Open Filed Test Research Articles

Transcranial magneto-acoustic stimulation enhances motor function and modulates cortical excitability of motor cortex in a Parkinson's disease mouse model

Parkinson's disease (PD) is a neurodegenerative disorder characterized primarily by motor dysfunction. Transcranial magneto-acoustic stimulation (TMAS), an emerging non-invasive brain neuromodulation technology, is increasingly being applied in the treatment of brain diseases. However, the effects of TMAS on PD are unknown, which is not well studied. Here, we utilized TMAS on PD model mice induced by MPTP to investigate the underlying mechanism of therapy. Our study found that TMAS improved the behavioral performance of PD model mice, enhancing the motor function and motivation for movement. Besides, it inhibited the increased beta oscillations in the motor cortex, while also reducing gamma oscillations. Moreover, the abnormally exaggerated beta-broad gamma phase amplitude coupling (PAC) was decreased after TMAS, and there was a significant negative correlation between PAC and both distance traveled and mean speed during the open filed test. Additionally, the ongoing stimulation could provide neuroprotection, implying that TMAS could ameliorate the loss of dopaminergic neurons, with no damage observed in the brain tissue of mice. Our findings suggest that TMAS could provide a non-invasive tool for the treatment of Parkinson's disease and beta-broad gamma phase amplitude coupling could be employed as a biomarker for PD.

Involvement of the Dopaminergic and Serotonergic Systems in the Antidepressant-like Effect Caused by Ethanolic Extract of Pistacia lentiscus in Tail Suspension Test

Background: Depression is one of the most common psychiatric disorders worldwide and causes disability. There is a need to produce new agents for the treatment of depression with the maximum efficiency and the lowest side effects. The positive effects of Pistacia lentiscus have been reported in the central nervous system and different disorders. Objectives: This study evaluated the antidepressant-like effect of the ethanolic extract of P. lentiscus (EEPL) in a mouse model and its possible mechanisms. Methods: The male NMRI mice (20 - 25 g) intraperitoneally (i.p.) received vehicle (10 mL/kg), imipramine (30 mg/kg), fluoxetine (20 mg/kg, i.p.), and EEPL (50 - 400 mg/kg). After 45 minutes, the animals were subjected to a tail suspension test (TST). The open-filed test (OFT) was used to assess the animal’s locomotion. To elucidate possible monoaminergic mechanisms, the mice were pre-treated with various receptor antagonists 1 hour before the most effective dose of EEPL. Results: The administration of EEPL (100 - 400 mg/kg) induced an antidepressant-like effect (37.5%, 49.3%, and 63.9% reduction, respectively) in the TST (P < 0.001) without considerable effects on animal locomotion in OFT (P > 0.05). The antidepressant-like effect of EEPL (200 mg/kg) was blocked by the pre-treatment of animals with SCH23390, sulpiride, haloperidol, ketanserin, WAY100135, and p-chlorophenylalanine (pCPA) (P < 0.001), but not with prazosin, yohimbine, or propranolol (P > 0.05). Conclusions: The results show that the antidepressant-like effect of EEPL is mediated by the modulation of dopaminergic and serotonergic systems. Overall, the results suggested that EEPL exerted an antidepressant-like activity in the mouse model of depression, which might be considered a useful drug in the management of depression.

Effects of Ginkgo biloba Extract on Cognitive Function Recovery and Inflammatory Factors in Rats After Anesthesia

This research was aimed to investigated the impacts of Ginkgo biloba extract (GbE) on cognitive function and inflammatory factors in rats after anesthesia. Firstly, the primary cultured cortical neurons of rats were prepared in culture medium, to which different concentrations of GbE were added, and cell viability was observed. Twenty SD rats were selected, among which 10 rats were made into a model of neurological dysfunction, and the other 10 were used as controls. The correlation between neurological dysfunction and inflammatory factors was analyzed using Spearman rank correlation (PRC) analysis. Another 40 SD rats were screened and grouped into 4 (a model (M) group, a treatment (T) group, a prevention (P) group, and a blank (B) group). Rats in the P and T treatments were injected intraperitoneally with 10 mg/kg GbE injection before or after anesthesia induction, while an equal amount of 0.9% NaCl solution was administrated in M and B groups once a day for 3 days. Morris water maze (MWM) and open filed test (OFT) were employed to assess the cognitive function of rats in different groups. Furthermore, the levels of inflammatory factors of rats in various groups were compared on day 1 and day 7. Results revealed that GbE can enhance neural cell viability, reduce lactate dehydrogenase (LDH) release, and alleviate changes in cell nuclear morphology and DNA fragmentation. In terms of correlation, the NIHSS score was positively associated with TNF-α and IL-1β, and negatively correlated with IL-10 (all P <0.05). Besides, the escape latency was greatly shortened, memory time was prolonged, and the TNF-α and IL-1β were downshifted in P and T groups to the conditions in the M group, showing great differences with P <0.05. This study demonstrated that GbE could inhibit neural cell apoptosis (NCA), remarkably improve the cognitive dysfunction in rats after anesthesia, and regulate the inflammatory factors.

Preventing Post-Traumatic Stress Disorder (PTSD) in rats with pulsed 810 nm laser transcranial phototherapy

Post-traumatic stress disorder (PTSD) is a debilitating condition that occurs following exposure to traumatic events. Current treatments, such as psychological debriefing and pharmacotherapy, often have limited efficacy and may result in unwanted side effects, making early intervention is a more desirable strategy. In this study, we investigated the efficacy of a single dose of pulsed (10 Hz) 810 nm laser-phototherapy (P-PT) as an early intervention for preventing PTSD-like comorbidities in rats induced by single inescapable electric foot shock following the single prolonged stress (SPS&S). As indicated by the results of the open filed test, elevated plus maze test, and contextual fear conditioning test, P-PT prevented the development of anxiety and freezing behaviors in rats exposed to the SPS&S. We also compared the effects of P-PT and continuous wave 810 nm laser-phototherapy (CW-PT) in preventing PTSD-like comorbidities in rats. The results revealed that P-PT was effective in preventing both freezing and anxiety behavior in stressed rats. In contrast, CW-PT only had a preventive effect on freezing behavior but not anxiety. Additionally, P-PT significantly reduced the c-fos expression in cingulate cortex area 1(Cg1) and infralimbic cortex (IL) of stressed rats, while CW-PT had no significant effects on c-fos expression. Taken together, our results demonstrate that P-PT is a highly effective strategy for preventing the occurrence of PTSD-like comorbidities in rats.

Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome.

Introduction: Dravet syndrome (DS) is an intractable epilepsy syndrome concomitant with neurodevelopmental disorder that begins in infancy. DS is dominantly caused by mutations in the SCN1A gene, which encodes the α subunit of a voltage-gated Na channel. Pre-synaptic inhibitory dysfunction is regarded as the pathophysiological mechanism, but an effective strategy for ameliorating seizures and behavioral problems is still under development. Here, we evaluated the effects of KRM-II-81, a newly developed positive allosteric modulator for α 2/3 subunit containing GABAA receptors (α2/3-GABAAR) in a mice model of DS both in vivo and at the neuronal level. Methods: We used knock-in mice carrying a heterozygous, clinically relevant SCN1A mutation (background strain: C57BL/6J) as a model of the DS (Scn1a WT/A1783V mice), knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V). Seizure threshold and locomotor activity was evaluated by using the hyperthermia-induced seizure paradigm and open filed test, respectively. Anxiety-like behavior was assessed by avoidance of the center region in locomotor activity. We estimated a sedative effect by the total distance traveled in locomotor activity and grip strength. Inhibitory post synaptic currents (IPSCs) were recorded from a hippocampal CA1 pyramidal neuron in an acutely prepared brain slice. Results: KRM-II-81 significantly increased the seizure threshold of Scn1a WT/A1783V mice in a dose-dependent manner. A low dose of KRM-II-81 specifically improved anxiety-like behavior of Scn1a WT/A1783V mice. A sedative effect was induced by relatively high dose of KRM-II-81 in Scn1a WT/A1783V mice, the dose of which was not sedative for WT mice. KRM-II-81 potentiated IPSCs by increasing its decay time kinetics. This effect was more prominent in Scn1a WT/A1783V mice. Discussion: Higher activation of α2/3-GABAAR by KRM-II-81 suggests a compensatory modification of post synaptic inhibitory function against presynaptic inhibitory dysfunction in Scn1a WT/A1783V. The increased sensitivity for KRM-II-81 may be relevant to the distinct dose-dependent effect in each paradigm of Scn1a WT/A1783V mice. Conclusion: Selective activation for α2/3-GABAAR by KRM-II-81 could be potential therapeutic strategy for treating seizures and behavioral problems in DS.

Diethylhexyl phthalate induces anxiety-like behavior and learning and memory impairment in mice probably by damaging blood-brain barrier

To investigate the effects of diethylhexyl phthalate (DEHP) exposure on anxiety-like behaviors and learning and memory ability in mice and explore the underlying mechanism. Forty male ICR mice were randomized equally into control group (0 mg/kg) and 10, 50 and 100 mg/kg DEHP exposure groups, in which the mice were exposed to DEHP at the indicated doses by gavage for 4 weeks. After the treatments, the mice were assessed for behavioral changes using open filed test, elevated plus-maze and Morris water maze test. Brain tissues were collected from the mice for determination of malondialdehyde (MDA) content, pathologies and expressions of ZO-1 and occludin in the hippocampus. Compared with the control group, the mice with DEHP exposure for 4 weeks exhibited no significant body weight change (P>0.05) but presented with obvious behavioral changes, manifested by reduced movement distance (P < 0.05) and time spent in the center of the open field (P < 0.05), reduced movement distance (P < 0.05) and time spent in the open arm of the elevated maze (P < 0.05), significantly increased latency of searching for the platform (P < 0.05), and decreased frequency of crossing the platform (P < 0.05). HE staining showed obvious vertebral cell death in the hippocampal CA1 to CA3 regions of the mice with DEHP exposure. The exposed mice showed significantly increased MDA content and decreased expressions of ZO-1 and occludin at both the mRNA and protein levels in the hippocampus (P < 0.05 or 0.01). Multivariate linear regression analysis suggested a close correlation between anxiety-like behaviors and learning and memory abilities in DEHP-exposed mice. DEHP exposure may cause damages of the blood-brain barrier and the pyramidal cells in the hippocampus of mice, thereby inducing anxiety-like behaviors and learning and memory impairment.

Identification of a Novel Functional Non-synonymous Single Nucleotide Polymorphism in Frizzled Class Receptor 6 Gene for Involvement in Depressive Symptoms.

Although numerous susceptibility loci for depression have been identified in recent years, their biological function and molecular mechanism remain largely unknown. By using an exome-wide association study for depressive symptoms assessed by the Center for Epidemiological Studies Depression (CES-D) score, we discovered a novel missense single nucleotide polymorphism (SNP), rs61753730 (Q152E), located in the fourth exon of the frizzled class receptor 6 gene (FZD6), which is a potential causal variant and is significantly associated with the CES-D score. Computer-based in silico analysis revealed that the protein configuration and stability, as well as the secondary structure of FZD6 differed greatly between the wild-type (WT) and Q152E mutant. We further found that rs61753730 significantly affected the luciferase activity and expression of FZD6 in an allele-specific way. Finally, we generated Fzd6-knockin (Fzd6-KI) mice with rs61753730 mutation using the CRISPR/Cas9 genome editing system and found that these mice presented greater immobility in the forced swimming test, less preference for sucrose in the sucrose preference test, as well as decreased center entries, center time, and distance traveled in the open filed test compared with WT mice after exposed to chronic social defeat stress. These results indicate the involvement of rs61753730 in depression. Taken together, our findings demonstrate that SNP rs61753730 is a novel functional variant and plays an important role in depressive symptoms.

Inhibition of NMDA receptors by agmatine is followed by GABA/glutamate balance in benzodiazepine withdrawal syndrome

BackgroundDrug withdrawal syndrome occurs due to abrupt cessation of an addictive substance. Dependence to diazepam can be manifested by withdrawal syndrome which may include symptoms such as irritability, psychosis, sleep disturbance, seizures, mood disturbance, and anxiety. Studies have described the therapeutic role of agmatine in various neurological disorders such as depressive mood, learning deficits, anxiety, memory impairment, and psychosis. Various studies have also validated agmatine as a putant neuromodulator and revealed its mechanism of action with other neurotransmitters. The study was designed to reveal the potentials of agmatine in benzodiazepine withdrawal syndrome by maintaining GABA/glutamate balance. The study aimed to determine the underlying mechanism of action of agmatine at synaptic level using behavioral and biochemical evaluations.ResultsAgmatine significantly enhanced locomotion in open filed test and decreased anxiety as observed in elevated plus maze test (p < 0.01). Agmatine also reduced withdrawal symptoms scores along with compulsive behaviors in marble burying test and improved muscular strength by decreasing latency to fall in inverted screen test (p < 0.01). Moreover, agmatine established GABA/glutamate balance by increasing GABA levels and decreased glutamate concentration significantly (p < 0.01).ConclusionThe present study reveals the possible mechanism of action of agmatine on NMDA receptor at GABA interneurons and glutamate post synaptic neuron that may lead to GABA/glutamate balance during withdrawal syndrome.

The effect of electroacupuncture on regulating pain and depression-like behaviors induced by chronic neuropathic pain.

Recently, the role of electroacupuncture (EA) in chronic neuropathic pain has been widely reported. However, its specific mechanisms and ability to mitigate depression-like behaviors induced by chronic pain remains unclear. This study aims to determine the analgesic and antidepressant effect of EA. The mechanical threshold sensory and hot plate tests were employed to measure mechanical hyperalgesia and thermal allodynia. The open filed test (OFT) and tail suspension test (TST) were used to observe depressive behavior in chronic constrictive injury (CCI) mice. In addition, the 5-hydroxytryptamine (5-HT) and brain-derived neuropathic factor (BDNF) levels in the anterior cingulate cortex (ACC) and spinal cord were assessed using enzyme-linked immunosorbent assay (ELISA). The protein levels of cAMP-response element-binding protein (CREB) and BDNF in the ACC were analyzed by western blotting. Our results demonstrated that EA treatment could increase the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values. Also, EA improved the CCI-induced depression-like behaviors, and significantly reversed the down-regulation of BDNF and 5-HT expression in the ACC and spinal cord after CCI. Furthermore, EA regulated the level of CREB in the ACCs and spinal cords of mice. These results suggested that the analgesic and antidepressant effect of EA is achieved through regulating CREB-5-HT/BDNF signaling pathway in the ACCs and spinal cords of mice.

Role of Dopamine D2 Receptor in the Leptin Receptor‐expressing Neurons in Modulation of Compulsive‐like Eating Behavior

Leptin, a hormone secreted by adipose tissue, is known to modulate satiety, caloric intake and body weight. There are six alternative spliced isoforms of leptin receptors (LepRa‐f). LepRb is highly expressed in the hypothalamic arcuate nucleus (ARC) which is involved in the regulation of food intake and body weight. Leptin activates pro‐opiomelanocortin‐expressing (POMC) neurons and inhibits agouti‐related peptide (AgRP)‐expressing neurons in the ARC.A recent study shows that dopamine modulates neuronal activities of arcuate POMC neurons and AgRP neurons. Dopamine inhibits arcuate POMC neurons via dopamine D2 receptor but activates AgRP neurons through dopamine D1 receptor. Dopamine is a neurotransmitter that plays a key role in mood, motivation and satiety. Dysregulation of dopamine neurotransmission is involved in the drug addiction. Food addiction is a recently proposed concept and compulsive eating behavior is shown in food addiction as well as an obesity. Negative reinforcement in drug addiction is a concept that negative affect associated with drug withdrawal promotes drug taking to ‘self‐medicate’ or remove those negative states. In the present study, we generated mice lacking D2 receptor in cells expressing LepRb (D2R flox; LepRb‐Cre; D2R cKO). Mice were provided palatable food for more than two weeks to induce food‐addiction like phenotypes in mice. To examine the role of D2 receptor in the leptin receptor‐expressing neurons in modulation of compulsive‐like eating behavior, light‐dark conflict test (LD test) was performed during the palatable food withdrawal period. In addition, palatable food withdrawal‐mediated anxiety/depression‐like behavior were measured during marble burying test (MBT), elevated plus maze (EPM), open filed test (OFT), and forced swim test (FST). No significant changes were found in palatable food (PF) intake in the light box during LD test, suggesting that D2 receptor in cells expressing LepRb would not be involved in the regulation of compulsive eating behavior. Furthermore, there was no significant changes in anxiety/depression‐like behavior measured by MBT, EPM, OPT and FST during the PF withdrawal period.Support or Funding InformationThis research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1I1A1A01060007).

NEP1-40 alleviates behavioral phenotypes and promote oligodendrocyte progenitor cell differentiation in the hippocampus of cuprizone-induced demyelination mouse model

BackgroundStudies have demonstrated that the failure of oligodendrocyte precursor cells (OPCs) differentiation as a major cause of remyelination failure in demyelinating disease. The reasons for this failure are not completely understood. We hypothesized that the present of myelin debris in CNS play an important role in poor OPCs differentiation in the mouse model of demyelinating disease. MethodsMice were fed by the food mixed with normal or 0.2 % cuprizone (CPZ) for 6 weeks. Then the learning and memory impairment were tested by Morris water maze test. The spontaneous alternation behavior and depression-like symptoms were assessed by tail suspension test and open filed test. The number of OPCs and oligodendrocytes were counted by immunofluorescence. After exposed to CPZ for 6 weeks, the mice were then receiving stereotactic injection of NEP1-40 into the CA3 of hippocampus. The behavioral, learning and memory changes were assessed by tail suspension test and open field test. The differentiation of OPCs were detected by immunofluorescence and western blot. ResultsThe mice in CPZ group are more likely to show signs of depression and they showed impairment of long-term learning and memory function. The differentiation of OPCs were impaired in CPZ group. We found that mice treated with NEP1-40 showed less depression-like symptom in TST and higher locomotor activity in the OFT than the mice treated with PBS. ConclusionsOur study suggest that NEP1-40 can promote OPC differentiation and survival. Further study should focus on the effect of NEP1-40 on the differentiation and survival of OPCs in vitro.

Extract of Danggui-Shaoyao-San ameliorates cognition deficits by regulating DHA metabolism in APP/PS1 mice

Ethnopharmacological relevanceThe traditional Chinese medicine formula Danggui-Shaoyao-San (DSS) has been reported to show therapeutic effect on alleviating the symptoms of Alzheimer's disease (AD). Aim of the studyThe present study aims to investigate the relation between DSS treatment of AD and DHA metabolism and evaluates its neuroprotective effect on cognitive in APP/PS1 mice. Material and methodsDSS (1.6, 3.2, 6.4 g/kg/day) or Aricept (3 mg/kg/day) was orally administered (i.g.) to APP/PS1 mice, and saline was orally administered to Wild-type (WT) male mice as control group. Then, the Morris water maze (MWM) test, Y-maze spontaneous alternation test, open filed test and fear conditioning test were conducted for evaluation of learning and memory abilities. The DHA content was assessed by HPLC-MS/MS. Physiological indices were determined, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), ROS level, activity of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), PEG2, TXB2 and LTB4. The expressions of COX-1, COX-2, cPLA2, iPLA2, 15-LOX, and were assessed by Western blot. ResultsAPP/PS1 mice showed serious cognitive impairment in behavioral tests. However, treatment of DSS extract significantly ameliorated the cognitive deficits of APP/PS1 mice. Biochemical measurements showed the increases in TG, TC, LDL-c and the decrease in HDL-c in APP/PS1 mice compared with WT mice, and DSS extract significantly retarded these changes. Low content of DHA, low expression of iPLA2 and 15-LOX were observed both in hippocampus and cortex of APP/PS1 mice, while DSS extract significantly restored these changes. Additionally, the abnormal activity of SOD and ROS level, the decreased levels of MDA and GSH were observed in APP/PS1 mice, while DSS extract prominently lessened these changes. Moreover, DSS extract decreased the level of PEG2, TXB2 and LTB4 and also attenuated the expression of cPLA2, COX-1 and COX-2 in hippocampus as well as cortex of APP/PS1 mice. ConclusionsBased on these results, we suggest that DSS play a positive effective role in increasing DHA content by up-regulating iPLA2 and 15-LOX, resulting in ameliorating oxidative stress and inflammation and finally ameliorating cognition deficits in APP/PS1 mice.

Increased alcohol consumption and development of tolerance to alcohol‐induced sedation in NBCn1 knockout mice

The Na/HCO3 cotransporter NBCn1 plays a role in regulating synaptic pH. We recently reported that a human SLC4A7 gene polymorphism identified as a marker for polysubstance abuse is responsible for the production of a transporter variant that has a defect in function and expression. This finding prompted us to test whether NBCn1 is involved in alcoholism. Here, we examined alcohol‐drinking behaviors, as well as locomotor/anxiety and spatial learning behaviors, in NBCn1 knockout (KO) mice. In the open filed test, NBCn1 KO mice displayed decreased locomotor activity compared to wild type (WT) littermates. However, the activity in the elevated plus maze test was similar between WT and KO mice, indicating negligible change in anxiety. In the Morris water maze test, both groups of mice had learning behaviors improving each day with similar latency to escape in repeated trainings and distance traveled. The two groups learned the platform location with similar time spent in the trained quadrant during the probe trials. Thus, hippocampal‐based spatial learning was not altered in KO mice. Next, alcohol‐related behaviors were tested in a two‐bottle choice drinking experiment, in which mice were given to 3–15% ethanol with 3% increments at 4 days and alcohol consumption was measured. KO mice consumed more alcohol than WT mice with higher alcohol preference (p &lt; 0.05). The consumption was also increased after repeated alcohol withdrawals. In the loss of righting reflex test following alcohol administration (3.5 g/kg alcohol; intraperitoneal), KO mice had a longer duration of sedation, but blood alcohol concentration did not differ. The duration became shorter when KO mice were pretreated with alcohol for 7 days, indicating the development of tolerance to the hypnotic effects of alcohol. Whole cell current clamp of hippocampal neurons showed that neurons from KO mice had a higher action potential threshold, no recurrent action potential, and a more depolarized membrane potential. These results indicate that abnormalities in NBCn1 alter alcohol consumption and alcohol‐related behaviors by changing neuronal excitability. Increased voluntary alcohol consumption in KO mice is probably driven by decreased rewarding value of alcohol. Neurons from KO mice are less excitable, which would lead to decreased neurotransmitter release. Thus, the rewarding value of alcohol is reduced, requiring more alcohol to achieve the same level of hedonic response.Support or Funding InformationNIH and Emory URCThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of a selanylimidazopyridine on the acute restraint stress-induced depressive- and anxiety-like behaviors and biological changes in mice

In the last decades, selenium-containing compounds have received increasing attention due to their various biological and pharmacological properties. In the present study, we investigated the effects of 3-[(4-methoxyphenyl) selanyl]-2-phenylimidazo[1,2-a] pyridine (MPI; 1, 10 or 50 mg/kg, i.g.) on the acute restraint stress (ARS)-induced depressive- and anxiety-like behaviors in mice and its underlying mechanism of action. We used the open filed test, forced swimming test, and splash test to evaluate depressive-like behavior, and marble burying and elevated plus maze test to measure anxiety-like behavior. We found that MPI attenuated ARS-induced depressive- and anxiety-like behaviors in all behavioral tests, without having an effect in non-stressed mice. MPI prevented the increased in pro-inflammatory cytokines, indoleamine-2,3-dioxygenase (IDO) and inducible nitric oxide synthase (iNOS) expression in brain structures via canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) down-regulation. Additionally, MPI prevented ARS-induced downregulation of brain-derived neurotrophic factor (BDNF), increased reactive oxygen/nitrogen species generation and lipid peroxidation in prefrontal cortex and hippocampus of mice. In addition, MPI blocked the downregulation of glucocorticoid receptors in the prefrontal cortex and hippocampus and reduced the increased circulating level of corticosterone in stressed mice. These results suggested that MPI showed antidepressant- and anxiolytic-like properties and the effects might be associated with the biological changes in the prefrontal cortex and hippocampus.

Baicalin exerts antidepressant effects through Akt/FOXG1 pathway promoting neuronal differentiation and survival

Background and aimsImpaired neurogenesis in hippocampus may contribute to a variety of neurological diseases, such as Alzheimer's disease and depression. Baicalin (BA), which is mainly isolated from the root Scutellaria baicalensis Georgi (traditional Chinese herb), which was reported to facilitate neurogenesis, but how to play the role and the underlying molecular mechanisms are still unknown. Main methodsIn this study, we adopted the chronic unpredictable mild stress (CUMS)-induced mouse model of depression, and then explore antidepressant-like effects and possible molecular mechanisms. Key findingsWe found that BA significantly increased sucrose consumption in sucrose preference test, the number of crossing in open filed test and attenuated immobility time in tail suspension test. Additionally, BA administration notably promoted neuronal differentiation and the number of DCX+ cells. Moreover, BA facilitated immature neurons develop into mature neurons and their survival. FOXG1, a transcription factor gene, which is crucial for mammalian telencephalon development, specifically stimulates dendrite elongation. BA could reverse the decrease of p-Akt, FOXG1 and FGF2 caused by CUMS-induced. Additionally, the expression of FOXG1 and FGF2 significantly decreased when the Akt pathway were inhibited by LY294002 in SH-SY5Y cells. Interestingly, BA failed to counteract the decline. SignificanceThese results suggest that BA could promote the differentiation of neurons, which transformation into mature neurons and their survival via the Akt/FOXG1 pathway to exert antidepressant effects.

Effect of gallic acid on chronic restraint stress-induced anxiety and memory loss in male BALB/c mice.

Objective(s):Long-term exposure to stress leads to memory deficits and certain mood disorders such as depression and anxiety. We aimed to study the effect of gallic acid (GA) on chronic restraint stress (CRS) induced anxiety and memory deficits in male BALB/c mice.Materials and Methods:Ninety male BALB/c mice were assigned to nine groups including caged control (CC): food-water deprived (FWD), under chronic restraint stress (CRS), CRS+ gallic acid (5, 10, and 20 mg/kg), and gallic acid (5, 10, and 20 mg/kg). Behavioral assays were performed after 21 days of daily treatment with CRS and GA. Serum and brain levels of malondialdehyde (MDA) and total antioxidant capacity (TCA) and serum corticosterone level were also measured. Results:Treatment of CRS mice with GA significantly improved passive avoidance memory in the shuttle box and ameliorated anxiety-like behaviors in the elevated plus maze (EPM) and open filed test (OFT). GA treatment significantly reduced elevated levels of serum and brain MDA and increased brain TCA. CRS and GA did not affect serum corticosterone levels. Treatment of healthy mice with GA had some adverse effects and induced some anxiety and oxidative stress. Conclusion:GA exerted protective effects against stress-induced mood and memory deficit disorders.

Intranasal erythropoietin ameliorates neurological function impairments and neural pathology in mice with chronic alcoholism by regulating autophagy‑related Nrf2 degradation.

The neurological disorders and neural pathology brought about by chronic alcoholism are difficult to be reversed. Increasing evidence highlights the protective roles of erythropoietin (EPO) in neurodegenerative diseases and injuries of the central nervous system. In the present study, we investigated the therapeutic effects of EPO on the neurological function deficits and neural pathology caused by chronic alcoholism and the regulatory mechanisms. Using the canonical mouse model of chronic alcohol exposure designed to mimic the repeated cycles of heavy abuse typical of chronic alcoholism, it was found that EPO delivered via intranasal route effectively restored the alcohol-impaired motor cooperation in rotarod and beam walk tests, reversed alcoholic cognitive and emotional alterations in the novel location recognition task and open-filed test, and rescued alcohol-disrupted nervous conduction in the somatosensory-evoked potential (SSEP) test. Consistently, the intranasally administered EPO promoted the remyelination and synapse formation in chronic alcohol-affected neocortex and hippocampus as evidenced by immunofluorescence staining and transmission electron microscopy. Additionally, we discovered that the exogenous rhEPO, which entered the cerebrum through intranasal route, activated the erythropoietin receptor (EPOR) and the downstream ERKs and PI3K/AKT signaling, and suppressed autophagy-related degradation of nuclear factor, erythroid 2-like 2 (Nrf2). Furthermore, the intranasal EPO-exerted neuroprotection was almost abolished when the specific Nrf2 antagonist ATRA was administered intraperitoneally prior to intranasal EPO treatment. Collectively, our data demonstrated the repairing potential of EPO for the neurological disorders and neural pathology caused by chronic alcoholism, and identified the Nrf2 activity as the key mechanism mediating the protective effects of EPO.

Standardized Citrus unshiu peel extract ameliorates dexamethasone-induced neurotoxicity and depressive-like behaviors in mice.

Dried Citrus unshiu peel, also known as Chinpi, have been commonly used as a traditional medicine to improve for allergy, inflammation and hepatopathy. Many previously studies have reported that citrus flavonoids show neuroprotective activities. However, the antidepressant-related effects of C. unshiu peels have not been well characterized. Here, the antidepressant-like effects of standardized C. unshiu peel extract (SCP) were evaluated in in vivo and in vitro depression models induced by dexamethasone (DEX), a synthetic glucocorticoid. Male ICR mice (9-week-old) were injected the DEX (40mg/kg) and were orally given SCP daily (30, 100, and 300mg/kg) for 14 consecutive days. The depressive-like behaviors were determined by use of open filed test (OFT), sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST). We show that treatment with SCP significantly alleviated DEX-induced depressive-like behaviors and reduced neurotoxicity in a concentration dependent manner in SH-SY5Y cells. Additionally, repeated DEX injection markedly decreased brain derived neurotrophic factor (BDNF) level, tropomyosin receptor kinase B (TrkB), and cyclic AMP-response element-binding protein (CREB), while SCP treatment improved these levels in the cerebral cortex and hippocampus regions. Our findings suggest that SCP exhibits significant antidepressant-like effects in the DEX-induced depressive animal model, and this activity may be mediated by preventing corticosterone-induced neurotoxicity.

Adenosine A2A receptor involves in neuroinflammation-mediated cognitive decline through activating microglia under acute hypobaric hypoxia

Hypobaric hypoxia (HH) at high altitudes leads to a wide range of cognitive impairments which can handicap human normal activities and performances. However, the underlying mechanism is still unclear. Adenosine A2A receptors (A2ARs) of the brain are pivotal to synaptic plasticity and cognition. Besides, insult-induced up-regulation of A2AR regulates neuroinflammation and therefore induces brain damages in various neuropathological processes. The present study was designed to determine whether A2AR-mediate neuroinflammation involves in cognitive impairments under acute HH. A2AR knock-out and wild-type male mice were exposed to a simulated altitude of 8000 m for 7 consecutive days in a hypobaric chamber and simultaneously received behavioral tests including Morris water maze test and open filed test. A2AR expression, the activation of microglia and the production of TNF-α were evaluated in the hippocampus by immunohistochemistry and ELISA, respectively. Behavioral tests showed that acute HH exposure caused the dysfunction of spatial memory and mood, while genetic inactivation of A2AR attenuated the impairment of spatial memory but not that of mood. Double-labeled immunofluorescence showed that A2ARs were mainly expressed on microglia and up-regulated in the hippocampus of acute HH model mice. Acute HH also induced the accumulation of microglia and increased production of TNF-α in the hippocampus, which could be markedly inhibited by A2AR inactivation. These findings indicate that microglia-mediated neuroinflammation triggered by A2AR activation involves in acute HH-induced spatial memory impairment and that A2AR could be a new target for the pharmacotherapy of cognitive dysfunction at high altitudes.

Telmisartan Activates PPAR\u03b4 to Improve Symptoms of Unpredictable Chronic Mild Stress-Induced Depression in Mice

Major depression is a common mental disorder that has been established to be associated with a decrease in serotonin and/or serotonin transporters in the brain. Peroxisome proliferator-activated receptor δ (PPARδ) has been introduced as a potential target for depression treatment. Telmisartan was recently shown to activate PPARδ expression; therefore, the effectiveness of telmisartan in treating depression was investigated. In unpredictable chronic mild stress (UCMS) model, treatment with telmisartan for five weeks notably decrease in the time spent in the central and the reduced frequency of grooming and rearing in open filed test (OFT) and the decreased sucrose consumption in sucrose preference test (SPT) compared with the paradigms. Telmisartan also reversed the decrease in PPARδ and 5-HTT levels in the hippocampus of depression-like mice. Administration of PPARδ antagonist GSK0660 and direct infusion of sh-PPARδ into the brain blocked the effects of telmisartan on the improvement of depression-like behavior in these mice. Moreover, telmisartan enhanced the expression of PPARδ and 5HTT in H19-7 cells. In conclusion, the obtained results suggest that telmisartan improves symptoms of stress-induced depression in animals under chronic stress through activation of PPARδ. Therefore, telmisartan may be developed as a potential anti-depressant in the future.