Neurochemical Research最新文献

Background

Disease-modifying treatments for Parkinson’s disease (PD) are urgently needed, with the Nrf2/ARE pathway a promising target. This study aims to explore the effects of sinomenine on PD and Nrf2/ARE activation.

Methods

6-OHDA-treated Parkinsonian SH-SY5Y cells and rats were used. Apoptosis and cell viability were measured using flow cytometry and CCK-8 assays. Nrf2 and its downstream proteins were assessed by Western blotting, while ROS levels were detected with fluorescent dyes. Nrf2 silencing via shRNA evaluated sinomenine’s dependence on Nrf2 activation. In vivo, behavioral changes, tyrosine hydroxylase (TH) levels and malondialdehyde (MDA) levels were measured. Microglial inflammation was analyzed by measuring TNF-α and IL-1β expression and cytoskeleton analysis. Nrf2 nuclear translocation was verified by Western blotting and molecular docking was performed.

Results

Sinomenine reduced apoptosis and ROS, improved cell viability, upregulated Nrf2 and antioxidant enzyme expression. The protective effects against apoptosis were abolished by Nrf2 silencing. In PD animals, sinomenine improved motor deficits, enhanced Nrf2, GCLC, GCLM, NQO1, and HO-1 expression, decreased MDA levels, increased TH levels in the striatum and maintained count of dopaminergic neurons in substantia nigra. Additionally, it suppressed TNF-α and IL-1β levels in brain tissue and blood, preserving normal microglial morphology and reducing neuroinflammation. Sinomenine promoted Nrf2 nuclear translocation and showed high Keap1 affinity in docking.

Conclusions

Sinomenine activates the Nrf2/ARE pathway, mitigating oxidative stress and inflammation in PD models, possibly through Keap1 binding and Nrf2 nuclear translocation. These findings suggest sinomenine may serve as a potential disease-modifying therapy for Parkinson’s disease, pending further clinical validation.

The developing brain requires high energy demands and metabolic efforts to regulate oxidative stress and myelination. Early insults cause mitochondrial dysfunction and compromise these pathways, potentially leading to cerebral palsy (CP), a severe and incurable neurological disorder that begins in childhood. Through a rodent preclinical study, we demonstrated that vitamin B2 (riboflavin), administered at a high dose (100 mg/kg), is accumulated in healthy (B2C) or paralytic (B2CP) brains and participates in neurodevelopment. Redox homeostasis was maintained in B2C through decreased malondialdehyde and carbonyls and increased glutathione-S-transferase activity. In B2CP rodents, there was a reduction in carbonyls and increased superoxide dismutase activity. Mitochondrial morphometric analysis suggests that riboflavin treatment increases biogenesis in controls and reduces mitochondrial deformation in CP. Ultrastructural analysis revealed increased myelin sheath thickness in B2C. Additionally, myelin figure formation and mitochondrial and axonal disintegration in CP were reduced by B2. Our evidence supports vitamin B2 accumulation as a beneficial mechanism to support energy homeostasis and mitochondrial demands that occur during typical neurodevelopment or in the face of CP.

Alcohol consumption can affect the brain due to an elevation in oxidative stress and inflammation. Alcoholism influences the brain homeostasis and is often associated with cognitive, emotional and behavioral changes. Excessive alcohol intake can lead to poor sleep quality, and individuals with alcohol use disorder generally develop insomnia. Alcohol use affects the expression of clock genes, altering the physiological and immune function regulated by the biological clock, and hence elevating the production of reactive oxygen species. This study aimed to explore the alterations in neurobehavioral function associated with circadian disturbance and alcohol exposure, and to understand the potential therapeutic effect of methylsulfonylmethane on alcohol-administered and circadian-disrupted C57BL/6J mice. The sleep cycle of the mice was disturbed by 10 h light/10 h dark exposure, and 25% w/v alcohol was administered to the mice intragastrically. The concentration of trace elements in the mouse brain was measured using Inductively Coupled Mass Spectrometry (ICP-MS). An increase in anxiety-like behavior was observed in the mice exposed to alcohol and the circadian-disrupted groups. The administration of the drug significantly increased the expression of core clock genes in the alcohol and circadian-disrupted group. The levels of calcium and iron were increased in the MSM-administered mice, reversing the effects of circadian disruption and the alcohol-exposed group of mice. Our findings suggest that alcohol and circadian disturbance impact neurological function through alterations in immune homeostasis. MSM treatment can improve the expression of clock genes in alcohol and circadian-disrupted conditions, highlighting its neuroprotective potential by reducing inflammation.

Statins are widely prescribed and effective cholesterol-lowering drugs for the therapy of cerebrovascular and cardiovascular disorders. The main side effects limiting statin use are muscle-related adverse events, including weakness and myopathy. The precise mechanisms of statin-induced muscle damage remain to be elucidated. Possible alterations in neuromuscular transmission might contribute to the statin side effects. Here, we studied the action of one-month treatment with atorvastatin, the most prescribed statin, on the functioning of neuromuscular junctions and related processes in the mouse diaphragm. We found that atorvastatin treatment decreases evoked acetylcholine (ACh) release and involvement of synaptic vesicles in exocytosis during intense nerve activation, as well as recovery of ACh release after tetanic stimulation. This was accompanied by increased immunolabeling of synapsin 1, a protein retaining synaptic vesicles in a non-active pool, and decreased non-quantal ACh release under resting conditions. Additionally, atorvastatin administration decreased perimeters of postsynaptic ACh receptor clusters without signs of muscle denervation. Diaphragm contractile responses to phrenic nerve stimulation at moderate-to-high frequencies and peak inspiratory flow, an indicator of diaphragm function in vivo, were decreased in atorvastatin-treated mice, whereas diaphragm contractions elicited by direct stimulation of muscle fibers were unchanged. Thus, atorvastatin treatment caused a decline in evoked ACh release and synaptic vesicle recruitment into neurotransmission that could lead to a reduction of diaphragm contractile responses to phrenic nerve activity and peak inspiratory flow. These alterations, in combination with decreased non-quantal ACh release and neuromuscular junction size, may contribute to statin-associated muscle symptoms.

To investigate the role and mechanism of long non-coding RNA PVT1 in sevoflurane-induced oxidative stress and cognitive dysfunction. The expression level of PVT1 and the mRNA expressions of Caspase-3, Bax, and Bcl2 were detected by RT-qPCR. Cell viability and apoptosis rate were evaluated by MTT assay and flow cytometry, respectively. The levels of malondialdehyde (MDA), reactive oxygen species (ROS), and superoxide dismutase (SOD) were determined using commercial kits. The cognitive function of rats was assessed by Morris water maze (MWM) test. Online databases were used to predict the microRNAs (miRNAs) targeted by PVT1, and dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to verify the targeted binding relationship. PVT1 levels were significantly upregulated in hippocampal tissues of rats and HT22 cells treated with sevoflurane. Silencing of PVT1 effectively alleviated sevoflurane-induced cell apoptosis, oxidative stress, and cognitive dysfunction. Mechanistic studies showed that PVT1 targeted miR-486-5p. In sevoflurane-treated hippocampal tissues of rats and HT22 cells, inhibition of miR-486-5p counteracted the protective effects of PVT1 silencing, leading to increased cell apoptosis, exacerbated oxidative stress, and deteriorated cognitive dysfunction. PVT1 silencing mitigates oxidative stress response and cognitive dysfunction by targeting miR-486-5p, providing a novel research perspective for the treatment of sevoflurane-induced nerve injury.

Electroacupuncture (EA) therapy has been shown to significantly alleviate central poststroke pain (CPSP). However, current research on the mechanisms by which EA relieves CPSP is insufficient. This study explored the role of EA in ameliorating central nervous system inflammation in CPSP rats.The CPSP rat model was established by injecting collagenase IV into the right ventral posterolateral nucleus of the thalamus (VPL). The treatment group was treated with 15 Hz and 2 mA continuous wave EA every other day for a total of 8 sessions. The lncRNA MEG3 (MEG3) was knocked down or overexpressed by adeno-associated virus delivery in vivo in the rat brain. Pain thresholds were measured to assess the hypersensitivity of the rats to pain. Immunofluorescence, Nissl staining and enzyme-linked immunosorbent assay (ELISA) were used to assess the levels of MEG3 and glial fibrillary acidic protein (GFAP) in VPL brain tissue, neuronal injury, and the levels of substance P (SP), TNF-α, IL-1β and IL-6 in VPL brain tissue and serum, respectively. The levels of MEG3, Wnt3a, β-catenin and GFAP in VPL brain tissue were assessed by qRT‒PCR or Western blotting. EA inhibits the expression of MEG3 and neuroinflammatory injury in the VPL brain tissue of CPSP rats, ameliorating hyperalgesia symptoms in CPSP rats. The overexpression of MEG3 weakened the inhibitory effect of EA on the Wnt/β-catenin pathway in the VPL region of the brain, exacerbating pain hypersensitivity and neuroinflammatory damage in the brain hemorrhage regions of CPSP rats. Suppressing the expression of MEG3 in the VPL brain tissue of CPSP rats produced a therapeutic effect similar to that of EA intervention. EA could alleviate neuroinflammation and reduce pain in CPSP rats by suppressing the expression of MEG3. EA could regulate the Wnt/β-catenin signaling pathway via MEG3.

This study aimed to assess the neuroprotective effects of salidroside (SAL) on cerebral ischemia-reperfusion injury (CIRI) in a rat model and to elucidate the underlying mechanisms, with a focus on the role of estrogen receptor beta (ERβ) and BCL2 interacting protein 3 (BNIP3)-mediated mitochondrial autophagy as potential therapeutic targets in ischemic stroke. A total of 165 female Sprague-Dawley rats were randomly assigned into 11 groups (n = 15 per group). One group served as the control. The remaining animals underwent bilateral ovariectomy and were subsequently allocated into the following groups: ovariectomy-only, middle cerebral artery occlusion/reperfusion (MCAO/R), estradiol control, ERβ inhibitor, two inhibitor arms (inhibitor-only and inhibitor-plus-SAL), three SAL treatment groups (low, mediummitochondrial division, high dose), and a positive control (edaravone). All groups, except the control and ovariectomy-only groups, were subjected to MCAO for one hour followed by 24 h of reperfusion. Neurological function, cerebral infarct volume, blood-brain barrier (BBB) permeability, and brain water content were evaluated. Histopathological alterations were assessed, and transmission electron microscopy was employed to detect autophagosomes. Western blot analysis was performed to quantify protein expression levels of ERβ, BNIP3, NIP3-like protein X, and microtubule-associated protein 1 A/1B-light chain 3. Administration of SAL and edaravone significantly reduced neurological impairment, infarct volume, BBB disruption, and cerebral edema in the MCAO/R model. SAL treatment upregulated ERβ and BNIP3 expression and enhanced mitochondrial autophagy-associated protein levels. These effects were attenuated by the use of ERβ and mitochondrial division inhibitors, indicating a mechanistic link between SAL-mediated neuroprotection and activation of the ERβ/BNIP3 signaling axis. SAL exerts a neuroprotective effect against CIRI in rats, primarily through activation of ERβ and enhancement of BNIP3-mediated mitochondrial autophagy. These findings suggest that modulation of the ERβ/BNIP3 pathway may represent a promising therapeutic approach for ischemic stroke.

Parkinson’s disease (PD) is characterized by impairments in motor control following the degeneration of dopamine-producing neurons located in the substantia nigra pars compacta. Environmental pesticides such as Paraquat (PQ) and Maneb (MB) contribute to the onset of PD by inducing oxidative stress (OS). This study evaluated the therapeutic efficacy of moderate physical activity (PA) on both motor and non-motor symptoms in a Wistar rat model of Paraquat and Maneb (PQ/MB) induced PD. Thirty male Wistar rats were randomly divided into six groups: control, exercise (EX), PQ/MB, PQ/MB + L-dopa, PQ/MB + EX, and PQ/MB + EX + L-dopa. PD was induced via intraperitoneal (IP) injections of PQ (5 mg/kg) and MB (0.05 mg/kg) administered twice weekly for six weeks, followed by four weeks of moderate exercise in the designated groups. Motor and non-motor behaviors were then assessed, and OS markers were analyzed in the prefrontal cortex (PFC), striatum (ST), and hippocampus (HP). In our model, PQ/MB exposure induced characteristic PD symptoms, including motor dysfunction, anxiety, depression, and memory deficits. These symptoms were accompanied by elevated malondialdehyde (MDA) levels and reduced activity of antioxidant enzymes. However, moderate PA significantly improved several parameters: it enhanced coordination and balance, reduced anxiety and depressive-like behaviors, improved memory performance, attenuated lipid peroxidation, and increased antioxidant defense mechanisms, particularly the activity of catalase (CAT) and superoxide dismutase (SOD). These findings suggest that PA is a promising non-pharmacological therapeutic approach for the management of both motor and non-motor symptoms of PD.

Metabolic synergy between astrocytes and neurons is key to maintaining normal brain function. As the main supporting cells in the brain, astrocytes work closely with neurons through intercellular metabolic synergy networks to jointly regulate energy metabolism, lipid metabolism, synaptic transmission, and cerebral blood flow. This important synergy is often disrupted in neurological diseases such as Alzheimer’s disease, Parkinson’s disease, and stroke. This study systematically explores the physiological basis of this intercellular collaboration and its dysfunctional manifestations in the aforementioned diseases, and provides detailed insights into how abnormalities in specific collaborative pathways (such as impaired lactate transport, disrupted glutamate cycling, or lipid processing defects) significantly contribute to disease progression. By elucidating the molecular mechanisms underlying these collaborative impairments, this study aims to identify potential therapeutic targets, with the core strategy being to restore these critical intercellular collaborative relationships to alleviate neurological diseases.