Nanchang Xie

Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial

Aim: To investigate the efficacy, safety and tolerability of intradermal and/or submucosal administration of botulinum toxin type A (BTX-A) for patients with trigeminal neuralgia (TN). Methods: In this randomized, double-blind, placebo-controlled study, 42 TN patients were randomly allocated into two groups, namely, intradermal and/or submucosal injection of BTX-A (75 U/1.5 mL; n = 22) or saline (1.5 mL; n = 20) in the skin and/or mucosa where pain was experienced. The primary endpoints were pain severity (assessed by the visual analogue scale) and pain attack frequency per day. The secondary endpoint was the patient’s overall response to treatment, assessed using the Patient Global Impression of Change scale. Patients with ≥ 50% reduction in mean pain score at week 12 were defined as responders. Results: A total of 40 patients completed the study. BTX-A significantly reduced pain intensity at week 2 and pain attack frequency at week 1. The efficacy was maintained throughout the course of the study. More BTX-A treated patients reported that pain had improved by the end of the study. Significantly more responders were present in the BTX-A group (68.18%) than in the placebo group (15.00%). BTX-A was well tolerated, with few treatment-related adverse events. Conclusions: BTX-A may be an efficient, safe and novel strategy for TN treatment.

A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats

Mdivi-1 is a selective inhibitor of a mitochondrial fission protein Drp1. Recent studies demonstrated that inhibition of Drp1 provides neuroprotection in vitro and in vivo. In this study, we examined the role of mdivi-1 in hippocampal neuron death after seizures induced by pilocarpine. Our data showed that pretreatment with mdivi-1 (1.25 mg/kg) significantly attenuated the neuronal death in hippocampus induced by seizures. This neuroprotective effect was dose-dependent. In addition, the seizures resulted in up-regulation of Drp1 expression and mdivi-1 treatment had no effect on the expression. Moreover, we also found that mdivi-1 (1.25 mg/kg) treatment reversed the release of cytochrome c (CytC), translocation of apoptosis-inducing factor (AIF) induced by seizures while inhibiting the activated caspase-3. Altogether, our data suggested that mdivi-1 exerts neuroprotective effects against cell death of hippocampal neurons induced by seizures, and the underlying mechanism may be through inhibiting CytC release, AIF translocation and suppression of the mitochondrial apoptosis pathway.

Curcumin Improves Amyloid β-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway

Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects. Previous studies have suggested that curcumin reduces the levels of amyloid and oxidized proteins and prevents memory deficits and thus is beneficial to patients with Alzheimer’s disease (AD). However, the molecular mechanisms underlying curcumin’s effect on cognitive functions are not well-understood. In the present study, we examined the working memory and spatial reference memory in rats that received a ventricular injection of amyloid-β1-42 (Aβ1-42), representing a rodent model of Alzheimer’s disease (AD). The rats treated with Aβ1-42 exhibited obvious cognitive deficits in behavioral tasks. Chronic (seven consecutive days, once per day) but not acute (once a day) curcumin treatments (50, 100, and 200 mg/kg) improved the cognitive functions in a dose-dependent manner. In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus. Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor. These findings suggest that chronic curcumin ameliorates AD-related cognitive deficits and that upregulated BDNF-ERK signaling in the hippocampus may underlie the cognitive improvement produced by curcumin.

Inhibition of mitochondrial fission attenuates Aβ-induced microglia apoptosis.

Mitochondrial division inhibitor 1 (mdivi-1), a selective inhibitor of mitochondrial fission protein dynamin-related protein 1 (Drp1), has been reported to display neuroprotective properties in different animal models. In the present study, we investigated the protective effect of mdivi-1 on β-amyloid protein (Aβ)-induced cytotoxicity and its potential mechanisms in BV-2 and primary microglial cells. We found that mitochondrial fission was increased in Aβ treatment and inhibition of mitochondrial fission by mdivi-1 significantly reduced Aβ-induced expression of CD11b (a marker of microglial activation), viability loss and apoptotic rate increase in BV-2 and primary microglial cells. Moreover, we also found that mdivi-1 treatment markedly reversed mitochondrial membrane potential loss, cytochrome c (CytC) release and caspase-3 activation. Altogether, our data suggested that mdivi-1 exerts neuroprotective effects against Aβ-induced microglial apoptosis, and the underlying mechanism may be through inhibiting mitochondrial membrane potential loss, CytC release and suppression of the mitochondrial apoptosis pathway.

Puerarin Protects Hippocampal Neurons Against Cell Death in Pilocarpine-Induced Seizures Through Antioxidant and Anti-Apoptotic Mechanisms

Puerarin extracted from Radix puerariae has been shown to exert neuroprotective effects. However, it is still not known whether puerarin protects hippocampal neurons against cell death in pilocarpine-induced seizures. In this study, we found that pretreatment with puerarin significantly attenuated the neuronal death in the hippocampus of rats with pilocarpine-induced epilepsy. In addition, puerarin decreased the level of seizure-induced reactive oxygen species in mitochondria isolated from the rat hippocampi. Terminal deoxyuridine triphosphate nick-end labeling staining showed that puerarin exerted an anti-apoptotic effect on the neurons in the epileptic hippocampus. Western blot analysis showed that puerarin treatment significantly decreased the expression of Bax and increased the expression of Bcl-2. Moreover, puerarin treatment restored the altered mitochondrial membrane potential and cytochrome c release from the mitochondria in the epileptic hippocampi. Altogether, the findings of this study suggest that puerarin exerts a therapeutic effect on epilepsy-induced brain injury through antioxidant and anti-apoptotic mechanisms.

Botulinum Toxin A for the Treatment of a Child with SUNCT Syndrome

Background. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome is an unusual cause of headache, mainly described in older adults, and is rare in children. Pain attacks may be severe, frequent, and prolonged. The therapeutic benefits of many drugs are disappointing. Patient and Methods. A 12-year-old boy suffered severe headache and toothache for 20 days. As treatment with nonsteroidal anti-inflammatory drugs, anticonvulsants, and steroids proved ineffective, he was treated with ipsilateral multisite subcutaneous injections of botulinum toxin A 70 U around the orbit, the temporal area, and the upper gum. Results. The pain had reduced in frequency and severity by the fourth day after treatment and had completely disappeared after 7 days. There were no side effects or recurrence during a subsequent 17-month follow-up period. Conclusion. Botulinum toxin A can be used to treat the first episode of SUNCT in children over the age of 12 years.

Aminophylline for treatment of postdural puncture headache: A randomized clinical trial

Objective To investigate the efficacy and safety of IV aminophylline for patients with postdural puncture headache (PDPH). Methods We randomly assigned patients to groups receiving either 250 mg IV aminophylline or a placebo within 3 hours of symptom onset once daily for 2 consecutive days. The primary endpoint was headache severity 8 hours after treatment. We assessed this using visual analog scale (VAS) scores taken from patients in a standing position. We also recorded posttreatment VAS score changes, Patient Global Impression of Change (PGIC) scores, and adverse events. We performed an intention-to-treat analysis. Results We enrolled 126 patients with PDPH at 5 centers in China (62 assigned to the aminophylline group and 64 to the placebo group). The median age was 37 years, and 96 (76.2%) patients were women. Compared to the placebo-treated patients, the aminophylline-treated patients had significantly lower mean VAS scores 8 hours after treatment (5.34 vs 2.98, p < 0.001) and were significantly more likely to report improvements on the PGIC (39.1% vs 72.6%, p < 0.01). This therapeutic effect was already evident at the 30-minute time point and persisted for 2 days. There was no significant difference in the incidence of adverse events (4.8% vs 1.6%, p = 0.589). Conclusions IV aminophylline is an effective and safe early-stage treatment for patients with PDPH. ClinicalTrials.gov identifier NCT02522013. Classification of evidence This study provides Class I evidence that for people with PDPH, IV aminophylline reduces headache severity.

Association between small intestinal bacterial overgrowth and deep vein thrombosis in patients with spinal cord injuries.

Essentials Gastrointestinal dysfunction and vein thrombosis are complications after spinal cord injuries (SCI). We assess the deep vein thrombosis (DVT) and small intestinal bacterial overgrowth (SIBO) in SCI. 76 of the 377 SCI patients were DVT positive (20.2%) and 145 were defined as SIBO positive (38.5%). This study defines an association between SIBO and DVT in patient with SCI.

Inhibition of the mitochondrial calcium uniporter inhibits Aβ-induced apoptosis by reducing reactive oxygen species-mediated endoplasmic reticulum stress in cultured microglia

Amyloid-beta (Aβ) has been shown to induce microglial apoptosis, which is itself sensitive to disturbed mitochondrial calcium (Ca2+) homeostasis. The mitochondrial calcium uniporter (MCU) plays an important regulatory role in mitochondrial Ca2+ homeostasis, but its role in Aβ-induced microglia apoptosis is unknown. In this study, we found increased mitochondrial Ca2+ concentration in Aβ-treated primary microglia and BV-2 cells; also, the MCU inhibitor Ru360 significantly attenuated Aβ-induced microglial apoptosis, whereas the MCU activator spermine augmented it. In addition, Ru360 significantly attenuated Aβ-induced mitochondrial reactive oxygen species (ROS) production, as well as endoplasmic reticulum (ER) stress characterized by glucose-regulated protein 78 (GRP78) and C/-EBP homologous protein (CHOP) expression. Spermine, however, exerted the opposite effects on mitochondrial ROS production and ER stress. We also found that mitochondria-targeted antioxidant (Mito-TEMPO) treatment decreased GRP78 and CHOP expression in Aβ-treated microglia. Moreover, blocking endogenous CHOP expression using a CHOP small interfering RNA (siRNA) attenuated Aβ-induced cell death. Altogether, our data suggested that 1) inhibition of MCU exerts a neuroprotective effect on Aβ-induced microglia apoptosis, and 2) that the underlying mechanism may be related to reducing mitochondrial ROS-mediated ER stress.

Elevated trimethylamine N-oxide related to ischemic brain lesions after carotid artery stenting

Objectives To investigate whether the plasma level of trimethylamine N-oxide (TMAO), a proatherosclerotic intestinal microbiota metabolite, can be a predictor of ischemic brain injury secondary to carotid artery stenting (CAS). Methods In this multicenter, prospective cohort study, we enrolled patients with severe carotid artery stenosis (>70%) who were prepared for CAS. Plasma TMAO level was measured within 3 days before CAS, and MRI was performed 1 to 3 days after CAS. Results The mean age of the 268 eligible patients was 64.4 years. New lesions on diffusion-weighted imaging (DWI) were detected in 117 patients (43.7%). TMAO level was higher in patients with new (DWI) lesions than in patients without new lesions (median 5.2 vs 3.2 µmol/L; p < 0.001). Increased plasma TMAO levels were associated with an increased risk of having new lesions on DWI after CAS (adjusted odds ratio for the highest vs lowest quartile, 3.85; 95% confidence interval, 1.37–7.56, p < 0.001; adjusted odds ratio for the third vs lowest quartile, 1.86; 95% confidence interval, 1.09–4.66, p = 0.02). The area under the receiver operating characteristic curve of TMAO was 0.706 for new lesions on DWI, and the optimal cutoff value was 4.29 µmol/L. The sensitivity, specificity, positive predictive value, and negative predictive value of TMAO levels ≥4.29 µmol/L for predicting new lesions on DWI were 61.5%, 74.8%, 65.5%, and 65.5%, respectively. Conclusions Increased TMAO levels are associated with an increased risk of new ischemic brain lesions on post-CAS MRI scans.