Molecular Neurobiology最新文献

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus is an efficacious treatment option for patients with refractory epilepsy. Our previous study demonstrates that adenosine is a potential target of DBS for the treatment of epilepsy. Equilibrative nucleoside transporters-1 (ENT1) and ectonucleotidases (CD39, CD73) function as regulators of extracellular adenosine in the brain. It is unclear whether ENT1, CD39, and CD73 are involved in the mechanism of DBS for epilepsy. A total of 48 SD male rats were divided into four groups: control (naïve rats), Pilo (pilocarpine induced rats with epilepsy), DBS (rats with epilepsy treated with DBS for 8 weeks), and sham. In the present study, video electroencephalogram monitoring, Morris water maze assays, in vivo measurements of adenosine using fiber photometry, histochemistry, and western blot were performed on the hippocampus. DBS markedly attenuated spontaneous recurrent seizures (SRSs) and enhanced spatial learning in rats with epilepsy, assessed through video-EEG and water maze assays. Fibred photometry measurements of an adenosine sensor revealed dynamic increase in extracellular adenosine during DBS. The expressions of ENT1, CD39, and CD73 in Pilo group and sham group increased compared with the control group, while the expressions of ENT1, CD39, and CD73 in DBS group decreased compared to that of Pilo group and sham group. The findings indicate that DBS reduces the number of SRSs and improves spatial memory in rats with epilepsy with concomitant decrease of ENT1, CD39, and CD73 expressions. Adenosine-modulating enzymes might be the potential targets of DBS for the treatment of epilepsy.

Alzheimer's disease (AD) is a leading neurodegenerative disorder with substantial impacts on cognition and behavior. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, has been used to treat various neuropsychiatric disorders, but its efficacy in AD has not been thoroughly investigated. This study examines the neuroprotective effects of rTMS in the 5xFAD mouse model of AD, with a particular focus on its modulation of GABAergic neuronal activity via the GABRG2 and SNAP25 proteins. Transcriptomic sequencing of rTMS-treated 5xFAD mice revealed 32 genes influenced by the treatment, among which GABRG2 was identified as a critical modulatory target. Electrophysiological assessments, including whole-cell patch clamp recordings from frontal cortex neurons, demonstrated significant alterations in inhibitory synaptic currents following rTMS. Subsequent experiments involved sh-GABRG2 transduction combined with rTMS treatment (20Hz, 14 days), examining behavioral responses, GABAergic neuron functionality, cortical GABA expression, cerebrospinal fluid GABA concentrations, β-amyloid accumulation, and pro-inflammatory cytokine levels. The results indicated notable improvements in behavioral performance, enhanced functionality of GABAergic neurons, and reductions in β-amyloid deposition and neuroinflammation after rTMS treatment. Further analysis revealed that SNAP25 overexpression could counteract the negative effects of GABRG2 silencing, highlighting the crucial role of SNAP25 downstream of GABRG2 in mediating rTMS's therapeutic effects in AD. This research highlights rTMS's potential to modulate synaptic and vesicular transport mechanisms, offering a promising avenue for ameliorating symptoms of AD through neuroprotective pathways.

Results of previous studies suggested that programmed cell death 4 (PDCD4) was overexpressed in cerebral ischemia (CI), and mothers against decapentaplegic homolog 1 (SMAD1) is a transcription factor of PDCD4, and it is also elevated in CI; however, the regulatory mechanism of SMAD1/PDCD4 axis in CI remains unclear. The current work has been designed to explore the role and associated mechanisms of SMAD1/PDCD4 in CI. PDCD4 and SMAD1 expressions have been examined by real-time reverse transcription-polymerase chain reaction (RT-qPCR) method, and receiver operating characteristic (ROC) curve analysis has been performed to determine the potential diagnostic value of PDCD4 and SMAD1. An oxygen-glucose deprivation (OGD) model has been used to investigate the effects of PDCD4 and SMAD1 on CI in vitro. Cell apoptosis was evaluated using TdT-mediated dUTP nick end labeling (TUNEL) assays. The interaction between SMAD1 and PDCD4 axis has been confirmed by using dual-luciferase reporter as well as chromatin immunoprecipitation (Ch-IP) assays. Finally, the effects of SMAD1/PDCD4 axis on the ferroptosis of neuron cells have been examined. PDCD4 was overexpressed in blood samples of CI patients. ROC analysis showed the AUC for PDCD4 was 0.7478, and NIHSS and MRS scores were positively correlated with PDCD4 expression. Moreover, the cellular OGD model was established and knockdown of PDCD4 suppressed the apoptosis of neurons. Besides, knockdown of PDCD4 also inhibited ferroptosis of OGD-treated neuron cells in vitro. Additionally, SMAD1 was upregulated in blood samples of CI patients, NIHSS and MRS scores were positively correlated with SMAD1 expression, and SMAD1 is a transcriptional factor of PDCD4, and SMAD1 could transcriptionally regulate the expression of PDCD4. Finally, SMAD1 could regulate the ferroptosis of neuron cells through regulating the transcription of PDCD4. The SMAD1/PDCD4 axis regulates the growth, apoptosis, and ferroptosis of neuron cells, suggesting that targeting the SMAD1/PDCD4 axis may be a potential therapeutic method.

Stroke leaves a great economic burden due to its high morbidity and mortality. Rapid revascularization of targeted vessel(s) is the effective treatment for ischemic stroke, but subsequent ischemia-reperfusion (I/R) injury is a common complication following revascularization, leading to microcirculation dysfunction and infarct volume increase. Thrombo-inflammation, the interaction between thrombosis and inflammation, plays a critical role in the pathophysiology of ischemic stroke. In the context of I/R injury, thrombo-inflammation consists of platelet activation, endothelial injury, and inflammatory cell infiltration. Numerous studies are devoted to exploring methods of regulating thrombo-inflammation to mitigate I/R injury post-stroke, including blocking activations of platelets and neutrophils. Drugs such as antiplatelet medications, anticoagulants, and glucocorticoids have been confirmed to have the potential to regulate thrombo-inflammation. Furthermore, several recently developed drugs have also shown promises in relieving I/R injury by manipulating thrombo-inflammation. However, the majority of these studies are still in the preclinical stage. Herein, in this review, we will address the mechanisms of thrombo-inflammation in ischemic stroke, related research advances, and particularly the clinical feasibility of thrombo-inflammation as a therapeutic strategy against I/R injury.

Depression is one of the most common mood disorders among psychiatric diseases. It affects about 10% of the adult population. However, its etiopathogenesis remains poorly understood. Exploring the dynamics of stress-susceptibility and resilience will help in understanding the molecular and biological mechanisms underlying the etiopathogenesis of depression. This study aimed to determine the differences and/or similarities in factors responsible for susceptibility to depression-like behaviors in male and female Wistar rats subjected to chronic unpredictable mild stress (CUMS). Sixty Wistar rats (30 male and 30 female) weighing between 120 and 150 g were used for this study. The rats were divided into two sub-groups: control (10) and test (20) groups. Rats in the test groups were subjected to CUMS. Depression-like behaviors were assessed using light-dark box, sucrose preference, and tail suspension tests. Rats that showed depression-like behaviors following the behavioral tests (CUMS-susceptible group) were sacrificed, and their hippocampi were excised. Genomic deoxyribonucleic acid (gDNA) was purified from the hippocampal samples. Purified gDNA was subjected to whole genome sequencing (WGS). Base-calling of sequence reads from raw sequencing signal (FAST5) files was carried out, and variants were called from alignment BAM files. The corresponding VCF files generated from the variant calling experiment were filtered. Genes were identified, their impacts estimated, and variants annotated. Functional enrichment analysis was then carried out. Approximately 41% of the male and 49% of the female rats subjected to CUMS showed significant (p < 0.05) depression-like behaviors following assessment on behavioral tests. WGS of the hippocampal DNA revealed 289,839 single nucleotide polymorphisms variant types, 7002 insertions, and 34,459 deletions in males, and 1,570,186 single nucleotide polymorphisms variant types, 109,860 insertions, and 597,241 deletions in female Wistar rats. Three genes with high-impact variants were identified in male and 22 in female Wistar rats, respectively. In conclusion, female Wistar rats are more susceptible to depression-like behaviors after exposure to CUMS than males. They also have more gene variants (especially high-impact variants) than male Wistar rats.

The aim of this study was to develop a novel antidepressant with high activity. Based on the findings of molecular docking, eight novel curcumin analogues were evaluated in vitro to check for antidepressant efficacy. Among them, CACN136 had the strongest antidepressant effect. Firstly, CACN136 had a stronger 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate) radical ion scavenging ability (IC₅₀: 17.500 ± 0.267 μg/mL) compared to ascorbic acid (IC₅₀: 38.858 ± 0.263 μg/mL) and curcumin (27.189 ± 0.192 μg/mL). Secondly, only CACN136 demonstrated clear protective effects on cells damaged by glutamate and oxidative stress at all concentrations. Finally, only CACN136 showed ASP + inhibition and was more effective than fluoxetine hydrochloride (FLU) at low concentrations. To further confirm the antidepressant effect of CACN136 in vivo, the CUMS model was established. Following 28 days of oral administration of CUMS mice, CACN136 increased the central area residence time in the open-field test, significantly increased the sucrose preference rate in the sucrose preference test (P < 0.001) and significantly reduced the immobility period in the tail suspension test (P < 0.0001), all of which were more effective than those of FLU. Subsequent research indicated that the antidepressant properties of CACN136 were linked to a decrease in the metabolism of 5-HT and the modulation of oxidative stress levels in vivo. In particular, the activation of the Keap1-Nrf2/BDNF-TrkB signaling pathway by CACN136 resulted in elevated levels of antioxidant enzymes, enhancing the antioxidant capability in mice subjected to CUMS. In conclusion, CACN136 has the potential to treat depression and could be an effective antidepressant.

Spinal cord injury (SCI) is a serious, disabling injury to the central nervous system that can lead to motor, sensory, and autonomic dysfunction below the injury plane. SCI can be divided into primary injury and secondary injury according to its pathophysiological process. Primary injury is irreversible in most cases, while secondary injury is a dynamic regulatory process. Secondary injury involves a series of pathological events, such as ischemia, oxidative stress, inflammatory events, apoptotic pathways, and motor dysfunction. Among them, oxidative stress is an important pathological event of secondary injury. Oxidative stress causes a series of destructive events such as lipid peroxidation, DNA damage, inflammation, and cell death, which further worsens the microenvironment of the injured site and leads to neurological dysfunction. The nuclear factor erythrocyte 2-associated factor 2 (Nrf2) is considered to be a key pathway of antioxidative stress and is closely related to the pathological process of SCI. Activation of this pathway can effectively inhibit the oxidative stress process and promote the recovery of nerve function after SCI. Therefore, the Nrf2 pathway may be a potential therapeutic target for SCI. This review deeply analyzed the generation of oxidative stress in SCI, the role and mechanism of Nrf2 as the main regulator of antioxidant stress in SCI, and the influence of cross-talk between Nrf2 and related pathways that may be involved in the pathological regulation of SCI on oxidative stress, and summarized the drugs and other treatment methods based on Nrf2 pathway regulation. The objective of this paper is to provide evidence for the role of Nrf2 activation in SCI and to highlight the important role of Nrf2 in alleviating SCI by elucidating the mechanism, so as to provide a theoretical basis for targeting Nrf2 pathway as a therapy for SCI.

Alzheimer's disease (AD) is a progressive neurological disorder characterized by cognitive decline. This study was undertaken to evaluate the effects of selegiline (SEL) against AD-induced cognitive deficits and explore the possible involved mechanisms. AD was induced by unilateral intracerebroventricular (U-ICV) injection of 5 μg of amyloid beta_1-42 (Aβ_1-42), and oral administration of SEL (0.5 mg/kg/day) was performed for 30 consecutive days. Aβ injection resulted in spatial cognitive decline, as demonstrated by a decrease in the time spent in the target zone on the probe day (P < 0.01) in the Barnes maze test (BMT). This spatial cognitive decline was associated with disrupted synaptic plasticity, as indicated by reductions in both components of hippocampal long-term potentiation (LTP), namely population spike amplitude (P < 0.001) and field excitatory postsynaptic potential (P < 0.001). On the other hand, the injection of Aβ resulted in oxidative stress by decreasing total thiol group (TTG) content and increasing malondialdehyde (MDA) levels in the rat plasma (P < 0.001). Additionally, the number of healthy cells in the hippocampal dentate gyrus (DG) and CA1 regions was reduced in AD rats (P < 0.001). However, oral administration of SEL improved spatial cognitive decline in the Aβ-induced AD rats. The results suggest that improvement of neuroplasticity deficiency, regulation of oxidant/antioxidant status, and suppression of neuronal loss by SEL may be the mechanisms underlying its beneficial effect against AD-related spatial cognitive impairment.

Neuropathic pain (NP) is a chronic pain caused by injury or disease of the somatosensory nervous system, or it can be directly caused by disease. It often presents with clinical features like spontaneous pain, hyperalgesia, and dysesthesia. At present, voltage-gated calcium ion channels (VGCCs) are known to be closely related to the development of NP, especially the α2δ subunit. The α2δ subunit is a regulatory subunit of VGCCs. It exists mainly in the brain and peripheral nervous system, especially in nerve cells, and it plays a crucial part in regulating presynaptic and postsynaptic functions. Furthermore, the α2δ subunit influences neuronal excitation and pain signaling by promoting its expression and localization through binding to VGCC-related subunits. The α2δ subunit is widely used in the management of NP as a target of antiepileptic drugs gabapentin and pregabalin. Although drug therapy is one of the treatments for NP, its clinical application is limited due to the adverse reactions caused by drug therapy. Therefore, further research on the therapeutic target α2δ subunit is needed, and attempts are made to obtain an effective treatment for relieving NP without side effects. This review describes the current associated knowledge on the function of the α2δ subunit in perceiving and modulating NP.

Hemorrhagic stroke is a global health problem owing to its high morbidity and mortality rates. Nicotinamide riboside is an important precursor of nicotinamide adenine dinucleotide characterized by a high bioavailability, safety profile, and robust effects on many cellular signaling processes. This study aimed to investigate the protective effects of nicotinamide riboside against collagenase-induced hemorrhagic stroke and its underlying mechanisms of action. An intracerebral hemorrhage model was constructed by stereotactically injecting collagenase into the right striatum of adult male Institute for Cancer Research mice. After 30 minutes, nicotinamide riboside was administered via the tail vein. The mice were sacrificed at different time points for assessments. Nicotinamide riboside reduced collagenase-induced hemorrhagic area, significantly reduced cerebral water content and histopathological damage, promoted neurological function recovery, and suppressed reactive oxygen species production and neuroinflammation. Nicotinamide riboside exerts neuroprotective effects against collagenase-induced intracerebral hemorrhage by inhibiting neuroinflammation and oxidative stress.