisms, it is important to clarify the accurate roles of these neurons in general anesthesia procedure. METHODS: Based on two transgenic mouse lines expressing SOM-IRES-Cre and PV-IRES-Cre, we used a combination of genetic activation, inactivation, and chronic ablation approaches to further explore the behavioral and electroencephalography (EEG) roles of BFSOM and BFParv neurons in general anesthesia. After a single intravenous injection of propofol and the induction and recovery times of isoflurane anesthesia, the anesthesia time was compared. The changes in cortical EEG under different conditions were also compared. RESULTS: Activation of BF GABASOM neurons facilitates both the propofol and isoflurane anesthesia, manifesting as a longer anesthesia duration time with propofol anesthesia and a fast induction time and longer recovery time with isoflurane anesthesia. Moreover, BF GABASOM -activated mice displayed a greater suppression of cortical electrical activity during anesthesia, showing an increase in δ power bands or a simultaneous decrease in high-frequency power bands. However, only a limited and nuanced effect on propofol and isoflurane anesthesia was observed with the manipulated BF GABAParv neurons. CONCLUSIONS: Our results suggested that BF GABASOM neurons play a critical role in propofol and isoflurane general anesthesia, while BF GABAParv neurons appeared to have little effect.

Basal Forebrain Cholinergic Activity Modulates Isoflurane and Propofol Anesthesia.

Cholinergic neurons in the basal forebrain (BF) have long been considered to be the key neurons in the regulation of cortical and behavioral arousal, and cholinergic activation in the downstream region of the BF can arouse anesthetized rats. However, whether the activation of BF cholinergic neurons can induce behavior and electroencephalogram (EEG) recovery from anesthesia is unclear. In this study, based on a transgenic mouse line expressing ChAT-IRES-Cre, we applied a fiber photometry system combined with GCaMPs expression in the BF and found that both isoflurane and propofol inhibit the activity of BF cholinergic neurons, which is closely related to the consciousness transition. We further revealed that genetic lesion of BF cholinergic neurons was associated with a markedly increased potency of anesthetics, while designer receptor exclusively activated by designer drugs (DREADD)-activated BF cholinergic neurons was responsible for slower induction and faster recovery of anesthesia. We also documented a significant increase in δ power bands (1-4 Hz) and a decrease in ß (12-25 Hz) power bands in BF cholinergic lesioned mice, while there was a clearly noticeable decline in EEG δ power of activated BF cholinergic neurons. Moreover, sensitivity to anesthetics was reduced after optical stimulation of BF cholinergic cells, yet it failed to restore wake-like behavior in constantly anesthetized mice. Our results indicate a functional role of BF cholinergic neurons in the regulation of general anesthesia. Inhibition of BF cholinergic neurons mediates the formation of unconsciousness induced by general anesthetics, and their activation promotes recovery from the anesthesia state.

Xiaochaihutang Inhibits the Activation of Hepatic Stellate Cell Line T6 Through the Nrf2 Pathway.

Xiaochaihutang (XCHT) is one of classic prescriptions in Treatise on Febrile Diseases in China which was reported to have the effect of anti-hepatic fibrosis in vivo. Activation of hepatic stellate cells (HSCs) is now well established as a central driver of fibrosis in liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important element for anti-oxidative damage which is one of the key factors responsible for occurrence. This study was to investigate the effect of XCHT compound serum on HSCs activation and focus on the Nrf2 pathway. Rats in treatment groups were given the appropriate doses of XCHT granules (5 g/kg) and Silybin (50 mg/kg) for 6 days, and the serum were obtained. The compound serum was used to intervene HSCs. The results found that XCHT compound serum significantly inhibited the proliferation of HSCT6 cells. The number of α-SMA positive stained cells in HSCT6 cells and the content of Collagen type I (collagen-I) in supernatant were significantly decreased indicating suppression of activated HSCs. Compared with the control group, the nuclear transcription of Nrf2 and the expressions of Nqo1, GCLC, and GCLM were significantly increased in XCHT group. However, the effects of XCHT were inhibited in Nrf2-siRNA transfected HSCT6 cells. These studies demonstrated that XCHT could inhibit HSCT6 cell proliferation and activation. The mechanism might be related to up-regulation of the Nrf2 pathway against oxidative stress.

Three new 1-(p-hydroxybenzyl)phenanthrenes from Bletilla striata.

Three new benzylphenanthrenes, named 1-(p-hydroxybenzyl)-4,7-dimethoxyphenanthrene-2-ol (1), 1-(p-hydroxybenzyl)-4,7-dimethoxyphenanthrene-2,8-diol (2), and 1-(p-hydroxybenzyl)-4,7-dimethoxyphenanthrene-2,6-diol (3), along with a known analog were isolated from tubers of Bletilla striata. The structures of these new compounds were established by means of HR-ESI-MS, 1D, and 2D NMR.

[Effect of Corydalis Rhizoma and L-tetrahydropalmatine on dopamine system of hippocampus and striatum in morphine-induced conditioned place preference rats].

To investigate the effects of Corydalis Rhizoma and L-tetrahydropalma-tine (L-THP) on the levels of dopamine neurotransmitter (DA), dopamine transporter (DAT) and the second dopamine receptor (D2R) in learning and memory-related brain areas, hippocampus and striatum, the DA, DAT and D2R were detected in conditioned place preference (CPP) rats suffered from morphine. And comparation the degree of similarity and consistency of the pharmacological effects was also studied. The rats were trained in black compartments and white ones (drug-paired compartment) with the increasing doses of morphine for 10 days (hypodermically injected from 10 mg•kg⁻¹ to 100 mg•kg⁻¹). Models of CPP were validated in those psychological dependence rats after 48 h training. The dopamine contents were detected as soon as the materials of hippocampus and striatum are harvested from rats of NS control group and model group. The DAT and D2R levels are measured by Western blot. The high, medium and low dose group of Corydalis Rhizoma are given Corydalis Rhizoma 2, 1, 0.5 g•kg⁻¹ water extraction liquid respectively (which contains L-THP were 0.274, 0.137 and 0.137 mg respectively), and the high, medium and low dose group of L-THP were given L-THP 3.76, 1.88, 0.94 mg•kg⁻¹ lavage treatment respectively, NS treatment group were lavaged normal saline for 6 days and they were killed after test of CPP, again tested DA levels and expression of DAT and D2R similar to the front of materials. The reduction effects of CPP were observed in the groups of both Corydalis Rhizoma (2, 1 g•kg⁻¹) and L-THP (3.76, 1.88 mg•kg⁻¹) subjected to medicine for 6 days (P<0.01). Compared with the NS treatment group and the model group, the higher values including in the contents of neurotransmitter dopamine were detected of hippocampus and striatum (P<0.01, P<0.05), the DAT and D2R protein expression of Corydalis Rhizoma (2, 1 g•kg⁻¹) and L-THP (3.76, 1.88 mg•kg⁻¹) increased in hippocampus and striatum (P<0.01). Learning and memory-related brain regions hippocampus and striatum was another neuroanatomical sites of action in the treatment of mental dependence of fumarate and L-THP, its mechanism was related to lowering its elevated DA neurotransmitter levels, and increasing the expression of DAT and D2R. Corydalis Rhizoma could be play 14-times roles in effect of L-THP. The similar effects were observed on the neurotransmitter dopamine, DAT and D2R in learning and memory-related brain areas, hippocampus and striatum of the morphine- dependent rats.

[Effect of Corydalis yanhusuo and L-THP on Gastrointestinal Dopamine System in Morphine-Dependent Rats].

OBJECTIVE: To investigate the protective mechanism of Corydalis yanhuso and L-THP in morphine-dependent gastrointestinal injury rats. METHODS: 180 male rats were randomly divided into nine groups, 20 rats for each group: saline group (N), model group (M), NS treatment group and three different dosage of Corydalis yanhusuo and L-THP groups (low dose group,middle dose group and high dose group). The rat CPP (conditioned place preference) model was established by injecting the rats with an increasing dosage of morphine, all groups received CPP training in a black compartments and white ones (drug-paired compartment) for ten days. At 48 h after the final training, the performance of CPP models were assessed to make sure all models were exported correctly. Then the treatment groups were administered with different concentration of Corydalis yanhuso (0.5, 1 and 2 g/kg) and L-THP (0.94, 1.88 and 3.76 mg/kg) for six days. All rats were immediately killed after finish the last CPP test. For each group, ten rats were killed to detect the contents of DA in the stomach and duodenum through the fluorescence spectrophotometer. The expression levels of D2 receptor( D2R) in different tissues (gastric cardia, gastric body, pylorus and duodenum) were checked by Western-blot in the other rats. RESULTS: In the NS treatment group, the time when rats stay in the white ones were significantly decreased compared with the Corydalis yanhusuo treated groups (1 and 2 g/kg) and L-THP treated groups (1.88 and 3.76 mg/kg) (P < 0.01), the high expression of DA contents in the stomach and duodenum were significantly decreased (P < 0.01). However the protein level of D2R were notably lower in gastric cardia, gastric body, pylorus and duodenum (P < 0.01). CONCLUSION: Injuries of the gastrointestinal tract followed lower DA contents and an abnormal increase of D2R in the stomach and duodenum of rats, which induced by morphine-dependent could be reversed by treatment with Corydalis yanhusuo and L-THP. This is one of mechanism underlying the protective effects of gastrointestinal tract in morphine-dependent rats.

[Study on effects of Corydalis yanhusuo and L-THP on dopamine of reward circuitry in conditioned place preference rats and comparison].

OBJECTIVE: To study and compare the effect of Corydalis yanhusuo and L-THP on dopamine neurotransmitter and D2 receptor of reward circuitry in various cerebral areas of conditioned place preference model rats and the comparison of their effects. METHOD: The CPP model was established by injecting morphine in rats with increasing doses for 10 days. The initial dose of 10 mg x kg(-1), and the final dose of 100 mg x kg(-1), with 10 mg x kg(-1) increased each day. At 48 h after the final training, CPP was adopted to detect the successful establishment of the model. On the same day (12 d), they were orally administered with 2, 1, 0.5 g x kg(-1) C. yanhusuo (containing 0.153, 0.077 and 0.038 mg L-THP) and L-THP (3.76, 1.88, 0.94 mg x kg(-1)) for six days. On 18 d, CPP test was performed again. Next day, HPLC was adopted to determine the content of dopamine neurotransmitters of reward circuitry in VTA-NAc-PFC; Immunohistochemistry and Western blotting were adopted to detect the expression of D2 receptors. RESULT: Compared with the physiological saline treatment group, C. yanhusuo (2, 1 g x kg(-1)) and L-THP (3.76, 1.88 mg x kg(-1)) groups showed that rats stayed in a notably shorter period in white boxes (morphine-accompanied boxes) (P < 0.01 or P < 0.05), and revealed a remarkably lower dopamine content in VTA, NAc and PFC and the significant increase in the expression of D2 receptor (P < 0.01 or P < 0.05). CONCLUSION: The down-regulation of the increased dopamine content in reward nervous circuitry and the up-regulation of the expression of D2 receptor may be one of mechanisms of C. yanhusuo and L-THP in accelerating the recession of morphine's CPP effect Regarding the inhibition of morphine's CPP effect and the effect on dopamine system, the effect of C. yanhusuo traditional Chinese medicine containing one-fold L-THP monomer is equal to that of the independent application of around 24-fold L-THP monomer.