Neurochemistry international最新文献

Cyclic AMP (cAMP) is an important second messenger in virtually all animal cell types, including astrocytes. In the brain, it modulates energy metabolism, development and synaptic plasticity. Dopamine receptors are G protein-coupled receptors that affect cAMP production by adenylyl cyclases. They are divided into two subgroups, D1-like receptors linked to G_s proteins stimulating cAMP production and D2-like receptors linked to G_i/o proteins inhibiting cAMP production. In the present study, we investigated the effect of dopamine receptor activation on cAMP dynamics in astrocytes of the mouse olfactory bulb, the brain region with the largest population of dopaminergic neurons. Using the genetically encoded cAMP sensor Flamindo2 we visualized changes in the cytosolic cAMP concentration and showed that dopamine application results in a transient increase in cAMP. This cAMP increase could be mimicked by the D1-like receptor agonist A 68930 and was inhibited by the D1-like receptor antagonist SCH 23390, whereas D2-like receptor ligands had no effect on the astrocytic cAMP concentration. Thus, olfactory bulb astrocytes express D1-like receptors that are linked to cAMP production.

Discrete components of tea possess multitude of health advantages. Escalating evidence advocate a consequential association between habitual tea consumption and a subsided risk of Parkinson's disease (PD). l-theanine is a non-protein amino acid inherent in tea plants, which exhibits structural resemblance with glutamate, the copious excitatory neurotransmitter in brain. Neuromodulatory effects of l-theanine are evident from its competency in traversing the blood brain barrier, promoting a sense of calmness beyond enervation, and enhancing cognition and attention. Despite the multifarious reports on antioxidant properties of l-theanine and its potential to regulate brain neurotransmitter levels, it is obligatory to understand its exact contribution in ameliorating the pathophysiology of PD. In this study, MPTP-induced mouse model was established and PD-like symptoms were developed in test animals where an increasing dosage of l-theanine (5, 25, 50, 100 and 250 mg/kg) was intraperitoneally administered for 23 days. 50 and 100 mg/kg dosage of l-theanine alleviated motor impairment and specific non-motor symptoms in Parkinsonian mice. The dosage of 100 mg/kg of l-theanine also improved striatal dopamine and serotonin level and tyrosine-hydroxylase positive cell count in the substantia nigra. Most crucial finding of the study is the proficiency of l-theanine to diminish astroglial injury as well as nitric oxide synthesis, which suggests its possible credential to prevent neurodegeneration by virtue of its anti-inflammatory attribute.

TRPV1 acts as a unique polymodal ion channel having distinct structure and gating properties. In this context, TRPV1-R575D represents a special mutant located at the inner lipid-water-interface (LWI) region that has less possibility of interaction with membrane cholesterol. In control conditions, this lab-generated mutant of TRPV1 shows no “ligand-sensitivity”, reduced surface expression, reduced localization in the lipid rafts, yet induces high cellular lethality. Notably, the cellular lethality induced by TRPV1-R575D expression can be rescued by adding 5′I-RTX (a specific inhibitor of TRPV1) or by introducing another mutation in the next position, i.e. in TRPV1-R575D/D576R. In this work we characterized TRPV1-R575D and TRPV1-R575D/D576R mutants in different cellular conditions and compared with the TRPV1-WT. We report that the “ligand-insensitivity” of TRPV1-R575D can be rescued in certain conditions, such as by chelation of extracellular Ca²⁺, or by reduction of the membrane cholesterol. Here we show that Ca²⁺ plays an important role in the channel gating of TRPV1-WT as well as LWI mutants (TRPV1-R575D, TRPV1-R575D/D576R). However, chelation of intracellular Ca²⁺ or depletion of ER Ca²⁺ did not have a significant effect on the TRPV1-R575D. Certain properties related to channel gating of mutant TRPV1-R575D/D576R can be rescued partially or fully in a context -dependent manner. Cholesterol depletion also alters these properties. Our data suggests that lower intracellular basal Ca²⁺ acts as a pre-requisite for further opening of TRPV1-R575D. These findings enable better understanding of the structure-function relationship of TRPV1 and may be critical in comprehending the channelopathies induced by other homologous thermosensitive TRPVs.

A recent study showed that while autophagy is usually tied to protein and organelle turnover, it can also play dual roles in neurodegenerative diseases. Traditionally, autophagy was seen as protective since it removes damaged proteins and organelles. but new data suggests autophagy can sometimes promote neuron death. and This review tackles autophagy's seemingly contradictory effects in neurodegeneration, or the "autophagy paradox. " It offers a framework for understanding autophagy in neurodegenerative research and the cellular processes involved. In short, our data uncovers a harmful autophagy role in certain situations, conflicting the view that it's always beneficial. We describe the distinct, disease-specific autophagy pathways functioning in various neurodegenerative diseases. Part two concerns potential therapeutic implications of manipulating autophagy and current strategies targeting the autophagic system, suggesting interesting areas for future research into tailored modulators. This could eventually enable activating or controlling specific autophagy pathways and aid in developing more effective treatments. Researchers believe more molecular-level research is needed so patient-tailored autophagy-modulating therapeutics can be developed given this dilemma. Moreover, research must translate faster into effective neurodegenerative disease treatment options. This article aims to provide a wholly new perspective on autophagy's classically described role in these severe diseases, challenging current dogma and opening new therapeutic avenue options.

N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion-channel receptors, specifically activated by glutamate, that permit the activation of specific intracellular calcium-dependent pathways. Aberrant NMDA receptor activation leads to a condition known as excitotoxicity, in which excessive calcium inflow induces apoptotic pathways. To date, memantine is the only NMDA receptor antagonist authorized in clinical practice, hence, a better understanding of the NMDA cascade represents a need to discover novel pharmacological targets.

We previously reported non-conventional intracellular signaling triggered by which, upon activation, promotes the interaction between JNK2 and STX1A which enhances the rate of vesicular secretion. We developed a cell-permeable peptide, named JGRi1, able to disrupt such interaction, thus reducing vesicular secretion. In this work, to selectively study the effect of JGRi1 in a much simpler system, we employed neuroblastoma cells, SH-SY5Y. We found that SH-SY5Y cells express the components of the NMDA receptor-JNK2 axis and that the NMDA stimulus increases the rate of vesicle release. Both JGRi1 and memantine protected SH-SY5Y cells from NMDA toxicity, but only JGRi1 reduced the interaction between JNK2 and STX1A. Both drugs successfully reduced NMDA-induced vesicle release, although, unlike memantine, JGRi1 did not prevent calcium influx. NMDA treatment induced JNK2 expression, but not JNK1 or JNK3, which was prevented by both JGRi1 and memantine, suggesting that JNK2 may be specifically involved in the response to NMDA.

In conclusion, being JGRi1 able to protect cells against NMDA toxicity by interfering with JNK2/STX1A interaction, it could be considered a novel pharmacological tool to counteract excitotoxicity.

There is evidence that tumor necrosis factor alpha (TNFα) influences autonomic processes coordinated within the hypothalamic paraventricular nucleus (PVN), however, the signaling mechanisms subserving TNFα′s actions in this brain area are unclear. In non-neuronal cell types, TNFα has been shown to play an important role in canonical NADPH oxidase (NOX2)-mediated production of reactive oxygen species (ROS), molecules also known to be critically involved in hypertension. However, little is known about the role of TNFα in NOX2-dependent ROS production in the PVN within the context of hypertension. Using dual labeling immunoelectron microscopy and dihydroethidium (DHE) microfluorography, we provide structural and functional evidence for interactions between TNFα and NOX2 in the PVN. The TNFα type 1 receptor (TNFR1), the major mediator of TNFα signaling in the PVN, was commonly co-localized with the catalytic gp91^phox subunit of NOX2 in postsynaptic sites of PVN neurons. Additionally, there was an increase in dual labeled dendritic profiles following fourteen-day slow-pressor angiotensin II (AngII) infusion. Using DHE microfluorography, it was also shown that TNFα application resulted in a NOX2-dependent increase in ROS in isolated PVN neurons projecting to the spinal cord. Further, TNFα-mediated ROS production was heightened after AngII infusion. The finding that TNFR1 and gp91^phox are positioned for rapid interactions, particularly in PVN-spinal cord projection neurons, provides a molecular substrate by which inflammatory signaling and oxidative stress may jointly contribute to AngII hypertension.

Ischemic stroke is a devastating disease that causes morbidity and mortality. Malnutrition following ischemic stroke is common in stroke patients. During the rehabilitation, the death rates of stroke patients are significantly increased due to malnutrition. Nutritional supplements such as protein, vitamins, fish, fish oils, moderate wine or alcohol consumption, nuts, minerals, herbal products, food colorants, marine products, fiber, probiotics and Mediterranean diets have improved neurological functions in stroke patients as well as their quality of life. Platelets and their mediators contribute to the development of clots leading to stroke. Ischemic stroke patients are treated with thrombolytics, antiplatelets, and antithrombotic agents. Several systematic reviews, meta-analyses, and clinical trials recommended that consumption of these nutrients and diets mitigated the vascular, peripheral, and central complications associated with ischemic stroke (Fig. 2). Particularly, these nutraceuticals mitigated the platelet adhesion, activation, and aggregation that intended to reduce the risks of primary and secondary stroke. Although these nutraceuticals mitigate platelet dysfunction, there is a greater risk of bleeding if consumed excessively. Moreover, malnutrition must be evaluated and adequate amounts of nutrients must be provided to stroke patients during intensive care units and rehabilitation periods. In this review, we have summarized the importance of diet and nutraceuticals in ameliorating neurological complications and platelet dysfunction with an emphasis on primary and secondary prevention of ischemic stroke.

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.