Acute Administration of Lactate Exerts Antidepressant-like Effect Through cAMP-dependent Protein Synthesis.

Lactate acts as an important metabolic substrate and signalling molecule modulating neural activities in the brain, and recent preclinical and clinical studies have revealed its antidepressant effect after acute or chronic peripheral administration. However, the neural mechanism underlying the antidepressant effect of lactate, in particular when lactate is acutely administered remains largely unknown. In the current study, we focused on forced swimming test (FST) to elucidate the neural mechanisms through which acute intracerebroventricular (ICV) infusion of lactate exerts antidepressant-like effect. A total of 238 male Sprague Dawley rats were used as experimental subjects. Results showed lactate produced antidepressant-like effect, as indicated by reduced immobility, in a dose- and time-dependent manner. Moreover, the antidepressant-like effect of lactate was dependent of new protein synthesis but not new gene expression, lactate's metabolic effect or hydroxy-carboxylic acid receptor 1 (HCAR1) activation. Furthermore, lactate rapidly promoted dephosphorylation of eukaryotic elongation factor 2 (eEF2) and increased brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus in a cyclic adenosine monophosphate (cAMP)-dependent manner. Finally, inhibition of cAMP production blocked the antidepressant-like effect of lactate. These findings suggest that acute administration of lactate exerts antidepressant-like effect through cAMP-dependent protein synthesis.

Apelin-13 reduces lipopolysaccharide-induced neuroinflammation and cognitive impairment via promoting glucocorticoid receptor expression and nuclear translocation.

Neuroinflammation is usually associated with cognitive decline, which is involved in neurodegenerative diseases. Apelin, a neuropeptide, exerts various biological roles in central nervous system. Recent evidence showed that apelin-13, an active form of apelin, suppresses neuroinflammation and improves cognitive decline in diverse pathological processes. However, the underlying mechanism of apelin-13 in neuroinflammation remains largely unknown. The present study aimed to determine underlying mechanism of apelin-13 on neuroinflammation-related cognitive decline. The lipopolysaccharide (LPS) intracerebroventricular (i.c.v.) to is used to establish a rat model of neuroinflammation-related cognitive decline. The results showed that apelin-13 inhibits LPS-induced neuroinflammation and improves cognitive impairment. Apelin-13 upregulates the GR level and nuclear translocation in hippocampus of rats. Moreover, glucocorticoid receptor inhibitor RU486 prevents apelin-13-mediated neuroprotective actions on cognitive function. Taken together, apelin-13 could exert a protective effect in neuroinflammation-mediated cognitive impairment via the activation of GR expression and nuclear translocation.

[Glycogen phosphorylase inhibitor ameliorates pentylenetetrazole-induced acute seizure, neuroinflammation and memory impairment in rats].

OBJECTIVE: In the present study, we determined whether the glycogen phosphorylase(GP)inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) ameliorates pentylenetetrazole (PTZ)-induced acute seizure, neuroinflammation and memory impairment in rats. METHODS: In experiment 1, rats were randomly divided into the Vehicle (n=5) and PTZ (n=5) groups, and received intraperitoneal injection of saline or PTZ (70 mg/kg), respectively. Hippocampal tissues were collected 30 min after drug injection. Western blot was used to examine the levels of GP expression. Colorimetric assay was used to determine the levels of lactate. In experiment 2, rats were randomly divided into the Vehicle+Vehicle (n=18), DAB+Vehicle (n=18), Vehicle+PTZ (n=19) and DAB+PTZ (n=18) groups. Rats received intracerebroventricular injection of PBS or DAB (50 µg/2 µl) 15 min before receiving intraperitoneal injection of saline or PTZ (70 mg/kg). Behavioural assays and the Racine scale were used to evaluate seizure severity. Western blot was used to examine the levels of targeted protein of hippocampal tissues. Novel object recognition test was used to assess memory performance. RESULTS: ① Compared with the Vehicle group, the levels of GP and lactate in the hippocampal tissues of the PTZ group were increased significantly (both P＜0.01). ② Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of myoclonic body jerk latency, forelimb clonus latency and tonic-clonic seizure latency were increased significantly (all P＜0.01), while the duration of seizure and seizure scores were decreased significantly (both P＜0.01). ③ Compared with the Vehicle+Vehicle group, in the Vehicle +PTZ group, the levels of IL-1ß, IL-6, TNF-α, IBA-1 and GFAP in the hippocampal tissues were increased significantly (all P＜0.01), and the discrimination index in the novel object recognition test was decreased significantly (P＜0.01). Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of IL-1ß, TNF-α, IBA-1 and GFAP in the hippocampal tissues were decreased significantly (all, P＜0.01), while the discrimination index in the novel object recognition test was increased significantly (P＜0.01). CONCLUSION: DAB ameliorates PTZ-induced seizure, neuroinflammation and memory impairment in rats, suggesting that DAB may serve as a novel agent for potential clinical treatment of epilepsy.

Ketamine enhances novel object recognition memory reconsolidation via the BDNF/TrkB pathway in mice.

In addition to the antidepressant properties of ketamine at subanesthetic doses, studies have revealed ketamine's influence on memory acquisition, consolidation, and reconsolidation. The effects of acute low-dose ketamine administration on conditioned memory have been investigated extensively in rodents through conditioned fear memory and morphine-induced conditioned place preference. In contrast to conditioned memory, the novel object recognition (NOR) task assesses the natural format of memory by exploiting the rodents' natural preference for novelty. Acute low-dose ketamine administration impairs NOR acquisition and consolidation, but its influence on reconsolidation remains unclear. We investigated the issue as well as the involvement of BDNF/TrkB pathway in this process by administering ketamine (i.p., 10 mg/kg, immediately or 6 h after reactivation, or without reactivation) and ANA-12 (i.p., 0.5 mg/kg, 5 min after ketamine/vehicle administration). ANA-12 is a selective antagonist for the BDNF TrkB receptor. Ketamine administration, immediately after (rather than without) reactivation, significantly increased the NOR preference index, thus suggesting an enhanced memory reconsolidation rather than consolidation. Ketamine exerted no significant effect when administered 6 h after reactivation, thereby suggesting 6 h to be an effective time window. ANA-12 administration significantly reduced the ketamine-induced NOR preference index increase, thus suggesting that the blockage of ketamine improves NOR reconsolidation. However, this blockage had no significant effect on the ketamine-induced hippocampal BDNF level increase. In conclusion, acute low-dose ketamine administration improves NOR memory reconsolidation by increasing hippocampal BDNF levels and subsequent BDNF binding to the TrkB receptor.

Urocanic acid enhances memory consolidation and reconsolidation in novel object recognition task.

Urocanic acid (UCA) is an endogenous small molecule that is elevated in skin, blood and brain after sunlight exposure, mainly playing roles in the periphery systems. Few studies have investigated the role of UCA in the central nervous system. In particular, its role in memory consolidation and reconsolidation is still unclear. In the present study, we investigated the effect of intraperitoneal injection of UCA on memory consolidation and reconsolidation in a novel object recognition memory (ORM) task. In the consolidation version of the ORM task, the protocol involved three phases: habituation, sampling and test. UCA injection immediately after the sampling period enhanced ORM memory performance; UCA injection 6 h after sampling did not affect ORM memory performance. In the reconsolidation version of the ORM task, the protocol involved three phases: sampling, reactivation and test. UCA injection immediately after reactivation enhanced ORM memory performance; UCA injection 6 h after reactivation did not affect ORM memory performance; UCA injection 24 h after sampling without reactivation did not affect ORM memory performance. This UCA-enhanced memory performance was not due to its effects on nonspecific responses such as locomotor activity and exploratory behavior. The results suggest that UCA injection enhances consolidation and reconsolidation of an ORM task, which further extends previous research on UCA effects on learning and memory.

Neuroprotective gain of Apelin/APJ system.

Apelin is an endogenous ligand of G protein-coupled receptor APJ. In recent years, many studies have shown that the apelin/APJ system has neuroprotective properties, such as anti-inflammatory, anti-oxidative stress, anti-apoptosis, and regulating autophagy, blocking excitatory toxicity. Apelin/APJ system has been proven to play a role in various neurological diseases and may be a promising therapeutic target for nervous system diseases. In this paper, the neuroprotective properties of the apelin/APJ system and its role in neurologic disorders are reviewed. Further understanding of the pathophysiological effect and mechanism of the apelin/APJ system in the nervous system will help develop new therapeutic interventions for various neurological diseases.

Apelin-13 enhances contextual fear extinction in rats.

Fear extinction is considered as a new learning process that is valid to model features of post-traumatic stress disorder (PTSD). The neuropeptide apelin, such as apelin-13, apelin-17 and apelin-36, are endogenous ligands of the G-protein coupled receptor APJ. Apelin and its receptor APJ are widely distributed in the central nervous system. Accumulating evidence suggests the critical role of apelin-13 in modulation of learning and memory, however, its specific role in fear extinction remains unclear. In the present study, we investigated the effect of apelin-13 administration on contextual fear extinction in rats. The behavioral procedure included four sessions: habitation, conditioning, extinction training and extinction recall. Rats received intracerebroventricular infusion of apelin-13 (3 or 6 µg) 0.5 h prior to the extinction training. Percentage of freezing was utilized to assess the conditioned fear response. Results showed that apelin-13, with the dose of 6 but not 3 µg, significantly decreased freezing response during both extinction training and extinction recall test sessions. Furthermore, apelin-13 did not affect the levels of baseline freezing, locomotor activity and anxiety. The results suggest that apelin-13 dose-dependently enhances contextual fear extinction, and may function as a novel target for treatment of PTSD.

Apelin attenuates depressive-like behavior and neuroinflammation in rats co-treated with chronic stress and lipopolysaccharide.

Several experimental studies have proved that activation of neuroinflammation pathways may contribute to the development of depression, a neuropsychiatric disorder disease. Our previous studies have shown the antidepressant properties of apelin, but the mechanism was unkown. This study was performed to verify whether the antidepressant effect of apelin was related to its anti-inflammation effect in the central nervous system. To achieve our aim, we selected the co-treatment of chronic stress and LPS to induced an inflammatory process in rats. The effect of this co-treatment was evaluated through the expression of inflammatory markers and glial cell activation. LPS injection co-treated with unpredictable chronic mild stress resulted in the activation of microglial cell and astrocyte, expression of inflammatory markers and depressive behaviors. Treatment with apelin significantly attenuates the deleterious effects in these rats. Our results showed that apelin improved depressive phenotype and decreased the activation of glial cells in stress co-treatment group. The down-regulations of p-NF-κB and p-IKKß suggested that the effects are possibly mediated by inhibition of the NF-κB-mediated inflammatory response. These findings speculated that intracerebroventricular injection of apelin could be a therapeutic approach for the treatment of depression, and the antidepressant function of apelin may closely associated with its alleviation in neuroinflammation.

Apelin-13 ameliorates chronic water-immersion restraint stress-induced memory performance deficit through upregulation of BDNF in rats.

A large number of studies have demonstrated that the hippocampus has important influences on stress response and memory. The abundant expressions of apelin and its receptor APJ in the hippocampus may imply potential involvement of apelin/APJ signaling in modulating stress-related memory performance deficit. In our previous study, apelin-13 ameliorates memory performance deficit in acute stressed rats. Here, we further examined whether apelin-13 can ameliorate memory performance deficit in chronic stressed rats. Rats were exposed to chronic water-immersion restraint stress (CWIRS) for 4 weeks. After stress withdrawal, apelin-13 was intracerebroventricularly infused once a day for one week. The novel object recognition test (NORT) and Y-maze test (YMT), two hippocampus-dependent memory tasks, were performed to assess memory performance. We found that apelin-13 restored CWIRS-induced decline in the discrimination index and alternation ratio in NORT and YMT, respectively. Furthermore, apelin-13 ameliorated CWIRS-induced hippocampal BDNF expression deficit, and the TrkB receptor antagonist ANA-12 blocked the ameliorative effect of apelin-13 on memory performance deficit in CWIRS rats. The current observations indicate that apelin-13 ameliorates CWIRS-induced memory performance deficit through upregulation of BDNF in rats.

Glutamate transporter GLT1 inhibitor dihydrokainic acid impairs novel object recognition memory performance in mice.

Glutamate transporter GLT1 mediates glutamate uptake, and maintains glutamate homeostasis in the synaptic cleft. Previous studies suggest that blockade of glutamate uptake affects synaptic transmission and plasticity. However, the effect of GLT1 blockade on learning and memory still receives little attention. In the present study, we examined the effect of unilateral intracerebroventricular injection of dihydrokainic acid (DHK), a GLT-1 inhibitor, on novel object recognition (NOR) memory performance. The NOR task involved three sessions including habituation, sampling and test. In experiment 1, DHK injection 0.5 h pre-sampling impaired short-term NOR memory performance. In experiment 2, DHK injection 0.5 h pre-sampling impaired long-term NOR memory acquisition. In experiment 3, DHK injection immediately but not 6 h post-sampling impaired long-term NOR memory consolidation. In experiment 4, DHK injection 0.5 h pre-test impaired long-term NOR memory retrieval. Furthermore, DHK-induced memory performance impairment was not due to its effects on nonspecific responses such as locomotor activity and exploratory behavior. The current findings further extend previous studies on the effects of disruption of glutamate homeostasis on learning and memory.

Apelin-13 Upregulates BDNF Against Chronic Stress-induced Depression-like Phenotypes by Ameliorating HPA Axis and Hippocampal Glucocorticoid Receptor Dysfunctions.

Localization of apelin and its receptor APJ in limbic structures such as the hippocampus suggests potential involvement of apelin/APJ signaling in stress-related emotional responses. We have recently reported that apelin-13 exerts antidepressant-like actions in acute stressed rats, and that the hippocampus is a critical brain region mediating its actions. However, the neural mechanism underling antidepressant-like actions of apelin-13 is still largely unknown. The aim of the present study is to determine whether apelin-13 ameliorates chronic water-immersion restraint stress (CWIRS)-induced depression-like phenotypes and its neural mechanism in rats. Here, we report that CWIRS exposure leaded to upregulation of apelin/APJ signaling in the hippocampus. Apelin-13 ameliorated CWIRS-induced depression-like phenotypes including hedonic-like deficit and behavioral despairs. Moreover, apelin-13 ameliorated hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, and hippocampal BDNF expression deficit and glucocorticoid receptor (GR) nucleus translocation hypoactivity in chronic stressed rats. Finally, apelin-13-mediated effects were blocked by the selective TrkB receptor antagonist ANA-12. These results suggest that apelin-13 upregulates BDNF against chronic stress-induced depression-like phenotypes by ameliorating HPA axis and hippocampal GR dysfunctions.

Apelin-13 reverses memory impairment and depression-like behavior in chronic social defeat stressed rats.

The apelin/APJ signaling is composed of the short peptide apelin usually including apelin-13, apelin-17 and apelin-36, and its receptor APJ. This signaling is abundantly expressed in limbic structures such as the hippocampus, suggesting a potential role in stress response and learning and memory. We recently reported that apelin-13 reverses acute stress-induced memory impairment and depression-like behavior in rats. Here, we further investigate whether apelin-13 reverses memory impairment and depression-like behavior in chronic stressed rats. Rats were subjected to chronic social defeat stress (CSDS), and received intracerebroventricular infusion of apelin-13 for one week after stress withdrawal. Behavioral test battery was performed to assess memory performance and depression-like behavior. Results showed that apelin-13 reversed CSDS-induced decrease in the alternation ratio and discrimination index in the Y-maze and novel object recognition tests, respectively. Apelin-13 also reversed CSDS-induced social avoidance in the social interaction test, and behavioral despair in the forced swimming and tail suspension tests. Additionally, apelin-13 did not influence locomotor activity in the open field test. These observations suggest that apelin-13 reverses memory impairment and depression-like behavior in chronic stressed rats.

The Hippocampus is a Critical Site Mediating Antidepressant-like Activity of Apelin-13 in Rats.

The peptide apelin and its receptor APJ are found to express in multiple brain regions, especially in the regions such as the hippocampus and hypothalamus that play important roles in stress and depression. The distribution of apelin and APJ suggests that the apelinergic signaling may be a key mediator in the development of stress-related depressive behavior. We recently demonstrated that intracerebroventricular (i.c.v) injection of apelin-13 exerts an antidepressant-like activity in the rat forced swimming test (FST). However, the possible brain region mediating apelin-13's antidepressant-like activity remains unclear. In the present study, we determined whether the hippocampus and hypothalamus are the possible regions mediating antidepressant-like activity of apelin-13. We found that forced swimming exposure upregulated apelin and APJ protein expression levels in the hippocampus but not hypothalamus in rats. Further, intrahippocampal injection of apelin-13 exerted an antidepressant-like activity (as indicated by a decreased immobility behavior), and intrahippocampal infusion of APJ receptor antagonist F13A blocked the antidepressant-like activity produced by i.c.v injection of apelin-13 in the FST. Moreover, intrahypothalamic injection of apelin-13 did not affect the immobility behavior in the FST. These findings suggest that the hippocampus, but not hypothalamus, is a critical site mediating antidepressant-like activity of apelin-13 in rats.

Apelin-13 Prevents the Delayed Neuropathy Induced by Tri-ortho-cresyl Phosphate Through Regulation the Autophagy Flux in Hens.

Organophosphate-induced delayed neuropathy (OPIDN) is pathologically characterized by the swollen axon containing aggregations of microtubules, neurofilaments, smooth endoplasmic reticulum and multivesicular vesicles. At present, the exact mechanism of OPIDN is unclear and the effective therapeutic methods is not available to counter this syndrome. Recent studies had shown that the autophagy was involved in OPIDN. The adipocytokine Apelin is a peptide, Apelin and its receptor are abundantly expressed in the nervous system. Recent researches illuminated that Apelin was neuroprotective factor and Apelin could regulate the autophagy in vivo and vitro model. So we investigated the effect of Apelin-13 on the OPIDN induced by Tri-ortho-cresyl phosphate (TOCP) in hens and explored the role of autophagy in Apelin-13 preventing OPIDN. Adult Roman hens were given a single dose of 750 mg/kg TOCP by gavage for 21 days to induce OPIDN, and neural dysfunction were detected, and the formation of autophagosomes in spinal cord neurons was observed by transmission electron microscopy, and the molecular markers of autophagy microtubule-associated protein light chain-3 (LC3) and the autophagy substrates p62/SQSTM1 were determined by Western blot analysis. The results demonstrated that the obvious neurological dysfunction such as hindlimb paralysis and paralysis of gait was present, the number of autophagosomes in the neurons of spinal cords was significantly increased, the level of LC3-II and p62 expressions and the ratio of LC3-II/LC3-I in spinal cords and sciatic nerve were significantly increased in the OPIDN model group compared with the control group. Compared with the OPIDN model group, the neurological dysfunction of tens was obviously reduced, the clinical signs scores was significantly decreased, the number of autophagosomes in the neurons of hen spinal cords was significantly decreased, the level of LC3-II and p62 expressions and the ratio of LC3-II/LC3-I in spinal cords and sciatic nerve were significantly decreased in Apelin-13 treatment group. Our results suggested that Apelin-13 prevented against the OPIDN induced by TOCP in hens, which the mechanism might be associated with regulation autophagy flux by Apelin-13.

Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models.

AIM: To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice. METHODS: In the learned helplessness test (LH), Neu-P11 or melatonin (25-100 mg/kg, ip) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the number of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25-100 mg/kg, ip). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25-100 mg/kg, ip) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed. RESULTS: In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irrespective to the time of administration. Melatonin was effective only when administered in the afternoon. CONCLUSION: The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.

Effect of hydrogen sulphide on beta-amyloid-induced damage in PC12 cells.

1. Hydrogen sulphide (H(2)S) is a well-known cytotoxic gas. Recently, H(2)S has been shown to protect neurons against oxidative stress caused by glutamate, peroxynitrite and HOCl. Considerably lower H(2)S levels have been reported in the brain of Alzheimer's disease (AD) patients with accumulation of beta-amyloid (A beta). 2. The aim of present study was to explore the cytoprotection by H(2)S against A beta(25-35)-induced apoptosis and the molecular mechanisms underlying this effect in PC12 cells. 3. Our findings indicated that A beta(25-35) significantly reduced cell viability and induced apoptosis of PC12 cells, along with dissipation of the mitochondrial membrane potential (MMP) and overproduction of reactive oxygen species (ROS). 4. Sodium hydrosulphide (NaHS), an H(2)S donor, protected PC12 cells against A beta(25-35)-induced cytotoxicity and apoptosis not only by reducing the loss of MMP, but also by attenuating the increase in intracellular ROS. 5. The results of the present study suggest that the cytoprotection by H(2)S is related to the preservation of MMP and attenuation of A beta(25-35)-induced intracellular ROS generation. These findings could significantly advance therapeutic approaches to the neurodegenerative diseases that are associated with oxidative stress, such as AD.