Neurochemistry international最新文献

Inflammatory response mediated by M1 microglia is a crucial factor leading to the exacerbation of brain injury after ischemic stroke (IS). Under the stimulation of IS, vascular smooth muscle cells (VSMCs) switch to the synthetic phenotype characterized by exosome secretion. Previous studies have shown that exosomes play an important role in the regulation of microglial polarization. We reported that exosomes derived from primary human brain VSMCs under hypoxia (HExos), but not those under normoxia (Exos), significantly promoted primary human microglia (HM1900) shift to M1 phenotype. Proteomic analysis showed that the Src protein enriched in HExos was a potential pro-inflammatory mediator. In vitro experiments showed that the expression of Src and M1 markers were upregulated in HM1900 co-incubated with HExos. However, the Src inhibitor dasatinib (DAS) significantly promoted the transformation of HM1900 phenotype from M1 to M2. In vivo experiments of pMCAO mice also revealed that DAS could effectively inhibit the activation of M1 microglia/macrophages, protect neurons from apoptosis, and improve neuronal function. These data suggested that hypoxic-VSMCs-derived exosomes were involved in post-IS inflammation by promoting M1 microglial polarization through Src transmission. Targeting inhibition of Src potentially acts as an effective strategy for treating brain injury after IS.

The absent in melanoma 2 (AIM2) inflammasome contributes to ischemic brain injury by inducing cell pyroptosis and inflammatory responses. Our research group has previously demonstrated that ATP-sensitive potassium channels (KATP channels) openers can modulate neuronal synaptic plasticity post-ischemic stroke for neuroprotection. However, the specific mechanisms of KATP channels in the inflammatory response following ischemic stroke remain unclear. Here, we assessed cellular damage by observing changes in BV-2 morphology and viability. 2,3,5-Triphenyl tetrazolium chloride (TTC) staining, mNSS scoring, Nissl staining, and TdT-mediated dUTP nick end labeling (TUNEL) staining were used to evaluate behavioral deficits, brain injury severity, and neuronal damage in mice subjected to middle cerebral artery occlusion (MCAO). Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were used to measure cell pyroptosis and nuclear factor-kappaB (NF-κB) activation in vivo and in vitro. We observed that AIM2 protein expression was upregulated and localized within the cytoplasm of BV-2 cells. Notably, low-dose Nicorandil treatment reduced inflammatory cytokine secretion and pyroptosis-related protein expression, including AIM2, cleaved cysteinyl aspartate-specific protease-1 (cleaved caspase-1), and Gasdermin D N-terminal (GSDMD-NT). Further investigations revealed that the KATP channel inhibitor 5-HD upregulated p-NF-κB p65, NF-κB p65, and p-IκBα expression, reversing Nicorandil's neuroprotective effect in vivo. In summary, our results suggest that Nicorandil may serve as a potential therapeutic option for ischemic stroke. Targeting AIM2 and NF-κB represents effective strategies for inhibiting neuroinflammation.

Cinnamic alcohol (CA) is a phenylpropanoid found in the essential oil of the bark of the genus Cinnamomum spp. Schaeff. (Lauraceae Juss.), known as cinnamon. To evaluate the neuroprotective effect of CA and its possible mechanism of action on mice submitted to the pentylenetetrazole (PTZ) induced epileptic seizures model. Behavioral, neurochemical, histomorphometric and immunohistochemistry analysis were carried out. The administration of CA (50–200 mg/kg, i.p., 30 min prior to PTZ and 0.7–25 mg/kg, i.p., 60 min prior to PTZ) increased the latency to seizure onset and the latency to death. The effects observed with CA treatment at 60 min were partially reversed by pretreatment with flumazenil. Furthermore, neurochemical assays indicated that CA reduced the concentration of malondialdehyde and nitrite, while increasing the concentration of reduced glutathione. Finally, histomorphometric and immunohistochemistry analysis revealed a reduction in inflammation and an increase in neuronal preservation in the hippocampi of CA pre-treated mice. Taken together, the results suggest that CA seems to modulate the GABAA receptor, decrease oxidative stress, mitigate neuroinflammation, and reduce cell death processes.

Psychological stress induces neuroinflammatory responses, which are associated with the pathogenesis of various psychiatric disorders, such as posttraumatic stress disorder and anxiety. Osthole—a natural coumarin isolated from the seeds of the Chinese herb Cnidium monnieri—exerts anti-inflammatory and antioxidative effects on the central nervous system. However, the therapeutic benefits of osthole against psychiatric disorders remain largely unknown. We previously demonstrated that mice subjected to repeated social defeat stress (RSDS) in the presence of aggressor mice exhibited symptoms of posttraumatic stress disorder, such as social avoidance and anxiety-like behaviors. In this study, we investigated the therapeutic effects of osthole and the underlying molecular mechanisms. Osthole exerted therapeutic effects on cognitive behaviors, mitigating anxiety-like behaviors and social avoidance in a mouse model of RSDS. The anti-inflammatory response induced by the oral administration of osthole was strengthened through the upregulation of heme oxygenase-1 expression. The expression of PPARα was inhibited in mice subjected to RSDS. Nonetheless, osthole treatment reversed the inhibition of PPARα expression. We identified a positive correlation between heme oxygenase-1 expression and PPARα expression in osthole-treated mice. In conclusion, osthole has potential as a Chinese herbal medicine for anxiety disorders. When designing novel drugs for psychiatric disorders, researchers should consider targeting the activation of PPARα.

Current anti-seizure medications (ASDs) primarily target ion channels or neurotransmissions; however, their practicability is limited by unwanted side-effects and pharmacoresistance. Cumulative evidence has proposed pro-inflammatory caspase-1 as a potential target for developing ASDs. In this study, we showed that the small-molecular caspase-1 inhibitor CZL80 can prevent seizures in various models including the maximal electroshock (MES), the pentylenetetrazol (PTZ), and the amygdaloid kindled models. Specifically, we discovered that CZL80 prevented death, reduced the duration of generalized seizures, and increased the threshold of generalized seizures in a dose-dependent manner in the MES model. In the PTZ model, CZL80 decreased the seizure stages, prolonged the latency to stage 4 seizures, and decreased the death rate. And in amygdaloid kindled rats, CZL80 inhibited the seizure stages, shortened the durations of both generalized seizures and after-discharges. And the anti-seizure efficacy of CZL80 was diminished in caspase-1 knockout mice. In vitro electrophysiology recordings revealed that CZL80 was able to decreased the excitability of glutamatergic pyramidal neurons, as denoted by reducing the spontaneous neuronal firings and increasing the rheobase injected currents to elicit action potentials. Furthermore, CZL80 was able to increase the amplitudes of inhibitory post-synaptic currents (IPSC), while the excitatory post-synaptic currents (EPSC) were not influenced. Lastly, daily administration of CZL80 for 3 weeks did not influence the normal locomotor functions in mice. In sum, our results highlighted CZL80 as a potential anti-seizure therapy with therapeutic significance.

Depression is a complex mood disorder with multifactorial etiology and is also the most frequent non-motor symptom of Parkinson's disease. Emerging research suggests a potential link between mitochondrial dysfunction and the pathophysiology of major depressive disorder. By synthesizing current knowledge and research findings, this review sheds light on the intricate relationship between Parkin, a protein classically associated with Parkinson's disease, and mitochondrial quality control mechanisms (e.g., mitophagy, mitochondrial biogenesis, and mitochondrial dynamic), specifically focusing on their relevance in the context of depression. Additionally, the present review discusses therapeutic strategies targeting Parkin-medicated mitophagy and calls for further research in this field. These findings suggest promise for the development of novel depression treatments through modulating Parkin-mediated mitophagy.

It has been demonstrated that an enriched environment (EE) treatment can alter neuroplasticity in neurodegenerative diseases. However, the role of EE treatment in ischemic stroke remains unclear. Previous findings have revealed that EE treatment can promote cerebral activin-receptor-like-kinase-5 (ALK5) expression after cerebral ischemia/reperfusion (I/R) injury. ALK5 has been identified as a potential mediator of neuroplasticity through its modulation of Smad2/3 and Gadd45β. Therefore, the aim of this study was to investigate whether EE treatment could promote neurofunctional recovery by regulating the ALK5/Smad2/3/Gadd45β pathway. The study utilized the rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). The ALK5/Smad2/3/Gadd45β signaling pathway changes were evaluated using western blotting (WB). Brain injury was assessed by infarct volume and neurobehavioral scores. The effect of EE treatment on neurogenesis was evaluated using Doublecortin (DCX) and Nestin, axonal plasticity with biotinylated dextran amine (BDA) nerve tracing, and dendritic plasticity was assessed using Golgi-Cox staining. EE treatment has been demonstrated to modulate the Smad2/3/Gadd45β pathway by regulating the expression of ALK5. The protective effects of EE treatment on brain infarct volume, neurological function, newborn neurons, dendritic and axonal plasticity following cerebral I/R injury were counteracted by ALK5 silencing. EE treatment can enhance neurofunctional recovery after cerebral I/R injury, which is achieved by regulating the ALK5/Smad2/3/Gadd45β signaling pathway to promote neuroplasticity.

Dementia is a growing problem around the globe as the world's population continues to age. Multiple studies have identified potentially modifiable risk factors for the development of dementia suggesting that addressing some or all of these risk factors might have a significant impact on the aging population worldwide. However, this is not always as straightforward as it seems since many of these risk factors are currently treated with drugs specific to the risk factor. Moreover, since people can have multiple risk factors, addressing each of them individually could be highly problematic as it would likely lead to negative outcomes associated with polypharmacy and, in the long term, could do significant harm. A potential alternative is to identify compounds that have shown efficacy against a number of these different risk factors. As discussed in this review, there is strong evidence that the flavonol fisetin is one such compound. In animal studies it has shown efficacy against many of the risk factors that have been associated with an increased risk of developing dementia and also exhibits direct neuroprotective effects. Thus, further human research on fisetin in the context of dementia risk factors is clearly warranted.

Anxiety is a commonly prevailing psychological disorder that requires effective treatment, wherein phytopharmaceuticals and nutraceuticals could offer a desirable therapeutic profile. Hybanthus enneaspermus (L.) F. Muell. is a powerful medicinal herb, reportedly effective against several ailments, including psychological disorders. The current research envisaged evaluating the anxiolytic potential of the ethanolic extract of Hybanthus enneaspermus (EEHE) and its toluene insoluble biofraction (ITHE) employing experimental and computational approaches. Elevated Plus Maze, Light and Dark Transition, Mirror Chamber, Hole board and Open field tests were used as screening models to assess the antianxiety potential of 100, 200 and 400 mg/kg body weight of EEHE and ITHE in rats subjected to social isolation, using Diazepam as standard. The brains of rats exhibiting significant anxiolytic activity were dissected for histopathological and biochemical studies. Antioxidant enzymes like catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, glutathione reductase; and neurotransmitters viz. monoamines (serotonin, noradrenaline, dopamine), Gamma-aminobutyric acid (GABA), and glutamate were quantified in the different regions of rats’ brain (cortex, hippocampus, pons, medulla oblongata, cerebellum). Chromatographic techniques were used to isolate phytoconstituents from the fraction exhibiting significant activity that were characterized by spectroscopic methods and subjected to in silico molecular docking. ITHE at 400 mg/kg body weight significantly mitigated anxiety in all the screening models (p < 0.05), reduced the inflammatory vacuoles and necrosis (p < 0.05) and potentiated the antioxidant enzymes (p < 0.05). It enhanced the monoamines and GABA levels while attenuating glutamate levels (p < 0.01) in the brain. Three significant flavonoids viz. Quercitrin, Rutin and Hesperidin were isolated from ITHE. In silico docking studies of these flavonoids revealed that the compounds exhibited substantial binding to the GABA_A receptor. ITHE displayed a promising pharmacological profile in combating anxiety and modulating oxidative stress, attributing its therapeutic virtues to the flavonoids present.

The prevalence of the world's second leading neurodegenerative disorder Parkinson's disease (PD) is well known while its pathogenesis is still a topical issue to explore. Clinical and experimental reports suggest the prevalence of disturbed gut microflora in PD subjects, with an abundance of especially Gram-negative bacteria. The endotoxin lipopolysaccharide (LPS) released from the outer cell layer of these bacteria interacts with the toll-like receptor 4 (TLR4) present on the macrophages and it stimulates the downstream inflammatory cascade in both the gut and brain. Recent research also suggests a positive correlation between LPS, alpha-synuclein, and TLR4 levels, which indicates the contribution of a parallel LPS-alpha-synuclein-TLR4 axis in stimulating inflammation and neurodegeneration in the gut and brain, establishing a body-first type of PD. However, owing to the novelty of this paradigm, further investigation is mandatory. Modulating LPS biosynthesis and LPS-TLR4 interaction can ameliorate gut dysbiosis and PD. Several synthetic LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase; LPS-synthesizing enzyme) inhibitors and TLR4 antagonists are reported to show beneficial effects including neuroprotection in PD models, however, are not devoid of side effects. Plant-derived compounds have been long documented for their benefits as nutraceuticals and thus to search for effective, safer, and multitarget therapeutics, the present study focused on summarizing the evidence reporting the potential of phyto-compounds as LpxC inhibitors and TLR4 antagonists. Studies demonstrating the dual potential of phyto-compounds as the modulators of LpxC and TLR4 have not yet been reported. Also, very few preliminary studies have reported LpxC inhibition by phyto-compounds. Nevertheless, remarkable neuroprotection along with TLR4 antagonism has been shown by curcumin and juglanin in PD models. The present review thus provides a wide look at the research progressed to date in discovering phyto-compounds that can serve as LpxC inhibitors and TLR4 antagonists. The study further recommends the need for expanding the search for potential candidates that can render dual protection by inhibiting both the biosynthesis and TLR4 interaction of LPS. Such multitarget therapeutic intervention is believed to bring fruitful yields in countering gut dysbiosis, neuroinflammation, and dopaminergic neuron damage in PD patients through a single treatment paradigm.