Weiwei Qi

Curcumin inhibits Aβ-induced microglial inflammatory responses in vitro: Involvement of ERK1/2 and p38 signaling pathways

Amyloid β (Aβ) plays an important role in Alzheimers disease (AD) by inducing microglia activation. Once activated, microglial cells promote the release of reactive species and cytokines that are known to enhance immune responses in AD brain. Thus, negative regulators of microglia activation are considered as potential therapeutic candidates for AD. Curcumin, the major yellow pigment in turmeric (Curcuma longa), is proposed for its anti-inflammatory properties. Several studies have indicated the suppressive effects of curcumin on LPS-induced microglia activation and MAPK activities. However, the effects of curcumin on Aβ-treated microglia and the possible mechanisms are still not fully understood. In the present study, we found that curcumin improved microglial viability against Aβ42 in a time- and dose-dependent manner and remarkably suppressed Aβ42-induced CD68 expression. Moreover, curcumin concentration-dependently abolished Aβ42-induced interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production in mRNA and protein levels in microglia. Besides, curcumin exerted an inhibitory effect on phosphorylation of ERK1/2 and p38 in Aβ42-activated microglia. Further experiments indicated that blockage of ERK1/2 and p38 pathways reduced inflammatory cytokines production from microglia. These results show that curcumin suppresses ERK1/2 and p38 signaling, thus, attenuating inflammatory responses of brain microglia.

A Randomized, One‐Year Clinical Trial Comparing the Efficacy of Topiramate, Flunarizine, and a Combination of Flunarizine and Topiramate in Migraine Prophylaxis

OBJECTIVES The objective of this study was to observe the efficacy, safety, and side effects of a combination of flunarizine plus topiramate compared with either flunarizine and or toparamate alone for migraine prophylaxis. METHODS Out of 150 patients with migraine recruited into the study and randomly assigned to one of three conditions, 126 completed the trial in their group: flunarizine (39), topiramate (44), and flunarizine plus topiramate (43). Patient information was assessed at enrollment and at follow-up visits at the end of months 1-3, 6, 9, and 12. The primary measure of efficacy reduction in mean monthly migraine frequency of at least 50% as compared with baseline. Secondary efficacy parameters included reduction in mean monthly migraine days and severity of headache. Side effects were compared in the three groups by recording adverse reactions and weight changes. RESULTS The proportion whose monthly headache frequency decreased more than 50% was 66.7% (26/39) in the flunarizine group, 72.7% (32/44) in the topiramate group and 76.7% (33/43) in the combination group, respectively (P=0.593). The mean monthly days and severity of headache in the three groups also declined and was more significant in the flunarizine plus topiramate group than in the flunarizine group and the topiramate group (P<0.05). In the flunarizine group, the average weight change was 0.6kg. Topiramate was associated with a mean weight loss was of -0.9kg in the topiramate group and -0.2kg in the flunarizine plus topiramate group. CONCLUSION Flunarizine, topiramate, and the combination of flunarizine with topiramate are all effective and have good tolerability in migraine prophylaxis. Adding topiramate to flunarizine may reduce the latters impact on body weight.

Pleiotrophin promotes microglia proliferation and secretion of neurotrophic factors by activating extracellular signal-regulated kinase 1/2 pathway

Pleiotrophin (PTN) is an effective neuroprotective factor and its expression is strikingly increased in microglia after ischemia/reperfusion injury. However, whether PTN could provide neurotrophic support to neurons by regulating microglia function is not clear. In this study, we demonstrated that the expression of PTN was induced in microglia after oxygen-glucose deprivation/reperfusion. PTN promoted the proliferation of microglia by enhancing the G1 to S phase transition. PTN also stimulated the secretion of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and nerve growth factor (NGF) in microglia, but did not upregulate the expression of proinflammatory factors such as TNF-α, IL-1β and iNOS. Mechanistically, we found that PTN increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in microglia in both concentration-dependent and time-dependent manners. In addition, ERK1/2 inhibitor U0126 abolished the proliferation and G1 to S phase transition of microglia stimulated by PTN, and inhibited the production of BDNF, CNTF and NGF induced by PTN. In conclusion, our results demonstrated that PTN-ERK1/2 pathway plays important role in regulating microglia growth and secretion of neurotrophic factors. These findings provide new insight into the neuroprotective role of PTN and suggest that PTN is a new target for therapeutic intervention of stroke.

Telomerase: A Target for Therapeutic Effects of Curcumin and a Curcumin Derivative in Aβ1-42 Insult In Vitro

This study was designed to investigate whether telomerase was involved in the neuroprotective effect of curcumin and Cur1. Alzheimers disease is a consequence of an imbalance between the generation and clearance of amyloid-beta peptide in the brain. In this study, we used Aβ1-42 (10 µg/ml) to establish a damaged cell model, and curcumin and Cur1 were used in treatment groups. We measured cell survival and cell growth, intracellular oxidative stress and hTERT expression. After RNA interference, the effects of curcumin and Cur1 on cells were verified. Exposure to Aβ1–42 resulted in significant oxidative stress and cell toxicity, and the expression of hTERT was significantly decreased. Curcumin and Cur1 both protected SK-N-SH cells from Aβ1–42 and up-regulated the expression of hTERT. Furthermore, Cur1 demonstrated stronger protective effects than curcumin. However, when telomerase was inhibited by TERT siRNA, the neuroprotection by curcumin and Cur1 were ceased. Our study indicated that the neuroprotective effects of curcumin and Cur1 depend on telomerase, and thus telomerase may be a target for therapeutic effects of curcumin and Cur1.

White matter lesions in chronic migraine with medication overuse headache: a cross-sectional MRI study.

Analgesic overuse often happens to migraine patients, especially chronic migraineurs, and migraine has been demonstrated to be associated with white matter lesions (WMLs). The aim of this study was to investigate the relationship between medication overuse headache (MOH) and WMLs in chronic migraine (CM) patients. Subjects were enrolled and divided into three groups: healthy controls, CM without MOH (CMwoMOH), and CM with MOH (CM-MOH). Most of the CM patients used non-steroidal anti-inflammatory drugs (NSAIDs) as acute headache medications. All the participants underwent magnetic resonance imaging scans and images were obtained for WML evaluation with semiquantitative scales. One hundred and forty-one participants were included, 45 of them for controls, 38 for CMwoMOH, and 58 for CM-MOH. In women, CMwoMOH patients had a higher prevalence of high WML load compared with controls and CM-MOH patients. In men, however, all the study groups showed no differences in the prevalence of high WML load. CMwoMOH women had increased risks of high deep white matter lesion (DWML) load compared with controls, while they had no risks of high periventricular white matter lesion (PVWML) load. CM-MOH women had no risks of high DWML load, but they had reduced risks of high PVWML load. The association of CM-MOH with high WML load in women was not changed when compared with CMwoMOH. Age was independently associated with high WML load among women. These data suggest that MOH caused by NSAIDs is not a risk factor for WMLs. Rather, NSAID overuse probably protects MOH patients from WMLs through anti-inflammatory effects.

Pregabalin alleviates the nitroglycerin-induced hyperalgesia in rats.

The association between the clinical use of nitroglycerin (NTG) and migraine suggests NTG as an animal model trigger for migraine. NTG-induced hyperalgesia in rats has been extensively used as a migraine model for pre-clinical research. Pregabalin is an anti-epileptic drug and may play a role in the preventive treatment of migraine; however, the mechanism of this action remains to be clarified. Herein, we performed the present study to investigate the effect of pregabalin on the NTG-induced hyperalgesia in rats. Sixty male Sprague-Dawley rats were divided equally into six groups. Thirty minutes before NTG injection, the rats were pretreated with pregabalin. von Frey hair testing was employed to evaluate tactile sensitivity. Enzyme-linked immunosorbent assay was used to analyze plasma calcitonin gene-related peptide (CGRP) levels in the jugular vein. Immunohistochemistry was applied to detect c-Fos-immunoreactive neurons and western blot was performed to detect c-Fos protein expression in trigeminal nucleus caudalis (TNC). We found that pregabalin pretreatment alleviated the NTG-induced hyperalgesia. Moreover, pregabalin suppressed peripheral CGRP release, c-Fos-immunoreactive neurons and the protein expression of c-Fos in TNC as well. These data suggest that pregabalin could alleviate the NTG-induced hyperalgesia. Further studies are required to determine the mechanisms of action for this effect.

Overuse of paracetamol caffeine aspirin powders affects cerebral glucose metabolism in chronic migraine patients.

Overuse of analgesic plays a prominent role in migraine chronification. Paracetamol caffeine aspirin (PCA) powders are commonly used in Chinese migraineurs. This study investigated the effects of the specific combination analgesic on cerebral glucose metabolism in chronic migraine (CM).

MFG-E8 Selectively Inhibited Aβ-Induced Microglial M1 Polarization via NF-κB and PI3K-Akt Pathways

Activated microglia are classified into two specific states: classically activated (M1) and alternatively activated (M2) subtypes. It is believed that the polarization of M1/M2 phenotype plays an important role in Alzheimer’s disease (AD). However, the mechanisms regulating this process remain unclear. Thus, we addressed this question focusing on milk fat globule epidermal growth factor 8 (MFG-E8). MFG-E8 is a unique protein which can bind to microglia and regulate its inflammatory responses. It is speculated that it might play a role in the balance of microglial polarization. In the current study, we used fibril Aβ42 in vitro to stimulate mouse primary microglial cultures and found subsequent M1 marker expression, along with retained M2 marker production. Then, we discovered that MFG-E8 pretreatment reversed the increased trend of M1 markers and the decreased expression of M2 markers, which were induced by Aβ42. Moreover, MFG-E8 effects could be effectively blocked by an MFG-E8 antibody. Further analysis on the signaling pathways showed that NF-κB upregulation and Akt downregulation in microglial cultures were observed after Aβ42 incubation. And the alteration of these pathways could also be reversed by MFG-E8. We then assessed the effects of NF-κB and PI3K-Akt on M1/M2 alteration using their specific inhibitors. Pyrrolidine dithiocarbamate, a NF-κB inhibitor, inhibited M1 marker expression; moreover, LY294002, an Akt inhibitor, enhanced M1 marker expression. Our study indicated the regulatory role of MFG-E8 on microglia M1/M2 alteration for the first time, providing a basis for understanding the potential role of microglia activation in AD.

A satisfaction survey of current medicines used for migraine therapy in China: is Chinese patent medicine effective compared with Western medicine for the acute treatment of migraine?

OBJECTIVE To investigate the patient satisfaction with medications commonly used for migraine therapy in patients seen in headache clinic in China with emphasis on the evaluation of Chinese patent medicine (CPM) in relieving acute migraine attack. METHODS Patients admitted at headache clinics in the neurological departments of four hospitals during April to October 2011 were enrolled in the investigation. The questionnaire was designed based on the validation of a diagnostic questionnaire for a population-based survey in China in 2009. RESULTS Among 219 eligible patients, 58% had used CPM at the acute attack of migraine while the guideline-recommended treatments were seldom used. However, patients using CPMs were less satisfied than those using Western Medicines (WMs) in either single medication groups or mixed medication groups (P < 0.05). CONCLUSION Fifty-eight percent of the eligible respondents in Guangdong and Guangxi Province had used CPM at the acute attack of migraine, but based on our data, the effect of CPM on treating migraine attack was poor with low satisfaction compared with WMs. However, many factors may bias or explain our findings. This suggests the need for accelerated research in understanding patient choice, treatment availability, and use of medications.

Prevalence and burden of headache disorders in two neighboring provinces of China

To our knowledge, studies concerning the prevalence and burden of primary headache in China are limited to specific regions without comparison of different districts. A survey in a different area with similar climate and culture may enhance our knowledge of the factors causing primary headache and the burden of headache. We conducted a 1 year survey on the prevalence and burden of primary headache in the Chinese provinces of Guangdong and Guangxi. Our study also evaluated the factors behind similarities and differences affecting prevalence in the two regions of study. The survey methodology, which was used in an Expanded Program on Immunization by the World Health Organization, was adopted to investigate the prevalence and burden of headache patients. Random samples of 372 local residents in Guangdong and 182 local residents in Guangxi aged 18-65 years were invited to a face-to-face interview. The education level and mean household income were higher in Guangdong (p<0.05). The 1 year prevalence of primary headache was 22.6% (84/372) in Guangdong and 41.2% (75/182) in Guangxi (p<0.001). The average financial burden of primary headache is 2.1% and 3.7% of the mean household income in Guangdong and Guangxi, respectively (p=0.001). The district with lower economic status had a higher prevalence of primary headache, and inevitably bears a heavier burden even with the same disease cost.