Changes in Resting-State Neural Activity and Nerve Fibres in Ischaemic Stroke Patients with Hemiplegia.

Many neuroimaging studies have reported that stroke induces abnormal brain activity. However, little is known about resting-state networks (RSNs) and the corresponding white matter changes in stroke patients with hemiplegia. Here, we utilized functional magnetic resonance imaging (fMRI) to measure neural activity and related fibre tracts in 14 ischaemic stroke patients with hemiplegia and 12 healthy controls. Fractional amplitude of low-frequency fluctuations (fALFF) calculation and correlation analyses were used to assess the relationship between regional neural activity and movement scores. Tractography was performed using diffusion tensor imaging (DTI) data to analyse the fibres passing through the regions of interest. Compared with controls, stroke patients showed abnormal functional connectivity (FC) between some brain regions in the RSNs. The fALFF was increased in the contralesional parietal lobe, with the regional fALFF being correlated with behavioural scores in stroke patients. Additionally, the passage of fibres across regions with reduced FC in the RSNs was increased in stroke patients. This study suggests that structural remodelling of functionally relevant white matter tracts is probably an adaptive response that compensates for injury to the brain.

N-Butylphthalide vs. Human Urinary Kallidinogenase for the Treatment of Acute Ischemic Stroke: Functional Outcome and Impact on Serum VEGF and TNF-α Expressions.

OBJECTIVE: To compare the e!cacy and functional outcomes of dl-3-n-Butylphthalide (NBP) and human urinary kallidinogenase (HUK) on ischemic stroke patients and to determine their effects on serum tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF). METHODS: A prospective study was conducted on 57 ischemic stroke patients. Functional outcomes were assessed by the National Institute Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the activities of daily living score (ADL), whereas TNF-α and VEGF expressions were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: TNF-α was significantly down-regulated in the NBP group and upregulated in the control group two weeks after treatment (p=0.017 and p=0.047, respectively). A significant difference in VEGF expressions was observed between the two groups (330.25±120.64 vs. 437.15±137.68, p=0.041) two weeks after treatment. Both groups showed significant improvement in NIHSS and ADL scores three months after treatment (p<0.001), with the NBP group exhibiting improvement in NIHSS scores as early as two weeks after treatment (p=0.008). The three-month NIHSS scores of the two groups were significantly lower than those of the control group (p=0.010 and p=0.008, respectively). Both the NBP and HUK groups showed a significant decline in mRS scores two weeks and three months after treatment (p<0.05). CONCLUSIONS: Both treatments are effective and can significantly promote recovery in stroke patients. Additionally, both options have similar effects in promoting long-term recovery, with NBP exerting a greater impact on serum VEGF and TNF-α expressions.

White matter degeneration in remote brain areas of stroke patients with motor impairment due to basal ganglia lesions.

Diffusion tensor imaging (DTI) studies have revealed distinct white matter (WM) characteristics of the brain following diseases. Beyond the lesion-symptom maps, stroke is characterized by extensive structural and functional alterations of brain areas remote to local lesions. Here, we further investigated the structural changes over a global level by using DTI data of 10 ischemic stroke patients showing motor impairment due to basal ganglia lesions and 11 healthy controls. DTI data were processed to obtain fractional anisotropy (FA) maps, and multivariate pattern analysis was used to explore brain regions that play an important role in classification based on FA maps. The WM structural network was constructed by the deterministic fiber-tracking approach. In comparison with the controls, the stroke patients showed FA reductions in the perilesional basal ganglia, brainstem, and bilateral frontal lobes. Using network-based statistics, we found a significant reduction in the WM subnetwork in stroke patients. We identified the patterns of WM degeneration affecting brain areas remote to the lesions, revealing the abnormal organization of the structural network in stroke patients, which may be helpful in understanding of the neural mechanisms underlying hemiplegia.

Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model.

Background: Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods: To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results: Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-ß and NMDAR2-α subtypes as well as their downstream signaling proteins ß-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of ß-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-ß association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions: These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.

A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy.

Mutations in the DNAJB6 gene have been identified as rare causes of myofibrillar myopathies. However, the underlying pathophysiologica mechanisms remain elusive. DNAJB6 has two known isoforms, including the nuclear isoform DNAJB6a and the cytoplasmic isoform DNAJB6b, which was thought to be the pathogenic isoform. Here, we report a novel recessive mutation c.695_699del (p. Val 232 Gly fs*7) in the DNAJB6 gene, associated with an apparently recessively inherited late onset distal myofibrillar myopathy in a Chinese family. Notably, the novel mutation localizes to exon 9 and uniquely encodes DNAJB6a. We further identified that this mutation decreases the mRNA and protein levels of DNAJB6a and results in an age-dependent recessive toxic effect on skeletal muscle in knock-in mice. Moreover, the mutant DNAJB6a showed a dose-dependent anti-aggregation effect on polyglutamine-containing proteins in vitro. Taking together, these findings reveal the pathogenic role of DNAJB6a insufficiency in myofibrillar myopathies and expand upon the molecular spectrum of DNAJB6 mutations.

Melatonin Ameliorates Lipopolysaccharide-Induced Microglial Inflammation via Triggering SIRT1/HMGB1 Signaling Axis.

Stroke is one of the highest incidence neurological disorder with great morbidity and mortality rate. The secondary neuroinflammation contributed by microglial activation is a consequential response observed in the pathogenesis of stroke. High-mobility group box 1, a non-histone nuclear protein, interacts with immune cells, such as microglia, and leads to a cascade amplification of the secondary neuroinflammatory responses, which are related to neuronal damage later. Melatonin is a neurohormone, well-known as its anti-oxidative and anti-inflammatory effects. However, until now, more findings are required for better understanding about anti-inflammatory effect of melatonin on HMGB1 and HMGB1-triggered pathway in LPS-induced microglial activation. Melatonin effect on the viability of BV2 microglial cells was measured by CCK-8 assay; mRNA levels of HMGB1 and other inflammatory cytokines were determined by quantitative real-time polymerase chain reaction assay or enzyme-linked immunosorbent assays; the protein expression levels of TLR4/MyD88/NF-κB and SIRT1 were detected by Western blot, and HMGB1 translocation and release from BV2 microglial cells were examined by immunofluorescence assay. The results of this study demonstrated that melatonin suppressed LPS-triggered BV2 microglial activation-mediated inflammation by inhibiting high expression and release of HMGB1 and moderating the activation of subsequent TLR4/MyD88/NF-κB signaling pathway, which was activated by SIRT1 elevation. Furthermore, LPS-induced expression of pro-inflammatory cytokines (i.e., TNF-α, IL-6, and IL-1ß) was notably reversed by melatonin pre-treatment. In summary, our findings suggest that melatonin may act as a promising therapeutic agent for reducing post-stroke neuroinflammation by targeting HMGB1 and the subsequent signaling axis.

A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives.

The research of alternative treatment for ischemic stroke and degenerative diseases has always been a priority in neurology. 3-N-Butylphthalide (NBP), a family of compounds initially isolated from the seeds of Apium graveolens Linn., has shown significant neuroprotective effects. Previous extensive studies have demonstrated that NBP promotes a better poststroke outcome and exerts a multitargeted action on several mechanisms, from oxidative stress to mitochondrial dysfunction to apoptosis to inflammation. Additionally, recent findings on several neurological disorders have shown that NBP's beneficial effects extend beyond the management of stroke. However, despite the increasing number of studies toward a better understanding and the rapid advances made in therapeutic options, to date, dl-3-N-butylphthalide, a synthetic variation of l-3-N-butylphthalide, remains the only clinically approved anti-ischemic agent in China, stressing the difficulties for a viable and effective transition from experimental to clinical practice. Events indicate that NBP, due to its multitargeted effect and the adaptability of its basic structure, can be an important game changer and a precursor to a whole new therapeutic approach to several neurological conditions. The present review discusses recent advances pertaining to the neuroprotective mechanisms of NBP-derived compounds and the possibility of their clinical implementation in the management of various neurological conditions.