Electroacupuncture Exerts Neuroprotection through Caveolin-1 Mediated Molecular Pathway in Intracerebral Hemorrhage of Rats.

Spontaneous intracerebral hemorrhage (ICH) is one of the most devastating types of stroke. Here, we aim to demonstrate that electroacupuncture on Baihui (GV20) exerts neuroprotection for acute ICH possibly via the caveolin-1/matrix metalloproteinase/blood-brain barrier permeability pathway. The model of ICH was established by using collagenase VII. Rats were randomly divided into three groups: Sham-operation group, Sham electroacupuncture group, and electroacupuncture group. Each group was further divided into 4 subgroups according to the time points of 6 h, 1 d, 3 d, and 7 d after ICH. The methods were used including examination of neurological deficit scores according to Longa's scale, measurement of blood-brain barrier permeability through Evans Blue content, in situ immunofluorescent detection of caveolin-1 in brains, western blot analysis of caveolin-1 in brains, and in situ zymography for measuring matrix metalloproteinase-2/9 activity in brains. Compared with Sham electroacupuncture group, electroacupuncture group has resulted in a significant improvement in neurological deficit scores and in a reduction in Evans Blue content, expression of caveolin-1, and activity of matrix metalloproteinase-2/9 at 6 h, 1 d, 3 d, and 7 d after ICH (P < 0.05). In conclusion, the present results suggested that electroacupuncture on GV20 can improve neurological deficit scores and reduce blood-brain barrier permeability after ICH, and the mechanism possibly targets caveolin-1/matrix metalloproteinase/blood-brain barrier permeability pathway.

Buyang Huanwu Decoction Targets SIRT1/VEGF Pathway to Promote Angiogenesis After Cerebral Ischemia/Reperfusion Injury.

Background: Ischemia stroke is known as the major cause of morbidity and mortality. Buyang Huanwu Decoction (BHD), a classical traditional Chinese medicine (TCM) formula, has been used to prevent and treat stoke for hundreds of years. The purpose of present study is to investigate the effects of BHD on angiogenesis in rats after cerebral ischemia/reperfusion (I/R) injury targeting Silent information regulator 1 (SIRT1) / Vascular endothelial growth factor (VEGF) pathway. Methods: The cerebral I/R injury model was induced by middle cerebral artery occlusion (MCAO). Adult Sprag-Dawley (SD) rats were randomly divided into five groups: sham group, normal saline (NS) group, BHD group, BHD+EX527 (SIRT1 specific inhibitor) group, and NS+EX527 group. Each group was divided into the subgroups according to 1, 3, 7, or 14 days time-point after cerebral ischemia/reperfusion, respectively. Neurological function score (NFS) was evaluated by the Rogers scale; microvascular density (MVD) in brain tissue around infarction area was observed by immunofluorescence; and the expression of SIRT1 and VEGF was assessed by Western Blot and Quantitative Real-time-PCR. Results: BHD can significantly improve NFS (P < 0.05), increase the MVD in the boundary ischemic area (P < 0.01) and elevate the expression of protein and mRNA of SIRT1 and VEGF following I/R injury (P < 0.01). In contrast, treatment with EX527 reversed the BHD-induced improvements in NFS (P < 0.01) and decreased the MVD (P < 0.01) and the expression of SIRT1 and VEGF (P < 0.05). Conclusion: BHD exerts neuroprotection targeting angiogenesis through the up-regulation of SIRT1/VEGF pathway against cerebral ischemic injury in rats.

Adenosine A2A Receptor Gene Knockout Prevents l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia by Downregulation of Striatal GAD67 in 6-OHDA-Lesioned Parkinson's Mice.

l-3,4-Dihydroxyphenylalanine (l-DOPA) remains the primary pharmacological agent for the symptomatic treatment of Parkinson's disease (PD). However, the development of l-DOPA-induced dyskinesia (LID) limits the long-term use of l-DOPA for PD patients. Some data have reported that adenosine A2A receptor (A2AR) antagonists prevented LID in animal model of PD. However, the mechanism in which adenosine A2AR blockade alleviates the symptoms of LID has not been fully clarified. Here, we determined to knock out (KO) the gene of A2AR and explored the possible underlying mechanisms implicated in development of LID in a mouse model of PD. A2AR gene KO mice were unilaterally injected into the striatum with 6-hydroxydopamine (6-OHDA) in order to damage dopamine neurons on one side of the brain. 6-OHDA-lesioned mice were then injected once daily for 21 days with l-DOPA. Abnormal involuntary movements (AIMs) were evaluated on days 3, 8, 13, and 18 after l-DOPA administration, and real-time polymerase chain reaction and immunohistochemistry for glutamic acid decarboxylase (GAD) 65 and GAD67 were performed. We found that A2AR gene KO was effective in reducing AIM scores and accompanied with decrease of striatal GAD67, rather than GAD65. These results demonstrated that the possible mechanism involved in alleviation of AIM symptoms by A2AR gene KO might be through reducing the expression of striatal GAD67.

Neuroprotection of Catalpol for Experimental Acute Focal Ischemic Stroke: Preclinical Evidence and Possible Mechanisms of Antioxidation, Anti-Inflammation, and Antiapoptosis.

Neuroprotection is defined as using a therapy that affects the brain tissue in the still-viable ischemic penumbra to salvage or delay the infarction. Catalpol, the main active principle of the root of Radix Rehmanniae, was reported to have pleiotropic neuroprotective effects in neurodegenerative diseases including ischemic stroke. Here, we evaluated the neuroprotective effects of catalpol in experimental acute ischemic stroke. Studies on catalpol in animal models of acute ischemic stroke were identified from 6 databases. Twenty-five studies involving 805 animals were included. Twelve comparisons showed significant effects of catalpol on decreasing infarct size according to 2,3,5-triphenyltetrazolium chloride staining compared with the control (P < 0.05). One study reported significant effect of catalpol on reducing infarct size according to magnetic resonance imaging scan compared with the control (P < 0.05). Meta-analysis of these studies indicated that catalpol significantly improved the neurological function score according to Zea Longa score, Bederson score, balance beam-walking test, adhesive removal test, bar-grasping score, and corner test compared with the control (P < 0.05). In conclusion, catalpol exerted neuroprotective effects for experimental acute focal ischemic stroke, largely through reducing oxidative reactions, inhibiting apoptosis, and repressing inflammatory reactions and autophagy. However, these apparently positive findings should be interpreted with caution because of the methodological flaws.

Chinese herbal medicine for Alzheimer's disease: Clinical evidence and possible mechanism of neurogenesis.

Currently, there is lack of cure or disease-modifying treatment for Alzheimer's disease (AD). Chinese herbal medicine (CHM) is purported to ameliorate AD progression, perhaps by promoting hippocampal neurogenesis. Here, we conducted an updated systematic review to investigate the efficacy and safety of CHM for AD based on high-quality randomized controlled trials (RCTs) and reviewed its possible mechanisms of neurogenesis according to animal-based researches. Twenty eligible studies with 1767 subjects were identified in eight database searches from inception to February 2017. The studies investigated the CHM versus placebo (n=3), CHM versus donepezil (n=9 with 10 comparisons), CHM plus donepezil versus donepezil (n=3), CHM versus a basic treatment (n=3), and CHM plus basic treatment versus basic treatment (n=2). Adverse events were reported in 11 studies, analyzed but not observed in 3 studies, and not analyzed in 6 studies. The main findings of present study are that CHM as adjuvant therapy exerted an additive anti-AD benefit, whereas the efficacy of CHM as a monotherapy was inconclusive. Additionally, CHMs were generally safe and well tolerated in AD patients. Active molecules in frequent constituents of CHMs can alter multiple critical signaling pathways regulating neurogenesis. Thus, the present evidence supports, to a limited extent, the conclusion that CHM can be recommended for routine use in AD patients and its possible mechanism enhances adult hippocampal neurogenesis through activating the multi-signal pathways.

Sham Electroacupuncture Methods in Randomized Controlled Trials.

Sham electroacupuncture (EA) control is commonly used to evaluate the specific effects of EA in randomized-controlled trials (RCTs). However, establishing an inert and concealable sham EA control remains methodologically challenging. Here, we aimed to systematically investigate the sham EA methods. Eight electronic databases were searched from their inception to April 2015. Ten out of the 17 sham EA methods were identified from 94 RCTs involving 6134 participants according to three aspects: needle location, depth of needle insertion and electrical stimulation. The top three most frequently used types were sham EA type A, type L and type O ordinally. Only 24 out of the 94 trials reported credibility tests in six types of sham EA methods and the results were mainly as follows: sham EA type A (10/24), type B (5/24) and type Q (5/24). Compared with sham EA controls, EA therapy in 56.2% trials reported the specific effects, of which the highest positive rate was observed in type N (3/4), type F (5/7), type D (4/6) and type M (2/3). In conclusion, several sham EA types were identified as a promising candidate for further application in RCTs. Nonetheless, more evidence for inert and concealable sham EA control methods is needed.

Bioactive components of Chinese herbal medicine enhance endogenous neurogenesis in animal models of ischemic stroke: A systematic analysis.

BACKGROUND: Chinese herbal medicine (CHM) has been used to treat stroke for thousands of years. The objective of the study is to assess the current evidence for bioactive components of CHM as neurogenesis agent in animal models of ischemic stroke. METHODS: We searched PubMed, China National Knowledge Infrastructure, WanFang Database, and VIP Database for Chinese Technical Periodicals published from the inception up to November 2015. The primary measured outcome was one of neurogenesis biomarker, including Bromodeoxyuridine (BrdU), Nestin, doublecortin (DCX), polysialylated form of the neural cell adhesion molecule (PSA-NCAM), neuronal nuclear antigen (NeuN), and glial fibrillary acidic protein (GFAP). RESULTS: Thirty eligible studies were identified. The score of quality assessment ranged from 2 of 10 to 7 of 10. Compared with controls, 10 studies conducting neurobehavioral evaluation showed significant effects on bioactive components of CHM for improving neurological deficits score after ischemic insults (P < 0.01 or P < 0.05); 6 studies in Morris water-maze test showed bioactive components of CHM significantly decreased escape latency and increased residence time (P < 0.05); 5 studies demonstrated that bioactive components of CHM significantly reduced infarct volume after ischemic stroke (P < 0.05); 25 of 26 studies showed that bioactive components of CHM significantly increased the expression of BrdU and/or Nestin markers in rats/mice brain after ischemic injury (P < 0.05, or P < 0.01); 4 of 5 studies for promoting the expression of PSA-NCAM or DCX biomarker (P < 0.05); 5 studies for improving the expression of NeuN biomarker (P < 0.05); 6 of 7 studies for promoting the expression of GFAP biomarker in brain after ischemic stroke (P < 0.05). CONCLUSION: The findings suggest that bioactive components of CHM may improve neurological function, reduce infarct volume, and promote endogenous neurogenesis, including proliferation, migration, and differentiation of neural stem cells after ischemic stroke. However, evidences are supported but limited because only a few studies were available for each descriptive analysis. Further rigor study is still needed.