scholarly journals D-serine has antidepressant effects in mice through suppression of the BDNF signaling pathway and regulation of synaptic plasticity in the nucleus accumbens

2021 ◽  
Author(s):  
Zhenzhen Chen ◽  
Zhenyu Tang ◽  
Ke Zou ◽  
Zhihong Huang ◽  
Liuer Liu ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Signaling Pathway ◽  
Essential Role ◽  
Therapeutic Agent ◽  
Experimental Approach ◽  
Antidepressant Effects ◽  
The Central Nervous System ◽  
Bdnf Signaling ◽  
Electrophysiological Methods ◽  
Preference Tests

Background and Purpose: D-serine is a crucial endogenous co-agonist of NMDARs in the central nervous system and can affect the function of the BDNF system, which plays an essential role in modulating synaptic plasticity. The aim of the current investigation was to systematically evaluate the role and mechanisms of D-serine in depressive behavior in NAc. Experimental Approach: D-Serine concentration in the CSDS model in NAc was measured by HPLC. The antidepressant-like effects of D-serine were identified by the FST and TST in control mice, and then assessed in the CSDS model. We applied social interaction and sucrose preference tests to identify the susceptibility of CSDS model. Western blotting was further performed to assess the changes of BDNF signaling cascade in NAc after CSDS and D-serine treatment. The BDNF signaling inhibitor (K252a) was also used to clarify the antidepressant mechanism of D-serine. Moreover, effects of D-serine on synaptic plasticity in NAc were investigated by electrophysiological methods. Key Results: D-serine injections into the NAc exhibited antidepressant effects in the FST, TST and CSDS model. Next, D-serine down-regulated the BDNF signaling pathway in NAc during the CSDS procedure. Moreover, K252a enhanced the antidepressant effects of D-serine. We also found that D-serine was essential for NMDARs-LTD. Conclusion and Implications: Our results provide the first evidence that D-serine exerts antidepressant effects in mice mediated through restraining the BDNF signaling pathway and regulating synaptic plasticity in NAc, which indicates that D-serine may be an effective therapeutic agent for depression. KEYWORDS D-serine, depression, NAc, BDNF, CSDS, LTD

scholarly journals d-Serine produces antidepressant-like effects in mice through suppression of BDNF signaling pathway and regulation of synaptic adaptations in the nucleus accumbens

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Zhenzhen Chen ◽  
Zhenyu Tang ◽  
Ke Zou ◽  
Zhihong Huang ◽  
Liuer Liu ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nucleus Accumbens ◽  
Signaling Pathway ◽  
High Performance ◽  
Forced Swim Test ◽  
Tail Suspension Test ◽  
Antidepressant Effects ◽  
Chronic Social Defeat Stress ◽  
The Central Nervous System ◽  
Bdnf Signaling

Abstract Objective d-Serine is a crucial endogenous co-agonist of N-methyl-d-aspartate receptors (NMDARs) in the central nervous system and can affect the function of the brain derived neurotrophic factor (BDNF) system, which plays an essential role in modulating synaptic plasticity. The current study aimed to systematically evaluate the role and mechanisms of d-serine in depressive behavior in nucleus accumbens (NAc). Methods d-Serine concentration in the chronic social defeat stress (CSDS) model in NAc was measured using high-performance liquid chromatography (HPLC). The antidepressant-like effects of d-serine were identified using forced swim test (FST) and tail suspension test (TST) in control mice and then assessed in CSDS model. We applied social interaction and sucrose preference tests to identify the susceptibility of CSDS model. Western blotting was further performed to assess the changes of BDNF signaling cascade in NAc after CSDS and d-serine treatment. The BDNF signaling inhibitor (K252a) was also used to clarify the antidepressant-like mechanism of d-serine. Moreover, d-serine effects on synaptic plasticity in NAc were investigated using electrophysiological methods. Results d-Serine concentration was decreased in depression susceptible mice in NAc. d-Serine injections into NAc exhibited antidepressant-like effects in FST and TST without affecting the locomotor activity of mice. d-Serine was also effective in CSDS model of depression. Moreover, d-serine down-regulated the BDNF signaling pathway in NAc during CSDS procedure. Furthermore, BDNF signaling inhibitor (K252a) enhanced the antidepressant effects of d-serine. We also found that d-serine was essential for NMDARs-dependent long-term depression (LTD). Conclusion d-Serine exerts antidepressant-like effects in mice mediated through restraining the BDNF signaling pathway and regulating synaptic plasticity in NAc.

scholarly journals An Integrative Pharmacology-Based Pattern to Uncover the Pharmacological Mechanism of Ginsenoside H Dripping Pills in the Treatment of Depression

2021 ◽  
Vol 11 ◽  
Author(s):  
Libin Zhao ◽  
Rui Guo ◽  
Ningning Cao ◽  
Yingxian Lin ◽  
Wenjing Yang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Camp Signaling ◽  
Ginsenoside Rh2 ◽  
Ppi Network ◽  
Pharmacological Mechanism ◽  
Camp Signaling Pathway ◽  
Antidepressant Effects ◽  
Bdnf Signaling ◽  
Major Target ◽  
Tof Ms

Objectives: To evaluate the pharmacodynamical effects and pharmacological mechanism of Ginsenoside H dripping pills (GH) in chronic unpredictable mild stress (CUMS) model rats.Methods: First, the CUMS-induced rat model was established to assess the anti-depressant effects of GH (28, 56, and 112 mg/kg) by the changes of the behavioral indexes (sucrose preference, crossing score, rearing score) and biochemical indexes (serotonin, dopamine, norepinephrine) in Hippocampus. Then, the components of GH were identified by ultra-performance liquid chromatography-iron trap-time of flight-mass spectrometry (UPLC/IT-TOF MS). After network pharmacology analysis, the active ingredients of GH were further screened out based on OB and DL, and the PPI network of putative targets of active ingredients of GH and depression candidate targets was established based on STRING database. The PPI network was analyzed topologically to obtain key targets, so as to predict the potential pharmacological mechanism of GH acting on depression. Finally, some major target proteins involved in the predictive signaling pathway were validated experimentally.Results: The establishment of CUMS depression model was successful and GH has antidepressant effects, and the middle dose of GH (56 mg/kg) showed the best inhibitory effects on rats with depressant-like behavior induced by CUMS. Twenty-eight chemical components of GH were identified by UPLC/IT-TOF MS. Subsequently, 20(S)-ginsenoside Rh2 was selected as active ingredient and the PPI network of the 43 putative targets of 20(S)-ginsenoside Rh2 containing in GH and the 230 depression candidate targets, was established based on STRING database, and 47 major targets were extracted. Further network pharmacological analysis indicated that the cAMP signaling pathway may be potential pharmacological mechanism regulated by GH acting on depression. Among the cAMP signaling pathway, the major target proteins, namely, cAMP, PKA, CREB, p-CREB, BDNF, were used to verify in the CUMS model rats. The results showed that GH could activate the cAMP-PKA-CREB-BDNF signaling pathway to exert antidepressant effects.Conclusions: An integrative pharmacology-based pattern was used to uncover that GH could increase the contents of DA, NE and 5-HT, activate cAMP-PKA-CREB-BDNF signaling pathway exert antidepressant effects.

scholarly journals EGCG treats ICH via up-regulating miR-137-3p and inhibiting Parthanatos

2020 ◽  
Vol 11 (1) ◽  
pp. 371-379
Author(s):  
Jianjun Wang ◽  
Xuejun Kuang ◽  
Zhao Peng ◽  
Conghui Li ◽  
Chengwu Guo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Functional Recovery ◽  
Essential Role ◽  
Therapeutic Agent ◽  
Mice Model ◽  
The Central Nervous System ◽  
Novel Strategy ◽  
Antioxidant Effects ◽  
Promising Therapeutic Agent

AbstractIntracranial hemorrhage (ICH) causes high mortality and disability without effective treatment in the clinical setting. (−)-Epigallocatechin-3-gallate (EGCG) exerts an essential role in the central nervous system and offers a promising therapeutic agent for the treatment of oxidative damage-related diseases. MiR-137 can inhibit the oxidative stress and apoptosis to attenuate neuronal injury. However, the role of EGCG in regulating miR-137-3p and neuronal Parthanatos remains to be unclear. In the present study, we build the ICH mice model to investigate the antioxidant effects of EGCG via upregulating miR-137-3p and inhibiting neuronal Parthanatos. We revealed that EGCG upregulated miR-137-3p and inhibited neuronal Parthanatos, and promoted the functional recovery, alleviated ICH-induced brain injury, and reduced oxidative stress in mice following ICH. However, following the inhibition of miR-137-3p and activation of Parthanatos, EGCG was unable to exert neuroprotective roles. These combined results suggest that EGCG may upregulate miR-137-3p and inhibit neuronal Parthanatos to accelerate functional recovery in mice after ICH, laying the foundation for EGCG to be a novel strategy for the treatment of neuronal injuries related to Parthanatos.

scholarly journals The Function of Selenium in Central Nervous System: Lessons from MsrB1 Knockout Mouse Models

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1372
Author(s):  
Tengrui Shi ◽  
Jianxi Song ◽  
Guanying You ◽  
Yujie Yang ◽  
Qiong Liu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Mouse Models ◽  
Knockout Mouse ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Knockout Mouse Model ◽  
The Central Nervous System

MsrB1 used to be named selenoprotein R, for it was first identified as a selenocysteine containing protein by searching for the selenocysteine insert sequence (SECIS) in the human genome. Later, it was found that MsrB1 is homologous to PilB in Neisseria gonorrhoeae, which is a methionine sulfoxide reductase (Msr), specifically reducing L-methionine sulfoxide (L-Met-O) in proteins. In humans and mice, four members constitute the Msr family, which are MsrA, MsrB1, MsrB2, and MsrB3. MsrA can reduce free or protein-containing L-Met-O (S), whereas MsrBs can only function on the L-Met-O (R) epimer in proteins. Though there are isomerases existent that could transfer L-Met-O (S) to L-Met-O (R) and vice-versa, the loss of Msr individually results in different phenotypes in mice models. These observations indicate that the function of one Msr cannot be totally complemented by another. Among the mammalian Msrs, MsrB1 is the only selenocysteine-containing protein, and we recently found that loss of MsrB1 perturbs the synaptic plasticity in mice, along with the astrogliosis in their brains. In this review, we summarized the effects resulting from Msr deficiency and the bioactivity of selenium in the central nervous system, especially those that we learned from the MsrB1 knockout mouse model. We hope it will be helpful in better understanding how the trace element selenium participates in the reduction of L-Met-O and becomes involved in neurobiology.

scholarly journals Monitoring and Modulating Inflammation-Associated Alterations in Synaptic Plasticity: Role of Brain Stimulation and the Blood–Brain Interface

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 359
Author(s):  
Maximilian Lenz ◽  
Amelie Eichler ◽  
Andreas Vlachos
Keyword(s):  
Synaptic Plasticity ◽  
Brain Stimulation ◽  
Vascular Function ◽  
Neuropsychiatric Symptoms ◽  
Systemic Infection ◽  
Brain Functions ◽  
Blood Brain ◽  
Brain Interface ◽  
The Central Nervous System

Inflammation of the central nervous system can be triggered by endogenous and exogenous stimuli such as local or systemic infection, trauma, and stroke. In addition to neurodegeneration and cell death, alterations in physiological brain functions are often associated with neuroinflammation. Robust experimental evidence has demonstrated that inflammatory cytokines affect the ability of neurons to express plasticity. It has been well-established that inflammation-associated alterations in synaptic plasticity contribute to the development of neuropsychiatric symptoms. Nevertheless, diagnostic approaches and interventional strategies to restore inflammatory deficits in synaptic plasticity are limited. Here, we review recent findings on inflammation-associated alterations in synaptic plasticity and the potential role of the blood–brain interface, i.e., the blood–brain barrier, in modulating synaptic plasticity. Based on recent findings indicating that brain stimulation promotes plasticity and modulates vascular function, we argue that clinically employed non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, could be used for monitoring and modulating inflammation-induced alterations in synaptic plasticity.

Some Aspects of the Psychopharmacological Activity of Maprotiline (Ludiomil®): Effects of Single and Repeated Treatments

1978 ◽  
Vol 6 (6) ◽  
pp. 421-429 ◽  
Author(s):  
A Delini-Stula ◽  
E Radeke ◽  
A Vassout
Keyword(s):  
Nervous System ◽  
Chronic Treatment ◽  
Conditioned Fear ◽  
Conditioned Avoidance ◽  
Repeated Treatment ◽  
Antidepressant Effects ◽  
The Central Nervous System ◽  
Pre Treatment ◽  
High Doses ◽  
Psychopharmacological Activity

Three different aspects of the psychopharmacological activity of the antidepressant maprotiline were investigated: its influence on serotoninergic functions the effects produced by chronic treatment its central nervous depressant and anxiolytic properties. Study of the effects of maprotiline on 5-HTP-induced head-twitch in mice pre-treated with pargyline or on hyperpyrexia in rats provided no evidence that the drug interferes with serotonin-mediated functions in the central nervous system even after quite high doses. These findings corroborate the results of extensive neurobiochemical investigations, which failed to demonstrate any influence of maprotiline on the metabolism of serotonin. Chronic studies showed that classical effects of maprotiline such as antagonism against reserpine-induced ptosis or tetrabenazine-induced catalepsy do not change in their intensity after daily administration of the drugs in a dose of 30 mg/kg p.o.for 11 days. A new component of the action of the compound, not detectable after one single dose, seems to appear, however, after repeated treatment (8 days). This effect is manifested in the restoration of conditioned avoidance behaviour after its suppression by pre-treatment with reserpine. The same effect is produced by imipramine. It is suggested that this restorative effect may be due to an additional activation of the dopaminergic nervous system and may have a bearing on the appearance of clinical antidepressant effects. Maprotiline was found to potentiate central nervous depressant effects of drugs like chlorpromazine, phenobarbitone and propranolol. This affords further confirmation that, in addition to its antidepressant qualities, it possesses sedative actions. An anxiolytic component was also demonstrated in rats in which maprotiline suppressed the conditioned, fear-induced rise in body-temperature.

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