Acta neurobiologiae experimentalis最新文献

Multiple sclerosis (MS) is a chronic autoimmune illness characterized by demyelination and neurodegeneration, which causes physical disability and severe alterations in the neurological system, including gliosis and neuron loss. The disease primarily affects myelinated parts of the central nervous system (CNS), such as the optic nerves, cerebellum, brain stem, and spinal cord. T cells play an important role in MS pathogenesis by inducing demyelination, and risk factors include genetic predisposition, environmental effects, and lifestyle decisions. The prevalence of MS is rising, especially among women and the elderly population. Iron dysregulation is a critical element in MS pathogenesis, with excess iron causing neurodegeneration via ferroptosis and immune response modulation. Excess iron amplifies inflammation by triggering the activation of macrophages with inflammatory properties, and promoting microglial polarization toward the pro‑inflammatory phenotype. This causes increased oxidative stress, mitochondrial malfunction, and the release of reactive oxygen species, which harm neurons. Furthermore, proinflammatory cytokines like IL‑6 regulate iron metabolism and encourage the formation of Th17 cells, which exacerbates CNS inflammation. Macrophages and microglia, which are implicated in inflammatory responses, collect iron during MS, exacerbating neuroinflammation and demyelination. Disrupted iron homeostasis is a major contributor to MS pathology, with iron deficiency affecting immunological function and changing T‑cell responses, both of which are necessary for disease progression. Lumbar puncture, oligoclonal bands analysis, and magnetic resonance imaging are all used to diagnose MS and confirm disease activity and progression. The blood‑brain barrier is frequently disrupted in MS, allowing the influx of inflammatory cells. The aim of this paper is to demonstrate the cause‑effect relationship between the amount of iron and the health status of patients with MS.

Methyl‑CpG binding domain protein 3 (Mbd3), a component of the NuRD chromatin remodeling complex, plays a role in transcriptional regulation and has been implicated in neuronal development; however, its role in epilepsy remains unclear. This study investigated the effects of Mbd3 downregulation on seizure susceptibility and behavior in rats, using adeno‑associated viral vectors that code for short hairpin RNA to downregulate Mbd3 expression in the basolateral amygdala. Behavioral assessments included the open field test, elevated plus maze test, and hyperexcitability test. Seizure susceptibility was evaluated using the PTZ challenge and PTZ kindling models. A decreased Mbd3 level significantly increased latency to seizure onset in the PTZ challenge, indicating a raised seizure threshold. Rats with reduced Mbd3 expression also exhibited increased anxiety‑like behavior in the open‑field test. Mbd3 downregulation did not affect the progression of epileptogenesis in the PTZ kindling model. These findings suggest that Mbd3 contributes to acute seizure susceptibility and emotional behavior but not to the long‑term development of epilepsy, highlighting its potential as an epigenetic modulator in seizure regulation.

Numerous experimental data point to therapeutic effects of electrical stimulation of peripheral nerves. Stimulation of low‑threshold proprioceptive afferents to motoneurons (MNs) innervating the ankle extensor muscles of the rat increases glutamatergic Ia MN inputs and spinal and muscle expression of neurotrophin‑3, instrumental for proprioceptive afferent‑MN connections. We aimed to examine morphological consequences of the cuff electrode implanted around the tibial nerve used for chronic stimulation which may cause unwanted effects through its long‑lasting contact with the nerve. We addressed also the questions if stimulation of low‑threshold proprioceptive afferents may contribute to neural damage, affect capillary vessels and macrophage morphology reflecting functional state of the nerve. Their consequences on axonal and nerve ultrastructure have not been previously evaluated. To examine the effect of cuff electrodes and of 7‑day low‑threshold stimulation applied in the 4th week post‑implantation on the tibial nerve, electrodes were implanted bilaterally, and a stimulation was added unilaterally. Non‑implanted group was the control. The counts of myelinated axons, their cross‑sectional area (>1 μm2) and circularity were measured on photomicrographs captured with use of light microscope from semi‑thin Epon sections stained with toluidine blue. Ultrastructural observations with TEM included myelin, axoplasm, Remak fibers, blood vessels, macrophages and fibroblasts. Four weeks after implantation of the cuff, the mean cross‑sectional area of the nerve, and counts, area and diameter of the myelinated fibers were lower compared to control. The largest fibers located in the external parts of the main nerve branches and dispersed in small branches were changed the most. No significant difference in either parameter between unstimulated (NS) and stimulated (S) nerve was found. Axons in Remak bundles were dispersed comparably in NS and S nerves. Thinly myelinated fibers demonstrating features of demyelination with remyelination were identified. We provide evidence that long-lasting presence of the cuff electrode is not neutral for nerve structure, causing mild shrinkage of large myelinated axons and impairment of organization of unmyelinated fibers. Since we demonstrated that low‑threshold proprioceptive stimulation of the tibial nerve results in a stable Hoffmann reflex and induces synaptic plasticity by increasing glutamatergic input to MNs, we conclude that the applied protocol maintains an adequate margin of safety.

The distribution and morphology of neuronal degeneration were observed and analyzed in each sector of the zona incerta in a lithium‑pilocarpine (LiCl) Wistar rat model of status epilepticus in 12, 15, 18, 21, and 25‑day‑old rats and survival intervals of 4, 8, 12, 24, and 48 hours. Status epilepticus was induced via intraperitoneal (IP) injection of LiCl (3 mmol/kg) 24 hours before an injection of pilocarpine (40 mg/kg, IP). Motor seizures were suppressed by paraldehyde (0.3‑0.6 ml/kg, IP) two hours after status epilepticus onset. Animals were anesthetized using urethane and perfused with phosphate‑buffered saline followed by 4% paraformaldehyde. Brains were sectioned and Nissl stained for map guidance, with fluoro‑Jade B fluorescence used to detect degenerated neurons. Fluoro‑jade B‑positive neurons were plotted to a standard stereotaxic atlas, their distribution was quantified, and their long‑axis diameter was measured. Fluoro‑jade B‑positive neurons were found in pups aged 15 days and older 24 hours after status epilepticus, in which their numbers increased, and their perikaryon size decreased with advancing age. Thus, neuronal damage severity was dependent on age and survival interval. Neuronal damage was only found in the rostral sector of the zona incerta, a region that exhibits a small number of inhibitory neurons and is reciprocally connected to the limbic cortex. This system of hyperactivity, coupled with inhibitory neurons, may be the underlying cause of the neuronal degeneration and explain why it was confined to the rostral sector of the zona incerta.

Caffeine, a widely consumed psychoactive substance, may affect the neurotoxicity of environmental toxins. The study aimed to investigate the effects of the combined administration of caffeine and heavy metal compounds (cadmium chloride and lead acetate) on brain tissue function, focusing on memory processes and oxidative stress parameters. Adult male Swiss mice were administered substances intraperitoneally for 10 days. A passive avoidance test evaluated long‑term memory, while the Y‑maze assessed spatial working memory. In addition, lipid peroxidation and glutathione levels, as well as superoxide dismutase, catalase, and acetylcholinesterase activity, were determined in mouse brains. The results showed that exposure to caffeine and cadmium or lead caused different neurotoxic effects. Unlike lead, cadmium interacted with caffeine in memory tests. Caffeine protected mice against cadmium‑induced spatial working memory impairment. The combination of caffeine and cadmium impaired learning in the passive avoidance test. Cadmium and lead caused oxidative stress in the brain, and caffeine had a preventive effect against it. The study showed that co‑exposure to caffeine and cadmium could affect learning and memory. The antioxidant activity of caffeine may play a protective role in cadmium‑induced spatial memory impairment.

Individuals with neurocognitive disorders such as dementia of the Alzheimer's type (DAT) and frontotemporal lobar degeneration sometimes show characteristic language dysfunctions. As neurocognitive disorders progress, different types of aphasia may present. To evaluate the disease‑related changes of language functions, and to determine the correlation between the regional cerebral blood flow (rCBF) and language dyfunctions in patients with DAT or the behavioral variant of frontotemporal dementia (bvFTD) or semantic dementia (SD), we used a scale for speech and reading impairment in Japanese (the Standard Language Test for Aphasia [SLTA]), and perfusion single photon emission computed tomography, and we analyzed the relationships among them. Significant differences were identified among the DAT, SD, and bvFTD groups in the SLTA subscales concerning kanji (morphographic) words. There were positive correlations between the SLTA subscales concerning kanji words and the rCBF in left temporo‑occipital regions. The patients with bvFTD showed relative rCBF preservation in the posterior cerebrum compared with the DAT and SD patients. Our results indicate that aphasia for Japanese kanji words might be related to the dysfunction of temporo‑occipital regions, and they suggest that in patients with bvFTD, preserving the CBF in the posterior cerebrum might help maintain the ability to handle morphographic words such as kanji.

The polyphenolic compounds ferulic acid (FA) and p‑coumaric acid (PCA) have been extensively studied for their free radical scavenging and anti‑inflammatory properties. Both compounds are present in food and beverages commonly consumed globally. Our molecular modeling, in‑vitro, and in‑vivo studies suggest that the compounds may be neuroprotective by modulating the nucleotide‑binding domain, leucine‑rich‑containing family, pyrin domain‑containing‑3 (NLRP3) inflammasome pathway. The current study explored the dose‑dependent neuroprotective potential of FA and PCA in a chronic unpredictable mild stress (CUMS) mouse model. Male Swiss albino mice were divided into nine groups consisting of control (CON), CUMS, FA10 (10 mg/kg FA), FA40 (40 mg/kg FA), FA160 (160 mg/kg FA), PCA10 (10 mg/kg PCA), PCA40 (40 mg/kg PCA), PCA160 (160 mg/kg PCA), and FLX (10 mg/kg fluoxetine). All animals, except the CON group, received random mild stressors for 21 days, and from day 22‑42, the treatments were administered alongside the stressors. Behavioral assessments were performed on day 42, followed by sample collection. Brain homogenates from CUMS‑exposed animals expressed elevated levels of the pro‑inflammatory cytokines interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑alpha (TNF‑α), and oxidative stress markers. Treatment with FA and PCA effectively reduced cytokine release and oxidative stress, alleviating the depressive‑like behavior.

Spontaneous synaptic activity mediated by GABAA receptor is associated with epileptogenicity in focal cortical dysplasia (FCD). miRNAs are potentially involved in the regulation of GABAA receptor subunit expression and activity. This study aimed to determine the expression of miRNAs in FCD and correlate their expression level with mRNA levels of GABAA receptor subunits. Expression of GABAA receptor subunits (α1 and α4) and miRNAs (miR‑155‑5p, miR‑186‑5p, and miR‑24‑3p) were evaluated using real‑time PCR in resected brain samples from FCD patients. miRNA levels were also determined in the serum of FCD patients. Spontaneous GABAA receptor‑mediated synaptic activity was measured using patch clamp technique. Significant increase in α1 and α4 subunit expression and miR‑155‑5p levels, while decrease in miR‑24‑3p and miR‑186‑5p levels, was observed in the brain samples of FCD. In the serum of FCD patients, miR‑155‑5p levels were increased, whereas miR‑24‑3p and miR‑186‑5p levels remained unaltered. Increased α4 subunit expression in FCD might be due to reduced levels of miR‑24‑3p and miR‑186‑5p. In addition, reduced miR‑186‑5p levels might be responsible for increased expression of α1 subunit. We also observed an increase in the spontaneous GABAA receptor‑mediated synaptic transmission in FCD. In conclusion, dysregulation of miRNAs and GABAA receptor expression suggest that these miRNAs may contribute to altered GABAA receptor‑mediated synaptic activity in FCD.