CNS Neuroscience and Therapeutics

This study investigated whether anticerebral ischemia new drug, l‐3‐n‐butylphthalide (l‐NBP), improved behavioral recovery and enhanced hippocampal neurogenesis after cerebral ischemia in rats.

The middle cerebral artery of rats was blocked for 2 h. The daily oral administrations of 30 mg/kg l‐NBPor vehicle were begun from the second day until the rats were sacrificed. L‐NBPtreatment markedly increased 5‐bromo‐2′‐deoxyuridine (BrdU)‐positive cells in the hippocampal dentate gyrus (DG) of injured hemisphere on day 28 after ischemia. The amount of newborn cells and newly mature neurons was also increased. The expressions of growth‐associated protein‐43 and synaptophysin were significantly elevated in l‐NBP‐treated rats. However, l‐NBPmarkedly reduced the percentage of BrdU⁺/GFAP⁺cells. Additionally, the levels of catalytical subunit of protein kinase A (PKA), protein kinase B (Akt), andcAMPresponse element‐binding protein (CREB) were significantly increased, and the activation of the signal transducer and activation of transcription 3 (STAT3) and the expressions of cleaved caspase‐3 and Bax were obviously inhibited by l‐NBP. Consequently, l‐NBPattenuated the behavioral dysfunction.

It first demonstrates that l‐NBPmay improve the behavioral outcome of cerebral ischemia by promoting neurogenesis and neuroplasticity. Activation ofCREBand Akt and inhibition ofSTAT3 signaling might be involved in.

This study investigated the neuroprotective properties of icariin (an effective component of traditional Chinese herbal medicine Epimedium) on neuronal function and brain energy metabolism maintenance in a triple‐transgenic mouse model of Alzheimer's disease (3 × Tg‐AD).

3 × Tg‐AD mice as well as primary neurons were subjected to icariin treatment. Morris water maze assay, magnetic resonance spectroscopy (MRS), Western blotting, ELISA, and immunohistochemistry analysis were used to evaluate the effects of icariin administration.

Icariin significantly improved spatial learning and memory retention in 3 × Tg‐AD mice, promoted neuronal cell activity as identified by the enhancement of brain metabolite N‐acetylaspartate level and ATP production in AD mice, preserved the expressions of mitochondrial key enzymes COX IV, PDHE1α, and synaptic protein PSD95, reduced Aβ plaque deposition in the cortex and hippocampus of AD mice, and inhibited β‐site APP cleavage enzyme 1 (BACE1) expression. Icariin treatment also decreased the levels of extracellular and intracellular Aβ1‐42 in 3 × Tg‐AD primary neurons, modulated the distribution of Aβ along the neurites, and protected against mitochondrial fragmentation in 3 × Tg‐AD neurons.

Icariin shows neuroprotective effects in 3 × Tg‐AD mice and may be a promising multitarget drug in the prevention/protection against AD.

Great interest persists in useful therapeutic targets in glioblastoma (GBM). Deregulation of microRNAs (miRNAs) expression has been associated with cancer formation through alterations in gene targets. In this study, we reported the role of miR‐101 in human glioblastoma stem cells (GSCs) and the potential mechanisms.

Quantitative real‐time PCR showed that miR‐101 expression was decreased in GSCs. Overexpression of miR‐101 reduced the proliferation, migration, invasion, and promoted apoptosis of GSCs. One direct target of miR‐101, the transcription factor Kruppel‐like factor 6 (KLF6), was identified using the Dual‐Luciferase Reporter Assay System, which mediated the tumor suppressor activity of miR‐101. This process was coincided with the reduced expression of Chitinase‐3‐like protein 1 (CHI3L1) whose promoter could be bound with and be promoted by KLF6 demonstrated by luciferase assays and chromatin immunoprecipitation assays. The downregulation of CHI3L1 led to the inactivation of MEK1/2 and PI3K signal pathways. Furthermore, nude mice carrying the tumors of overexpressed miR‐101 combined with knockdown of KLF6 produced the smallest tumors and showed the highest survival rate.

Our findings provided a comprehensive analysis of miR‐101 and further defining it as a potential therapeutic candidate for GBM.

Ferroptosis, a new form of iron‐dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model.

After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro‐Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin‐1(fer‐1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long‐term outcomes.

TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis‐related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid‐reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer‐1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long‐term motor and cognitive function.

This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.

Long noncoding RNAs (lncRNAs) play a key role in regulating immunological functions. Their impact on the chronic inflammatory disease multiple sclerosis (MS), however, remains unknown. We investigated the expression of lncRNAs in peripheral blood mononuclear cells (PBMCs) of patients with MS and attempt to explain their possible role in the process of MS.

For this study, we recruited 26 patients with MS according to the revised McDonald criteria. Then, we randomly chose 6 patients for microarray analysis. Microarray assays identified outstanding differences in lncRNA expression, which were verified through real‐time PCR. LncRNA functions were annotated for target genes using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and regulatory relationships between lncRNAs and target genes were analyzed using the “cis” and “trans” model.

There were 2353 upregulated lncRNAs, 389 downregulated lncRNAs, 1037 upregulated mRNAs, and 279 downregulated mRNAs in patients with MS compared to healthy control subjects (fold change >2.0). Real‐time PCR results of six aberrant lncRNAs were consistent with the microarray data. The coexpression network comprised 864 lncRNAs and 628 mRNAs. Among differentially expressed lncRNAs, 10 lncRNAs were predicted to have 10 cis‐regulated target genes, and 33 lncRNAs might regulate their trans target genes.

We identified a subset of dysregulated lncRNAs and mRNAs. The differentially expressed lncRNAs may be important in the process of MS. However, the specific molecular mechanisms and biological functions of these lncRNAs in the pathogenesis of MS need further study.

Huntington's disease (HD) is an autosomal dominant disorder, for which clinically available drugs offer only symptomatic relief. These prescription drugs are not free of side effects, and the patients usually suffer from anxiety and depression. We investigated quercetin, a dietary flavonoid with free radical scavenging properties, for its beneficial potential if any, in 3‐nitropropionic acid (3‐NP)‐induced HD in rats where both drugs were administered simultaneously.

Performance of rats on beam balancing, elevated plus maze and gait traits were investigated following 3‐NP and/or quercetin treatments for 4 days. Striatal biogenic amine levels and monoamine oxidase activity were assayed. Striatal sections were examined for Cd11B and glial fibrillary acidic protein immunoreactivity, and for evidences of neuronal lesion.

Quercetin significantly attenuated 3‐NP‐induced anxiety, motor coordination deficits, and gait despair. While the dopaminergic hyper‐metabolism was unaffected, quercetin provided a significant reduction of 3‐NP mediated increase in serotonin metabolism. Quercetin failed to affect 3‐NP‐induced striatal neuronal lesion, but decreased microglial proliferation, and increased astrocyte numbers in the lesion core.

These results taken together suggest that quercetin could be of potential use not only for correcting movement disturbances and anxiety in HD, but also for addressing inflammatory damages.

Microglia and infiltrated macrophages play important roles in inflammatory processes after ischemic stroke. Modulating microglia/macrophage polarization from pro‐inflammatory phenotype to anti‐inflammatory state has been suggested as a potential therapeutic approach in the treatment of ischemic stroke. Melatonin has been shown to be neuroprotective in experimental stroke models. However, the effect of melatonin on microglia polarization after stroke and underlying mechanisms remain unknown.

In vivo, cerebral ischemia was induced by distal middle cerebral artery occlusion (dMCAO) in C57BL/6J mice. Melatonin was injected intraperitoneally (20 mg/kg) at 0 and 24 hours after ischemia. In vitro, the microglial cell line BV2 was stimulated to the pro‐inflammatory state with conditioned media (CM) collected from oxygen‐glucose deprivation (OGD) challenged neuronal cell line Neuro‐2a (N2a). Real‐time PCR was utilized to detect the mRNA expression of microglia phenotype markers. Activation of signal transducer and activator of transcription 3 (STAT3) pathway was determined by Western blot of phosphorylated STAT3 (pSTAT3). A neuron‐microglia co‐culture system was used to determine whether melatonin can inhibit the neurotoxic effect of pro‐inflammatory microglia to post‐OGD neurons.

Melatonin treatment reduced brain infarct and improved neurological functions 3 days after dMCAO, which was accompanied by decreased expression of pro‐inflammatory markers and increased expression of anti‐inflammatory markers in the ischemic brain. In vitro studies confirmed that melatonin directly inhibited the pro‐inflammatory responses in BV2 cells upon exposure to OGD neuron CM. The microglia possessing pro‐inflammatory phenotype exacerbated post‐OGD N2a cells death, whereas melatonin reduced such neurotoxic effect. Further, melatonin enhanced the otherwise inhibited pSTAT3 expression in BV2 cells treated with OGD neuron CM. STAT3 blockade significantly reduced the effect of melatonin on microglial phenotype shift. Conclusion: Melatonin treatment ameliorates brain damage at least partially through shifting microglia phenotype from pro‐inflammatory to anti‐inflammatory polarity in a STAT3‐dependent manner.