Repetitive Transcranial Magnetic Stimulation Alleviates Neurological Deficits After Cerebral Ischemia Through Interaction Between RACK1 and BDNF exon IV by the Phosphorylation-Dependent Factor MeCP2.

Repetitive transcranial magnetic stimulation (rTMS) is acknowledged as a form of neurostimulation, especially for functional recovery. The foundational knowledge of molecular mechanism is limited regarding its role in cerebral ischemia, for which the present study was designed. Primary neurons were treated with oxygen-glucose deprivation (OGD) and repetitive magnetic stimulation (rMS), in which brain-derived neurotrophic factor (BDNF) and transcription of BDNF exons were examined. Then, adenovirus vectors carrying siRACK1 sequence were delivered to primary neurons, followed by detection of the transcription of BDNF exons and the extent of methyl CpG binding protein 2 (MeCP2) phosphorylation. Results showed that BDNF and the transcription of BDNF exons were upregulated by rMS and OGD treatment, but decreased by extra treatment of RACK1 siRNA. Then, the mechanism investigations demonstrated that rMS increased the extent of MeCP2 phosphorylation to promote the interaction between RACK1 and BDNF exon IV. The aforementioned findings were further confirmed in vivo in middle cerebral artery occlusion (MCAO)-induced rat models, as indicated by improved neurological functions and reduced area of cerebral infarction. The study offers potential evidence for improvement of neurological deficits, highlighting the important role of rTMS for treatment of cerebral ischemia.

Restraint devices for repetitive transcranial magnetic stimulation in mice and rats.

INTRODUCTION: Repetitive transcranial magnetic stimulation has been widely used for the treatment of neurological and psychiatric diseases. Rodent animals including mice and rats are often used to investigate the potential cellular and molecular mechanisms for the therapeutic effects of repetitive transcranial magnetic stimulation. So far there is no report about an easy-to-use device to restrain rodent animals for repetitive transcranial magnetic stimulation. METHODS AND RESULTS: We introduced the design and use of the restraint device for mice or rats. In the mouse device, western blot and real-time PCR analysis showed that，in stimulated mouse frontal cortex, 10 Hz high frequency stimulation for 10 sessions resulted in enhanced expression of NR2B-containing N-methyl-D-aspartic acid receptors and reduced α1 subunit of inhibitory GABAA receptors, whereas 0.5 Hz low frequency stimulation for 10 sessions caused decreased expression of NR2B subunit and increased α1 subunit of GABAA receptors. In the rat device, measures of motor evoke potentials indicated that 10 Hz stimulation for 10 sessions increased the excitability of stimulated cortex, whereas 0.5 Hz for 10 sessions reduced it. CONCLUSIONS: These results suggested the effectiveness of the devices. Thus, the two devices are practical and easy-to-use to investigate the mechanisms of repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation in combination with neuromuscular electrical stimulation for treatment of post-stroke dysphagia.

OBJECTIVE: This study was performed to determine whether repetitive transcranial magnetic stimulation (rTMS) combined with neuromuscular electrical stimulation (NMES) effectively ameliorates dysphagia and how rTMS protocols (bilateral vs. unilateral) combined with NMES can be optimized. METHODS: Sixty-four patients were randomly divided into four groups using a random distribution table: the sham rTMS plus NMES (Sham-rTMS/NMES), ipsilesional 10-Hz rTMS plus NMES (Ipsi-rTMS/NMES), contralesional 1-Hz rTMS plus NMES (Contra-rTMS/NMES), and bilateral rTMS plus NMES (Bi-rTMS/NMES) groups. Cortical excitability as measured by the amplitude of the motor evoked potential at the mylohyoid muscle cortical representative area, swallowing function as measured by the Standardized Swallowing Assessment, and the degree of dysphagia were evaluated at baseline, after the stimulation course, and at the 1-month follow-up. RESULTS: Bi-rTMS/NMES produced higher cortical excitability and better swallowing function recovery. Compared with NMES alone, unilateral rTMS plus NMES had additional effects on cortical excitability and rehabilitation of dysphagia, but there were no differences between the Contra-rTMS/NMES and Ipsi-rTMS/NMES groups. No adverse events occurred. CONCLUSION: The combination of rTMS with NMES was superior to NMES alone in improving the recovery of post-stroke dysphagia, and the combination of bilateral rTMS with NMES was more effective than unilateral rTMS combined with NMES.

The effect of bilateral low-frequency rTMS over dorsolateral prefrontal cortex on serum brain-derived neurotropic factor and serotonin in patients with generalized anxiety disorder.

To investigate the effect of bilateral low-frequency repetitive transcranial magnetic stimulation (rTMS) over dorsolateral prefrontal cortex on serum brain-derived neurotropic factor (BDNF) and serotonin (5-HT) in patients with generalized anxiety disorders (GAD). As compared with before treatment, the HARS score in patients markedly decreased after treatment, and the levels of serum BDNF and 5-HT were significantly higher. Pearson correlation analysis revealed that the increase in the level of serum 5-HT was positively associated with the increase of the level of serum BDNF, and the change of anxiety score was negatively associated with the change of the level of serum BDNF and 5-HT. The results suggested that alleviation of GAD by bilateral low-frequency rTMS may be involved in the increase of the level of BDNF and the release of 5-HT in the brain.

The role of S-nitrosylation of kainate-type of ionotropic glutamate receptor 2 in epilepsy induced by kainic acid.

Epilepsy is a chronic brain disease affecting millions of individuals. Kainate receptors, especially kainate-type of ionotropic glutamate receptor 2 (GluK2), play an important role in epileptogenesis. Recent data showed that GluK2 could undergo post-translational modifications in terms of S-nitrosylation (SNO), and affect the signaling pathway of cell death in cerebral ischemia-reperfusion. However, it is unclear whether S-nitrosylation of GluK2 (SNO-GluK2) contributes to cell death induced by epilepsy. Here, we report that kainic acid-induced SNO-GluK2 is mediated by GluK2 itself, regulated by neuronal nitric oxide synthase (nNOS) and the level of cytoplasmic calcium in vivo and in vitro hippocampus neurons. The whole-cell patch clamp recordings showed the influence of SNO-GluK2 on ion channel characterization of GluK2-Kainate receptors. Moreover, immunohistochemistry staining results showed that inhibition of SNO-GluK2 by blocking nNOS or GluK2 or by reducing the level of cytoplasmic calcium-protected hippocampal neurons from kainic acid-induced injury. Finally, immunoprecipitation and western blotting data revealed the involvement of assembly of a GluK2-PSD95-nNOS signaling complex in epilepsy. Taken together, our results showed that the SNO-GluK2 plays an important role in neuronal injury of epileptic rats by forming GluK2-PSD95-nNOS signaling module in a cytoplasmic calcium-dependent way, suggesting a potential therapeutic target site for epilepsy.

Association Between Serum Cystatin C Level and Total Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease in Patients With Acute Lacunar Stroke.

OBJECTIVE: Chronic kidney disease (CKD) is associated with cerebral small vessel disease (cSVD). However, the relationship between serum cystatin C (CysC) level, a highly sensitive marker of impaired kidney function, and cSVD has not been fully understood. This study aimed to investigate the association between serum CysC level and total burden of cSVD on magnetic resonance imaging (MRI) in patients with acute lacunar stroke. MATERIALS AND METHODS: A total of 210 patients with first-ever acute lacunar stroke occurring within 1 week after onset were included in this study. Serum CysC level, decreased estimated glomerular filtration rate (eGFR), and proteinuria were used to evaluate kidney function. The combined effect of the markers of cSVD on MRI, including lacunar, white matter lesions, cerebral microbleeds, and enlarged perivascular spaces, were used to evaluate the comprehensive cSVD burden. RESULTS: There is a positive association between total cSVD burden and hypertension, low eGFR level, and serum CysC level. After adjustments for potential confounders by ordinal logistic regression, elevated levels of CysC as well as impaired eGFR and the presence of proteinuria were correlated with the burden of total cSVD (odds ratio [OR] 2.633, 95% confidence interval [CI] 1.284-5.403; OR 2.442, 95% CI 1.213-4.918; and OR 2.151, 95% CI 1.162-3.983, respectively). CONCLUSIONS: The elevated level of serum CysC is associated with the total burden of cSVD in patients with acute lacunar stroke independent of conventional risk factors.