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.

The quality of reporting of randomized controlled trials of electroacupuncture for stroke.

BACKGROUND: Electroacupuncture (EA), as an extension technique of acupuncture based on traditional acupuncture combined with modern electrotherapy, is commonly used for stroke in clinical treatment and researches. However, there is still a lack of enough evidence to recommend the routine use of EA for stroke. This study is aimed at evaluating the quality of reporting of randomized controlled trials (RCTs) on EA for stroke. METHODS: RCTs on EA for stroke were evaluated by using CONSORT guidelines and STRICTA guidelines. Microsoft Excel 2010 and the R software were used for descriptive statistics analyses. RESULTS: Seventy studies involving 5468 stroke patients were identified. The CONSORT scores ranged from 16.2 to 67.6% and STRICTA scores from 29.4 to 82.4%. The central items in CONSORT as eligibility criterion, sample size calculation, primary outcome, method of randomization sequence generation, allocation concealment, implementation of randomization, description of blinding, and detailed statistical methods were reported in 100, 6, 68, 37, 14, 10, 16, and 97% of trials, respectively. The reporting of items in STRICTA as acupuncture rationale was 1a (91%), 1b (86%) and 1c 0%; needling details 2a (33%), 2b (97%), 2c (29%), 2d (64%), 2e (100%), 2f (55%) and 2 g (66%); treatment regimen 3a (69%) and 3b (100%); other components of treatment 4a (86%) and 4b (13%); practitioner background item 5 (16%); control intervention(s) 6a (93%) and 6b (10%). CONCLUSIONS: The quality of reporting of RCTs on EA for stroke was generally moderate. The reporting quality needs further improvement.

Dihuang Yinzi, a Classical Chinese Herbal Prescription, for Amyotrophic Lateral Sclerosis: A 12-Year Follow-up Case Report.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease with no effective treatment and death within 2 to 5 years after symptom onset. Here, we reported a case of ALS patient using modified Dihuang Yinzi (DHYZ), a classical traditional Chinese medicine (TCM) prescription, who has survived 12 years with significant improvement in bulbar paralysis.A 41-year-old Chinese Han nationality woman was admitted to the hospital with complaints of weakened bilateral grip, slurred speech, stumbling, and muscle twitching for 3 years. The electromyography showed neurogenic injury in bilateral upper limbs and tongue. She was diagnosed with ALS according to the revised El escorial criteria. The patient was orally administrated with Riluzole 100 mg daily for 10 months and then stopped. Subsequently, she resorted to TCM. Based on the TCM theory, the patient was diagnosed with Yinfei syndrome because of kidney deficiency. DHYZ was chosen because it has the function of replenishing kidney essence to treat Yinfei syndrome. Up to now, she has been using modified DHYZ continuously for 12 years. The patient survived with ALS and did not require permanent continuous ventilator. In addition, the symptoms of choking on liquids are improved, and the utility of 30 mL water swallow test was improved with grade 2. The symptoms of muscle fibrillations of limbs are also reduced. However, muscle strength worsened slowly. The repeated electromyography showed motor conduction amplitude reducing gradually and velocity not changing more when compared with the initial electromyography.Our findings suggested that DHYZ can be potentially used in ALS patients because of its multi-targeted neuroprotection and general safety, although ALS does not have a cure. In addition, we identified the area that is worthy of further study and DHYZ as a promising candidate for further clinical application and ALS trials. Rigorous randomized controlled trials are needed in the future.

Preconditioning with recombinant high-mobility group box 1 induces ischemic tolerance in a rat model of focal cerebral ischemia-reperfusion.

Preconditioning with ligands of toll-like receptors (TLRs) is a powerful neuroprotective approach whereby a low dose of stimulus confers significant protection against subsequent substantial brain damage by reprogramming the ischemia-activated TLRs signaling. Herein, we aim to explore whether preconditioning with recombinant high-mobility group box 1 (rHMGB1), one of the TLRs ligands, decreases cerebral ischemia-reperfusion injury (IRI). Rats were intracerebroventricularly pretreated with rHMGB1, 1 or 3 days before induction of middle cerebral artery occlusion. Results showed that preconditioning with rHMGB1 1 day, but not 3 days, prior to ischemia dramatically reduced neurological deficits, infarct size, brain swelling, cell apoptosis, and blood-brain barrier permeability. Interleukin-1R-associated kinase-M (IRAK-M), a critical negative regulator of TLRs signaling, was robustly increased in response to brain IRI and was further elevated by rHMGB1 pretreatment, indicating its role associated with the rHMGB1 preconditioning-mediated ischemic tolerance. In vitro and in vivo assays indicated that the induced IRAK-M expression was localized in microglia. In addition, TLR4 specific inhibitor TAK-242 abolished the neuroprotective effects and the induction of IRAK-M offered by rHMGB1 preconditioning. Collectively, our study demonstrates that rHMGB1 preconditioning is neuroprotective during cerebral IRI, which is associated with activated TLR4/IRAK-M signaling in microglia. We found that high-mobility group box 1 (HMGB1) pretreatment conditioned the brain against subsequent ischemia-reperfusion injury. We propose the following mechanism for HMGB1 preconditioning-mediated ischemic tolerance: through toll-like receptor TLR4, HMGB1 preconditioning magnifies the up-regulation of interleukin-1R-associated kinase-M (IRAK-M) induced by ischemia-reperfusion in microglia, resulting in the decreased phosphorylation of IRAK-1. These findings are helpful in understanding the endogenous mechanisms that counteract ischemic insults.

Promoting blood circulation for removing blood stasis therapy for acute intracerebral hemorrhage: a systematic review and meta-analysis.

AIM: To conduct a systematic review and meta-analysis to assess the current evidence available regarding the promoting blood circulation and removing blood stasis (PBCRBS) therapy for Chinese patients with acute intracerebral hemorrhage (ICH). METHODS: Six databases were searched from their inception to November 2013. The studies assessed in ≥ 4 domains with 'yes' were selected for detailed assessment and meta-analysis. The herbal compositions for PBCRBS therapy for acute ICH patients were also assessed. RESULTS: From the 6 databases, 292 studies claimed randomized-controlled clinical trials (RCTs). Nine studies with 798 individuals were assessed in ≥ 4 domains with 'yes' by using the Cochrane RoB tool. Meta-analysis showed that PBCRBS monotherapy and adjuvant therapy for acute ICH could improve the neurological function deficit, reduce the volume of hematoma and perihematomal edema, and lower the mortality rate and dependency. Moreover, there were fewer adverse effects when compared with Western conventional medication controls. Xueshuantong Injection and Fufang Danshen Injection, Buyang Huanwu Decoction and Liangxue Tongyu formula, and three herbs (danshen root, sanqi and leech) were the most commonly used Chinese herbal patent injections, herbal prescriptions and single herbs, respectively. CONCLUSION: Despite the apparently positive findings, it is premature to conclude that there is sufficient efficacy and safety of PBCRBS for ICH because of the high clinical heterogeneity of the included studies and small number of trials in the meta-analysis. Further large sample-sizes and rigorously designed RCTs are needed.