Neurochemical Research最新文献

The formation of intracranial aneurysms (IAs) is linked to metabolic problems and functional abnormalities in vascular smooth muscle cells (VSMCs). Berberine (BBR), a tetracyclic alkaloid having anti-inflammatory, antioxidant, and energy metabolism regulatory capabilities, has an unknown impact in IA progression. The purpose of this study is to look at the effects of BBR on IA development and the molecular mechanisms that drive it. An elastase-induced rat IA model was established as previously described, with in vivo measurements of aneurysm incidence, rupture rates, and artery structural integrity. An in vitro damage model was created by using primary VSMCs treated with Ang II. Inflammatory reactions, oxidative stress, mitochondrial function, and energy metabolism were investigated. The SIRT1/HMGB1/NF-κB signaling axis was investigated by Western blotting, immunofluorescence, pharmacological inhibition (EX-527), genetic manipulation (SIRT1 overexpression or HMGB1 knockdown/overexpression), and mitochondrial-targeted therapies (Antimycin A, MitoTEMPO). BBR dramatically reduced IA development and rupture in rats, reducing arterial inflammation and structural damage. In vitro, BBR restored Ang II-induced VSMC dysfunction, including mitochondrial depolarization, ROS overproduction, glycolytic shift, and inflammation, by upregulating SIRT1, increasing its binding to HMGB1, and decreasing HMGB1 acetylation, cytoplasmic translocation, and NF-κB activity. EX-527 eliminated these benefits, whereas SIRT1 overexpression replicated them, revealing SIRT1’s important involvement. Loss- and gain-of-function studies revealed that HMGB1 operates downstream of SIRT1, and that mitochondrial integrity is critical: Antimycin A inhibited BBR’s actions, but MitoTEMPO mimicked them. BBR promotes SIRT1 to deacetylate HMGB1, preventing its cytoplasmic translocation and NF-κB-mediated inflammation. Importantly, mitochondrial dysfunction caused by Ang II or IA disease is a primary driver of metabolic dysregulation and inflammatory activation in VSMCs. By maintaining mitochondrial integrity, BBR restores bioenergetic and redox equilibrium, breaking the inflammatory-metabolic vicious cycle. These coordinated responses inhibit the formation and evolution of cerebral aneurysms.

Postoperative cognitive dysfunction (POCD) is common in elderly surgical patients, and it can prolong recovery time and affect the quality of life. Although esketamine has been reported to alleviate POCD, its specific mechanism is not yet fully understood. This study investigates the effects of esketamine on POCD and its underlying molecular mechanisms. After exploratory laparotomy under isoflurane anesthesia, aged mice were treated with 10 mg/kg of esketamine via intraperitoneal injection. The findings of this study indicate that intraperitoneal administration of esketamine could alleviate POCD, as demonstrated through a suite of behavioral tests. Moreover, we collected hippocampal samples and used proteomics to obtain differentially expressed proteins, then cross-referenced them with the GO database to identify Rho-associated coiled-coil kinase 2 (Rock2) as a potential target molecule for esketamine to alleviate POCD. We further confirmed using Western blotting that esketamine downregulates the increase in Rock2 expression and the phosphorylation of the Ser726 site on alpha-adducin (S726-Add1) induced by anesthesia and surgery in aged mice. Furthermore, the damage to dendritic spine density, dendritic complexity, and synaptic plasticity in the hippocampal region caused by anesthesia and surgery showed improvement to a certain extent after esketamine treatment, as demonstrated by Golgi staining, transmission electron microscopy, and electrophysiological assessments. In summary, esketamine improved POCD in aged mice, indicating that its mechanism may involve the protection of synaptic plasticity through the Rock2/Add1 pathway. This research may provide new perspectives for the pharmacological treatment of POCD.

Huntington’s disease (HD) pathogenesis involves diverse cellular mechanisms, yet the contributions of pyroptosis and ferroptosis remain elusive. Roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, has shown neuroprotective effects, but its precise mechanisms are yet to be elucidated. We evaluated the potential neuroprotective and therapeutic effects of roflumilast in 3-nitropropionic acid (3-NP)-induced HD-like neurodegeneration, focusing on pyroptotic and ferroptotic cell death signaling. Adult male Wistar rats were assigned to five groups: normal control (saline + 0.5% carboxymethyl cellulose), roflumilast-control (1 mg/kg/day, p.o. for 21 days), 3-NP (20 mg/kg/day, i.p. for seven days), roflumilast-prophylactic (1 mg/kg/day, p.o. for 21 days prior to 3-NP), and roflumilast-treatment (1 mg/kg/day, p.o. for 21 days post-3-NP). Behavioral outcomes of the open-field, rotarod, and grip strength tests were assessed. Striatal PDE-4, total and p-CREB, BDNF, interleukin-1β, and markers of pyroptosis (NLRP3, caspase-1, and gasdermin D) and ferroptosis (iron, GPx4, GSH, and malondialdehyde) were measured alongside histopathological alterations and GFAP and Iba-1 immunohistochemical staining. Bioinformatics was used to visualize the target genes’ protein-protein interaction network. Behavioral assessments revealed impaired locomotion, motor coordination, and muscle strength in the 3-NP-injected rats. Biochemical analysis showed increased striatal PDE-4 expression and decreased p-CREB/BDNF axis alongside NLRP3 inflammasome/caspase-1/gasdermin D activation and elevated interleukin-1β. In parallel, ferroptosis was evidenced by increased striatal iron and malondialdehyde levels, along with reduced GPx4 and GSH. Histopathological examination revealed pronounced striatal neurodegeneration, accompanied by enhanced GFAP and Iba-1 immunostaining, indicating astrogliosis and microglial activation. Roflumilast, administered prophylactically or therapeutically, significantly improved functional and behavioral abnormalities while ameliorating biochemical, histopathological, and immunohistochemical derangements induced by 3-NP. The therapeutic regimen exhibited superior efficacy relative to prophylaxis. Conclusively, roflumilast exerts therapeutic and neuroprotective effects in HD-like neurodegeneration by mitigating pyroptosis and ferroptosis, attenuating astrogliosis, microglial activation, and neuroinflammation, and restoring synaptic plasticity.

Graphical Abstract

A graphical abstract illustrating the proposed mechanistic pathway underlying the neuroprotection of the PDE-4 inhibitor roflumilast through reducing striatal pyroptosis, ferroptosis, microglial and astrocyte activation, and neuroinflammation, while restoring synaptic plasticity in experimental Huntington’s disease-like neurodegeneration induced by 3-NP.

Prenatal stress is related to the development of psychiatric disorders involving inflammation, oxidative stress, and hypothalamic-pituitary-adrenal (HPA) axis. Therefore, the aim of the present study was to evaluate the effects of prenatal stress on behavior, inflammation, oxidative stress, and the HPA-axis in the dams and their offspring treated with lithium. Thirteen pregnant Wistar rats were exposed to a prenatal chronic unpredictable stress protocol from the 14th day of gestation until birth. At the 60th postnatal day (PND), a treatment protocol was carried out in the offspring with lithium (intraperitoneally – 47.5 mg/kg) or saline for seven days (twice a day). The behavior was assessed in the open field test to evaluate free movements. The dams (21 PND) and offspring (after open field) were euthanized, their brains were dissected in frontal cortex, hippocampus, and striatum, and the serum was collected. In the brain and/or serum, the levels of oxidative stress, inflammation, and HPA axis parameters were evaluated. Female offspring from stressed dams showed hyperactivity. Besides behavior alterations, offspring brain and serum showed an increase in pro-inflammatory cytokines, oxidative damage markers, and HPA axis hormones levels. Lithium administration only reduced the biochemical alterations. The prenatal stress protocol induced long-lasting behavior, inflammatory, oxidative stress, and HPA-axis alterations in the offspring which could underlie the development of psychiatric disorders.

Hyperammonemia (HA) is a metabolic disorder characterized by elevated ammonia levels in the blood. Ammonia produced from the metabolism of amino acids is mainly detoxified in the liver through the urea cycle. However, defects in this cycle result in the buildup of ammonia in the blood, which is highly neurotoxic and disrupts multiple signaling pathways in the brain, including nitric oxide (NO). NO is produced from the enzyme nitric oxide synthase (NOS), which exists in three different isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). NO is an important signaling molecule that plays a crucial role in various physiological functions, like neurotransmission, synaptic plasticity, learning and memory, regulation of cerebral blood flow, and immune responses. The role of NO in HA pathophysiology remains debated, with evidence supporting both neurotoxic and neuroprotective effects. The present review explains the relationship between HA and different NOS isoforms in the discrete brain regions, highlighting their effects on NO production in both acute and chronic HA conditions. HA impairs the glutamate-NO-cGMP pathway through multiple mechanisms, including tonic NMDAR activation, CaMKII-mediated modulation of nNOS, neurosteroids, and neurotransmitter imbalances. Moreover, alterations in arginine transport via the y⁺LAT2 transporter, and elevated levels of methylarginine derivatives, such as asymmetric dimethylarginine, contribute to reduced NOS activity, leading to reduced NO production, increased oxidative stress, and an increased inflammatory response in HA. Understanding these multiple mechanisms underlying NOS modulation may provide new therapeutic strategies to improve neurological impairments associated with HA.

Alzheimer’s disease (AD) is a chronic and progressive neurological degeneration marked by cognitive impairment and memory deficits, with oxidative stress and disturbances in the cholinergic system serving as key pathological factors. The current investigation sought to evaluate the neuroprotective and cognition-enhancing properties of Citropten (5,7-dimethoxycoumarin), a bioactive compound belonging to the coumarin class, in a scopolamine-induced cognitive impairment model. Wistar rats were divided into vehicle control, scopolamine alone, standard drug, and two Citropten-treated groups (12.5 and 25 mg/kg), and treated orally once daily for 18 days. Cognitive impairments were induced by daily scopolamine administration (2 mg/kg, i.p.) from Day 8 onward. Behavioral performance was analysed with the Novel Object Recognition (NOR), Elevated Plus Maze (EPM) and Morris Water Maze (MWM). Post-behavioral testing, brain tissues were analysed for acetylcholinesterase (AChE) activity, level of malondialdehyde (MDA), reduced glutathione (GSH), and catalase (CAT) activity. Scopolamine significantly impaired spatial, and recognition memory, as well as EPM-based learning memory performance, increased AChE activity and MDA levels, and reduced GSH and CAT activity compared with vehicle control group. Citropten treatment dose-dependently improved escape latency and target quadrant time spent in the MWM, enhanced the discrimination index in NOR test, and reduced transfer latency in the EPM. Biochemically, Citropten significantly reduced AChE and MDA levels while restoring GSH and CAT activity, showing effects comparable to the standard drug, Donepezil. Our findings demonstrate that Citropten exhibits multi-targeted neuroprotective agent, with potential relevance for mitigating cognitive dysfunction associated with cholinergic and oxidative stress pathways in scopolamine-induced cognitive impairment model.

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Methylphenidate (MPH) is first-line pharmacotherapy for Attention Deficit Hyperactivity Disorder (ADHD). Misdiagnosis and misuse raise concerns about exposing children and adolescents to MPH. This study aimed to assess how clinically relevant oral doses of MPH influence the expression of brain proteins involved in synaptic plasticity and neuronal growth in both sexes. Thirty-seven Wistar-Kyoto (WKY) rats (18 males and 19 females) were divided into an MPH group (daily oral dose of 5 mg/kg MPH in a 5% sucrose solution) and a control group (equivalent volume of 5% sucrose solution). Daily gavage administration started on postnatal day (PND) 15 and lasted for 15 days, with sacrifice at PND 30. In five brain regions [prefrontal cortex (PFC), striatum, hippocampus, cerebellum, and diencephalon], GAP43, GAPDH and PSD-95 levels were measured by Western blot. Additionally, MAP2 and synaptophysin levels were assessed in the PFC, motor cortex, ventral and dorsal striatum, and hippocampus (including CA1, CA3, hilus, and dentate gyrus) using immunohistochemistry.

In MPH-treated males, GAP43 and synaptophysin levels were reduced in the cerebellum and CA1 region, respectively, while PSD-95 and GAPDH levels increased in the striatum and diencephalon. MPH-treated females showed only a significant decrease in PSD-95 levels in the PFC. Regarding MAP2 levels, no significant changes were observed in any of the analyzed regions or sexes. In control animals, males exhibited higher MAP2 levels in the striatum compared to females. In conclusion, MPH in healthy rats can alter proteins associated with synaptic plasticity differently, highlighting the importance of sex as a variable.

Post-traumatic epilepsy (PTE) is the consequence of traumatic brain damage (TBI), which poses an important health risk for the human population. The underlying mechanism of PTE is complex and appears to be linked with various cellular processes, including oxidative stress and neuroinflammation. Over the years, it has been recognized that most of the available antiseizure medicines are ineffective in preventing PTE. As a result, there is an urgent need to search for alternate treatment options. Naringenin is a flavonoid with multiple pharmacological properties and has shown beneficial effects in several health issues, including neurological disorders. In this study, we investigated the effect of naringenin-loaded polycaprolactone nanoparticles (NarNPs) on neuroinflammatory response in the PTE model. NarNPs were produced using the nanoprecipitation method, and their physicochemical properties were examined by DLS, TEM and AFM. To induce epilepsy in rats, FeCl₃ was injected intracortically, and naringenin (NAR), both free NAR and NarNPs, were administered orally, 15 days post-surgery. Epileptic seizures were observed by electroencephalography (EEG) patterns and spectral power analysis of γ-waves. Immunofluorescence analysis of GFAP, IBA1 and TNF-α was performed to examine the disease-modifying potential of NarNPs. Our findings demonstrated that NarNPs marginally reduced epileptiform seizure activity in epileptic rats. Further, the study reported that NarNPs lowered the expression of GFAP, IBA1, and TNF-α. Overall, our data imply that NarNPs have antiseizure and disease-modifying potential by attenuating glial activation and TNF-α production in PTE rats.

Gut microbiota and its derived metabolites affect brain physiology through several pathways. Dysfunction of gut-microbiota is involved in the pathogenesis of Parkinson’s disease (PD). Introduced the pleiotropic effect of probiotics (PBT) in the function of the central nervous system, can delay the disease progression through microbiota-gut-brain axis (MGBA). PD is characterized by aggregated alpha-synuclein (α-syn), oxidative stress and neuroinflammation leading to depletion of dopaminergic neurons in the midbrain region. Our study designed to assess the neuroprotective effect of PBT Bacillus coagulans (B. coagulans) against rotenone (ROT) induced PD rats. To eliminate hormone-based errors associated with estrous cycle, we only used male rats in this experiment. ROT (50 mg/kg/day) caused perturbation of intestinal barrier leading to gut microbiome disturbances along with accumulation of α-syn in intestine and brain with motor deficits. qPCR of gut homogenate interpreted that treatment with B. coagulans alter the gut microbial composition in experimental PD through MGBA. This formulation claims as a supportive agent to restore the progression and aid in the therapeutic management of PD.

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