Differential Effects of Physical and Social Enriched Environment on Angiogenesis in Male Rats After Cerebral Ischemia/Reperfusion Injury.

Different housing conditions, including housing space and the physiological and social environment, may affect rodent behavior. Here, we examined the effects of different housing conditions on post-stroke angiogenesis and functional recovery to clarify the ambiguity about environmental enrichment and its components. Male rats in the model groups underwent right middle cerebral artery occlusion (MCAO) followed by reperfusion. The MCAO rats were divided into four groups: the physical enrichment (PE) group, the social enrichment (SE) group, the combined physical and social enrichment (PSE) group and the ischemia/reperfusion + standard conditioning (IS) group. The rats in the sham surgery (SS) group were housed under standard conditions. In a set of behavioral tests, including the modified Neurological Severity Score (mNSS), rotarod test, and adhesive removal test, we demonstrated that the animals in the enriched condition groups exhibited significantly improved neurological functions compared to those in the standard housing group. Smaller infarction volumes were observed in the animals of the PSE group by MRI detection. The enriched conditions increased the microvessel density (MVD) in the ischemic boundary zone, as revealed by CD31 immunofluorescent staining. The immunochemical and q-PCR results further showed that environmental enrichment increased the expression levels of angiogenic factors after ischemia/reperfusion injury. Our data suggest that all three enrichment conditions promoted enhanced angiogenesis and functional recovery after ischemia/reperfusion injury compared to the standard housing, while only exposure to the combination of both physical and social enrichment yielded optimal benefits.

Use of Kinesio taping in lower-extremity rehabilitation of post-stroke patients: A systematic review and meta-analysis.

BACKGROUND: and purpose: The benefits of Kinesio taping (KT) in post-stroke rehabilitation have not been determined. This study aimed to evaluate its effects on lower-extremity rehabilitation in patients after a stroke. METHODS: A literature search was performed using EBSCOhost, Embase, Physiotherapy Evidence Database (PEDro), PubMed, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI), SinoMed, and Wanfang Data through June 2018. Randomized controlled trials (RCTs) on the use of KT during lower-extremity, post-stroke rehabilitation were selected. Meta-analysis was conducted. RESULTS: A total of 14 RCTs of low to moderate quality were reviewed and included 783 participants. Results indicated that KT significantly improved patients' lower extremity spasticity, motor function, balance, ambulation, gait parameters, and daily activities, with few adverse effects. CONCLUSION: KT may have positive effects on lower-extremity, post-stroke rehabilitation. Due to the limited number and quality of the research, additional studies are needed to identify KT benefits.

DJ-1 Suppresses Cytoplasmic TDP-43 Aggregation in Oxidative Stress-Induced Cell Injury.

DJ-1 (also called PARK7) is a multifunctional redox-sensitive protein that is protective against oxidative stress-induced cell death. TAR DNA-binding protein 43 (TDP-43) is a major protein component of pathological inclusions in amyotrophic lateral sclerosis and frontotemporal dementia. Reducing aberrant aggregation of TDP-43 is a potential approach to prevent cell death. To investigate whether DJ-1 might inhibit TDP-43 aggregation to exert a protective effect in oxidative stress-induced injury, we tested the protein level and subcellular localization of TDP-43 and DJ-1 in SH-SY5Y cells transfected with wild-type DJ-1, DJ-1 mutant (L166P) cDNA, or DJ-1 siRNA. We show that oxidative stress induced by paraquat leads to the formation of cytosolic TDP-43 aggregation in SH-SY5Y cells. DJ-1 overexpression decreases paraquat-induced cytoplasmic accumulation of TDP-43 in SH-SY5Y cells and protects against paraquat-induced cell death. Transfection of DJ-1 L166P mutant or DJ-1 siRNA leads to increased cytosolic aggregation of TDP-43 in paraquat-treated SH-SY5Y cells and promotes cell death. These data suggest that DJ-1 may protect against oxidative stress-induced cell death through the suppression of cytoplasmic TDP-43 aggregation.

Effect of Acupuncture Cooperated with Low-frequency Repetitive Transcranial Magnetic Stimulation on Chronic Insomnia: A Randomized Clinical Trial.

The effect of acupuncture cooperated with low-frequency repetitive transcranial magnetic stimulation (rTMS) on chronic insomnia was explored. Seventy-eight patients with chronic insomnia were randomly allocated into two groups: treatment group and control group. In the treatment group, the patients received acupuncture combined with rTMS treatment, and those in the control group were given acupuncture cooperated with sham rTMS treatment, 3 days per week for 4 weeks. Before and after treatment, the primary outcomes including the scores on Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI) and the secondary outcomes including total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), sleep efficiency (SE%) recorded by sleeping diary and actigraphy were observed in both groups. Seventy-five participants finished the study (38 in treatment group and 37 in control group respectively). After treatment, the scores in the two groups were improved significantly, more significantly in the treatment group than in the control group. It can be inferred that acupuncture cooperated with rTMS can effectively improve sleep quality, enhance the quality of life of patients and has less side effects.

Association Between MicroRNAs Polymorphisms and Risk of Ischemic Stroke: A Meta-Analysis in Chinese Individuals.

Objective: Previous studies have demonstrated that some single-nucleotide polymorphisms (SNPs) in miRNAs are related to the risk of ischemic stroke (IS), but the conclusions are still controversial and inconclusive. We performed this meta-analysis to further assess the association between miR-146a C>G (rs2910164), miR-149 T>C (rs2292832), miR-196a2 T>C (rs11614913), miR-499 A>G (rs3746444) and risk of IS in Chinese individuals. Methods: Relevant studies were identified in the databases of PubMed, Embase. The strength of correlation between microRNAs polymorphisms and IS risk was assessed by odds ratios (ORs) and 95% confidence intervals (95% CIs) under five genetic models. Results: 5 studies, containing 2,632 cases and 3,191 controls, were included in this meta-analysis. The overall results of meta-analysis indicated that there were no significant association between miR-146a C>G (rs2910164), miR-149 T>C (rs2292832), miR-196a2 T>C (rs11614913), and the IS risk in the overall analyses. MiR-499 A>G (rs3746444) was associated with an increased IS risk under allele model (OR = 1.30, 95% CI = 1.02-1.66), heterozygous model (OR = 1.35, 95% CI = 1.01-1.79) and dominant model (OR = 1.36, 95% CI = 1.02-1.80) in Chinese. The sensitivity analysis results of these four polymorphisms were similar to the overall results. Conclusion: MiR-499 A>G (rs3746444) G allele and AG, AG + AA genotype might be risk factors of IS in Chinese. No significant association was observed between miR-146a C>G (rs2910164), miR-149 T>C (rs2292832), miR-196a2 T>C (rs11614913), and IS risk. The associations may be different due to geographical factors of China. More explorations in more diverse geographically regions with large sample size are expected to further verify the findings in the future.

Bisperoxovandium (pyridin-2-squaramide) targets both PTEN and ERK1/2 to confer neuroprotection.

BACKGROUND AND PURPOSE: We and others have shown that inhibiting phosphatase and tensin homolog deleted on chromosome 10 (PTEN) or activating ERK1/2 confer neuroprotection. As bisperoxovanadium compounds are well-established inhibitors of PTEN, we designed bisperoxovandium (pyridin-2-squaramide) [bpV(pis)] and determined whether and how bpV(pis) exerts a neuroprotective effect in cerebral ischaemia-reperfusion injury. EXPERIMENTAL APPROACH: Malachite green-based phosphatase assay was used to measure PTEN activity. A western blot assay was used to measure the phosphorylation level of Akt and ERK1/2 (p-Akt and p-ERK1/2). Oxygen-glucose deprivation (OGD) was used to injure cultured cortical neurons. Cell death and viability were assessed by LDH and MTT assays. To verify the effects of bpV(pis) in vivo, Sprague-Dawley rats were subjected to middle cerebral artery occlusion, and brain infarct volume was measured and neurological function tests performed. KEY RESULTS: bpV(pis) inhibited PTEN activity and increased p-Akt in SH-SY5Y cells but not in PTEN-deleted U251 cells. bpV(pis) also elevated p-ERK1/2 in both SH-SY5Y and U251 cells. These data indicate that bpV(pis) enhances Akt activation through PTEN inhibition but increases ERK1/2 activation independently of PTEN signalling. bpV(pis) prevented OGD-induced neuronal death in vitro and reduced brain infarct volume and promoted functional recovery in stroke animals. This neuroprotective effect of bpV(pis) was blocked by inhibiting Akt and/or ERK1/2. CONCLUSIONS AND IMPLICATIONS: bpV(pis) confers neuroprotection in OGD-induced injury in vitro and in cerebral ischaemia in vivo by suppressing PTEN and activating ERK1/2. Thus, bpV(pis) is a bi-target neuroprotectant that may be developed as a drug candidate for stroke treatment.

Effect of enriched environment on angiogenesis and neurological functions in rats with focal cerebral ischemia.

The purpose of this study was to investigate the effect of enriched environment (EE) on cerebral angiogenesis after ischemia-reperfusion injury. Middle cerebral artery occlusion (MCAO) followed by reperfusion was performed in rats to set up an animal model of ischemia-reperfusion injury. In a set of behavioral tests, we demonstrated that the animals in the IEE (ischemia + enriched environment) group exhibited significantly improved neurological functions compared to those in the standard housing condition group. In consistent with the functional tests, smaller infarction volumes were observed in the animals of IEE group. Laser scanning confocal microscopy and 3D quantitative analysis of cerebral microvessels revealed that EE treatment increased the total vessel surface area and number of branch point in the ischemic boundary zone. IgG extraction assay showed that the blood brain barrier (BBB) leakage in the ischemic brain was attenuated after EE treatment. EE treatment also enhanced endothelial cells (ECs) proliferation and increased the expression levels of VEGF and its receptor Flk-1 after ischemia-reperfusion injury. Analyses of Spearman's correlation coefficients indicated a correlation of mNSS scores with enhanced cerebral angiogenesis. Together, the results suggest that EE treatment-induced cerebral angiogenesis may contribute to the improved neurological outcome of stroke animals after ischemia-reperfusion injury.

Effects of Tetramethylpyrazine on Functional Recovery and Neuronal Dendritic Plasticity after Experimental Stroke.

The 2,3,5,6-tetramethylpyrazine (TMP) has been widely used in the treatment of ischemic stroke by Chinese doctors. Here, we report the effects of TMP on functional recovery and dendritic plasticity after ischemic stroke. A classical model of middle cerebral artery occlusion (MCAO) was established in this study. The rats were assigned into 3 groups: sham group (sham operated rats treated with saline), model group (MCAO rats treated with saline) and TMP group (MCAO rats treated with 20 mg/kg/d TMP). The neurological function test of animals was evaluated using the modified neurological severity score (mNSS) at 3 d, 7 d, and 14 d after MCAO. Animals were euthanized for immunohistochemical labeling to measure MAP-2 levels in the peri-infarct area. Golgi-Cox staining was performed to test effect of TMP on dendritic plasticity at 14 d after MCAO. TMP significantly improved neurological function at 7 d and 14 d after ischemia, increased MAP-2 level at 14 d after ischemia, and enhanced spine density of basilar dendrites. TMP failed to affect the spine density of apical dendrites and the total dendritic length. Data analyses indicate that there was significant negative correlation between mNSS and plasticity measured at 14 d after MCAO. Thus, enhanced dendritic plasticity contributes to TMP-elicited functional recovery after ischemic stroke.

Effect of combined low-frequency repetitive transcranial magnetic stimulation and virtual reality training on upper limb function in subacute stroke: a double-blind randomized controlled trail.

The effect of combined low-frequency repetitive transcranial magnetic stimulation (LF rTMS) and virtual reality (VR) training in patients after stroke was assessed. In a double-blind randomized controlled trial, 112 patients with hemiplegia after stroke were randomly divided into two groups: experimental and control. In experimental group, the patients received LF rTMS and VR training treatment, and those in control group received sham rTMS and VR training treatment. Participants in both groups received therapy of 6 days per week for 4 weeks. The primary endpoint including the upper limb motor function test of Fugl-meyer assessment (U-FMA) and wolf motor function test (WMFT), and the secondary endpoint including modified Barthel index (MBI) and 36-item Short Form Health Survey Questionnaire (SF-36) were assessed before and 4 weeks after treatment. Totally, 108 subjects completed the study (55 in experimental group and 53 in control group respectively). After 4-week treatment, the U-FMA scores [mean difference of 13.2, 95% confidence interval (CI) 3.6 to 22.7, P<0.01], WMFT scores (mean difference of 2.9, 95% CI 2.7 to 12.3, P<0.01), and MBI scores (mean difference 16.1, 95% CI 3.8 to 9.4, P<0.05) were significantly increased in the experimental group as compared with the control group. The results suggested the combined use of LF rTMS with VR training could effectively improve the upper limb function, the living activity, and the quality of life in patients with hemiplegia following subacute stroke, which may provide a better rehabilitation treatment for subacute stroke.

Neuroprotective effects of different modalities of acupuncture on traumatic spinal cord injury in rats.

Spinal cord injury (SCI) can induce a series of histological, biochemical, and functional changes. Acupuncture is commonly used for SCI patients. Using male rats of spinal cord injury with the New York University (NYU) Impactor, we investigated the response of electroacupuncture (EA), manual acupuncture (MA), and transcutaneous acupoint electrical stimulation (TAES) at Shuigou (DU26) and Fengfu (DU16) acupoints to understand the effects and mechanisms of acupuncture in neuroprotection and neuronal function recovery after SCI. Histological study showed a restored neural morphology and an increase in the quantity of neurons after EA, MA, and TAES administrations. Acupuncture's antioxidation effects were demonstrated by alleviation of the post-SCI superoxide dismutase (SOD) activity increase and malondialdehyde (MDA) level decrease. The anti-inflammation effect of acupuncture was shown as the reduced expression of inflammatory cytokines including interleukin-1 ß (IL-1 ß ), interleukin-6 (IL-6), and tumor necrosis factor- α (TNF- α ) when SCI was treated. And the antiapoptosis role was approved by TUNEL staining. Our data confirmed that the role of acupuncture in neuroprotection and dorsal neuronal function recovery after rat SCI, especially, EA stimulating at Shuigou (DU26) and Fengfu (DU16) can greatly promote neuronal function recovery, which may result from antioxidation, anti-inflammation, and antiapoptosis effects of acupuncture.

Chinese herbal medicine for diabetic peripheral neuropathy: an updated meta-analysis of 10 high-quality randomized controlled studies.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is very common in people with diabetes. Chinese herbal medicine (CHM) therapy has been developed for DPN empirically over the years. The aim of this systematic review and meta-analysis was to assess the efficacy and safety of CHMs for patients suffering from DPN. METHODS: We performed a meta-analysis of randomized-controlled clinical trials (RCTs) evaluating the efficacy and safety of CHM on DPN. Six databases were searched up to November 2012. The primary outcome measures were the absolute values or changing of motor or sensory nerve conduction velocity (NCV), and the secondary outcome measurements were clinical symptoms improvements and adverse events. The methodological quality was assessed by Jadad scale and the twelve criteria recommended by the Cochrane Back Review Group. RESULTS: One hundred and sixty-three studies claimed RCTs. Ten studies with 653 individuals were further identified based on the Jadad score ≥ 3. These 10 studies were all of high methodological quality with a low risk of bias. Meta-analysis showed the effects of NCV favoring CHMs when compared with western conventional medicines (WCM) (P<0.05 or P<0.01). There is a significant difference in the total efficacy rate between the two groups (P<0.001). Adverse effects were reported in all of the ten included studies, and well tolerated in all patients with DPN. CONCLUSION: Despite of the apparently positive findings and low risk of bias, it is premature to conclude the efficacy of CHMs for the treatment of DPN because of the high clinical heterogeneity and small sample sizes of the included studies. However, CHM therapy was safe for DPN. Further standardized preparation, large sample-size and rigorously designed RCTs are required.

Clinical efficacy and safety of buyang huanwu decoction for acute ischemic stroke: a systematic review and meta-analysis of 19 randomized controlled trials.

Buyang Huanwu Decoction (BHD) is a well-known traditional Chinese herbal prescription for treating stroke-induced disability. The objective of this study was to evaluate the efficacy and safety of BHD for acute ischemic stroke. A systematic literature search was performed in 6 databases until February 2012. Randomized controlled clinical trials (RCTs) that evaluate efficacy and safety of BHD for acute ischemic stroke were included. Nineteen RCTs with 1580 individuals were identified. The studies were generally of low methodological quality. Only one of the trial included death or dependency as a primary outcome measure. Only 4 trials reported adverse events. Meta-analysis showed the clinical effective rate of neurological deficit improvement favoring BHD when compared with western conventional medicines (WCM), P < 0.001. There is significant difference in the neurologic deficit score between the BHD treatment group and the WCM control group, P < 0.001. In Conclusion, BHD appears to improve neurological deficit and seems generally safe in patients with acute ischemic stroke. However, the current evidence is insufficient to support a routine use of BHD for acute ischemic stroke due to the poor methodological quality and lack of adequate safety data of the included studies. Further rigorously designed trials are required.

[Effects of Angelica sinensis treatment on the expression of flt-1 and flk-1 mRNA after the ischemic brain injury in rats].

AIM: To investigate the effects of Angelica sinensis on the expression of Flt-1, Flk-1 mRNA after the ischemic brain injury in rats. METHODS: Wistar rats randomly divided into two groups: group A rats underwent middle cerebral artery occlusion (MCAO) for 2 hours by suture, group B rats underwent MCAO for 2 hours meanwhile received treatment with Angelica sinensis (5g/kg). At 1 st d, 3 rd d and 7 th d after reperfusion, 36 rats( n = 18 in each group) were assessed by neurological scale and brain tissue was taken to assess the lesion ration with 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The other rats (n = 3 at different time points in each group) were decapitated at 3 h, 6 h, 12 h , 1 st d, 3 rd d, 7 th d after reperfusion. Quantitative reverse transcription and polymerase chain reaction (RT-PCR) technique was used to examine the gene expression of Flt-1, Flk-1. RESULTS: The neurologic deficit score of rats in group B decreased significantly compared with group A at the same time point (P < 0.05). The infarct volume of group A was significant greater than group B at the same time point after reperfusion (P < 0.01). The results of RT-PCR revealed that the gene expression of Flt-1, Flk-1 in the two groups increased from 3 h after reperfusion and reached its peak at the time of 3 rd d after reperfusion, then declined gradually. The gene expression of Flt-1, Flk-1 in the group B was significantly increased than group A at the same time point (P < 0.01). The gene expression of Flk-1 was positive correlated with Flt-1 in two groups (r = 0.957). CONCLUSION: The increasing amount of Flt-1, Flk-1 expression was enhanced by Angelica sinensis following transient interruption of cerebral blood flow in rats.

The effects of Chinese herb Angelica in focal cerebral ischemia injury in the rat.

This experiment was designed to study the therapeutic mechanisms of Angelica on the focal cerebral ischemia injury of the rat. The ischemic area was determined by TTC stain. And terminal deoxynucleotidyl transferase (TDT) mediated DUTP-biotin nick end labeling (TUNEL) method was applied to detect neuronal apoptosis. The expressions of Bcl-2 and Bax proteins were observed by immunohistochemical staining methods. Results show that the treatment with angelica reduced the volume of cerebral infarction (p < 0.05), and that the number of neuronal apoptosis cells decreased significantly (p < 0.01). Also the expression level of Bax protein decreased (p < 0.01). These results suggest that Angelica can reduce the number of apoptosis cells by decreasing the expression of Bax protein. This is maybe one of the mechanisms of the therapeutic effect of Angelica on focal cerebral ischemia injury.

[Effects of Angelica sinensis injection on the neuronal metabolites and blood flow speed within reperfusion following the ischemic cerebral injury in rats].

AIM: To investigate the effects of Angelica sinensis injection on the neuronal metabolites and blood flow speed within reperfusion in the ischemic cerebral injury of rats. METHODS: Sixty-nine male Sprague Dawley rats with an average body weight of 150 to 170 g were used, and were randomly divided into three groups: sham operation group (n = 4), ischemia injury group (n = 30) underwent an operation of ischemic brain injury, Angelica-treated group (n = 35) underwent the same operation and received the treatment of Angelica sinensis injection (5 g/kg bw, i. p). The right middle cerebral artery occlusion (MCAO) of both ischemia injury group and Angelica-treated group rats was induced by 5/0 nylon suture for 2 hours. The reperfusion was conducted for three to four hours and five to six hours respectively following MCAO. T2 weighted-imaging (T2WI) and 1H magnetic resonance spectroscopy (1H MRS) were performed, to study the changes in imaging and neuronal metabolites N-acetyl aspartate (NAA), creatine/phosphocreatine (Cr/ PCr) and choline (Cho) following cerebral ischemia. The changes in blood flow speed were measured by laser Doppler flowmetry. The surface vascular density in right hemisphere were calculated. RESULTS: The hyperintense signals and volume in the right cerebrum in Angelica-treated group decreased compared with those of the ischemia injury group, the T2 values were decreased, and the level of NAA increased, the ratio of Cr/NAA and Cho/NAA decreased. The blood flow speed in Angelica-treated group was improved. The length of brain surface vessels in group C increased. CONCLUSION: The Angelica sinensis injection enhanced the blood circulation in the ischemic brain, improved the neuronal metabolisms.

[The effects of Erigeron breviscapus preparation on the imaging and neuronal metabolites at the early time points after reperfusion following the ischemic cerebral injury in rats].

OBJECTIVE: To investigate the effects of Erigeron breviscapus preparation on the imaging and neuronal metabolites after reperfusion in the ischemic cerebral injury in rats. METHOD: Twenty-three male Sprague Dawley rats with an average body weight of (165 +/- 15) g (mean +/- S) were used, and were randomly divided into two groups: group A rats (n = 11) underwent an operation of ischemic brain injury, group B rats (n = 12) underwent the same operation and received the treatment of Erigeron breviscapus preparation (1.5 mg.kg-1 weight, i.p.). The right middle cerebral artery occlusion (MCAO) of rats in both groups was induced by 5/0 nylon suture for 2 hours. The reperfusion was conducted for four hours and six hours respectively following MCAO. T2 weighted-imaging (T2WI) and 1H-magnetic resonance spectroscopy (1H-MRS) were performed, to study the changes of the imaging and the neuronal metabolites N-acetyl aspartate (NAA), creatine/phosphocreatine (Cr/PCr), choline (Cho) and lactose (Lac) in cerebrum following cerebral ischemia. RESULT: The hyperintense signals in the right cerebrum in group B decreased compared with those in group A, the T2 values decreased, the level of NAA increased, the ratio of Cr/NAA and Cho/NAA decreased, and no lactose was observed. The brain surface vessels of rats in group B were in the state of dilation. CONCLUSION: Erigeron breviscapus preparation is beneficial to the reestablishment of the blood circulation in the ischemic brain, and to the improvement of the neuronal metabolism and survival.