Publications by authors named "Xibin Liang"

22 Publications

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[Ilizarov metatarsal bone lengthening in treatment of diabetic foot ulcer complicated with chronic osteomyelitis of metatarsal head].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2020 Aug;34(8):1000-1004

Department of Orthopaedics, Beijing Chui Yang Liu Hospital Affiliated to Tsinghua University, Beijing, 100022, P.R.China;Department of Orthopaedics, Rehabilitation Hospital of the National Research Center for Rehabilitation Technical Aids, Beijing, 100176, P.R.China.

Objective: To explore the effectiveness of the first-stage debridement and Ilizarov metatarsal bone lengthening in treatment of diabetic foot ulcer complicated with chronic osteomyelitis of metatarsal head.

Methods: Between January 2015 and October 2018, 8 cases (9 feet, 11 sites) of diabetic foot ulcer complicated with chronic osteomyelitis of metatarsal head were treated by first-stage debridement and Ilizarov metatarsal bone lengthening. There were 3 males (4 feet, 5 sites) and 5 females (5 feet, 6 sites), with an average age of 57.5 years (range, 44-65 years). According to diabetic foot Wagner grade, 6 cases (7 feet) were grade 3 and 2 cases (2 feet) were grade 4. The chronic osteomyelitis located at left foot in 4 cases, right foot in 3 cases, and bilateral feet in 1 case. The duration of chronic osteomyelitis was 1-5 years (mean, 3.1 years). The chronic osteomyelitis site was the 1st metatarsal head in 3 feet, the 3rd metatarsal head in 1 foot, the 4th metatarsal head in 1 foot, and the 5th metatarsal head in 6 feet. Two patients had chronic osteomyelitis at 2 sites on 1 foot. The length of lengthened metatarsal bone, lengthening time, and the time of wearing external fixation frame were recorded, and the external fixation frame index was calculated. The healing conditions of foot ulcer and lengthening bone segment were observed, the healing time was recorded, and the healing index of lengthening bone was calculated. The ankle function was evaluated according to the American Orthopedic Foot and Ankle Society (AOFAS) score criteria.

Results: All patients were followed up 9-26 months with an average of 15.0 months. Except pin tract infection during the bone lengthening period, there was no complications such as skin necrosis and vascular or nerve injury occurred during treatment. The length of lengthened metatarsal bone was 12-35 mm with an average of 20.5 mm; the metatarsal bone lengthening time were 21-84 days with an average of 57.8 days. The average time of wearing external fixation frame was 14.6 weeks (range, 10.4-21.1 weeks) and the external fixation frame index was 54.3 days/cm (range, 42.9-59.2 days/cm). The ulcer wound healed with an average healing time of 30.5 days (range, 19-70 days) and no ulcer recurrence was observed during follow-up. Bone healing was obtained in all bone lengthening segments, and the average healing index was 42.5 days/cm (range, 37-51 days/cm). The average AOFAS score was 91.7 (range, 87-95); 5 feet were excellent and 4 feet were good. The excellent and good rate was 100%.

Conclusion: The metatarsal bone lengthening under Ilizarov law of tension-stress after debridement can promote diabetic foot ulcers healing and reconstructing the length of metatarsal to retain the function of metatarsal load and avoid amputation. This is an effective method for the treatment of diabetic foot ulcer complicated with chronic osteomyelitis of metatarsal head.
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http://dx.doi.org/10.7507/1002-1892.201911070DOI Listing
August 2020

[Modified Ilizarov hip reconstruction in treatment of adolescent hip instability].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2019 Nov;33(11):1379-1383

Department of Orthopaedics, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, 100144, P.R.China.

Objective: To evaluate the effectiveness of modified Ilizarov hip reconstruction in the treatment of hip instability.

Methods: The clinical data of 13 young patients with hip diseases treated with modified Ilizarov hip reconstruction between January 2010 and March 2018 were retrospectively analyzed. There were 2 males and 11 females, aged from 14 to 34 years, with an average age of 24.2 years. There were 1 case of hip dysplasia and dislocation due to spinal bifida, 3 cases of hip dysplasia after pyogenic arthritis of the hip, 2 cases of developmental dysplasiaof the hip (DDH) accompanying femoral head necrosis who rejected hip replacement, 6 cases of young DDH refused to undergo hip replacement, and 1 case of bilateral hip dysplasia with dislocation due to sputum cerebral palsy. The disease duration was 2-20 years, with an average of 8.5 years. Preoperative Trendelenburg sign was positive in 12 cases and negative in 1 case. The preoperative Harris score of hip joint was 53.5±8.9 and the unequal length of lower limbs was (46.08±15.73) mm. Postoperative Harris hip score and patients' satisfaction with effectiveness evaluated according to their self scoring were used to assess the effectiveness.

Results: All 13 patients were followed up 1-5 years, with an average of 2.6 years. Five patients developed postoperative needle infection, which improved after dressing change; 7 patients had limited knee joint activity and improved after knee joint function training. The Trendelenburg sign was negative at 1 year after operation, and the patient's hip pain symptoms were relieved or disappeared. The Harris hip score of patients at 1 year after operation was 84.5±6.1, which was significantly improved when compared with preoperative one ( =-10.538, =0.000). According to Harris hip score, the effectiveness results were excellent in 4 cases, good in 5 cases, and fair in 4 cases, with an excellent and good rate of 69.2%. The unequal length of lower limbs was (15.38±7.27) mm, which was significantly better than that before operation ( =11.826, =0.000). At last follow-up, the patients' satisfaction score was 80%-95%, with an average of 88%.

Conclusion: Modified Ilizarov hip reconstruction can be used to treat young patients with hip disease who are unsuitable or refuse to undergo artificial hip replacement. Its effectiveness is reliable, and it has unique advantages in limb limp improvement and limb shortening correction.
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http://dx.doi.org/10.7507/1002-1892.201904107DOI Listing
November 2019

PGE signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia.

Proc Natl Acad Sci U S A 2019 05 29;116(20):10019-10024. Epub 2019 Apr 29.

Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA 94305;

The inflammatory prostaglandin E2 (PGE) EP2 receptor is a master suppressor of beneficial microglial function, and myeloid EP2 signaling ablation reduces pathology in models of inflammatory neurodegeneration. Here, we investigated the role of PGE EP2 signaling in a model of stroke in which the initial cerebral ischemic event is followed by an extended poststroke inflammatory response. Myeloid lineage cell-specific EP2 knockdown in Cd11bCre;EP2 mice attenuated brain infiltration of Cd11bCD45 macrophages and CD45Ly6G neutrophils, indicating that inflammatory EP2 signaling participates in the poststroke immune response. Inducible global deletion of the EP2 receptor in adult ROSA26-CreER (ROSACreER);EP2 mice also reduced brain myeloid cell trafficking but additionally reduced stroke severity, suggesting that nonimmune EP2 receptor-expressing cell types contribute to cerebral injury. EP2 receptor expression was highly induced in neurons in the ischemic hemisphere, and postnatal deletion of the neuronal EP2 receptor in Thy1Cre;EP2 mice reduced cerebral ischemic injury. These findings diverge from previous studies of congenitally null EP2 receptor mice where a global deletion increases cerebral ischemic injury. Moreover, ROSACreER;EP2 mice, unlike EP2 mice, exhibited normal learning and memory, suggesting a confounding effect from congenital EP2 receptor deletion. Taken together with a precedent that inhibition of EP2 signaling is protective in inflammatory neurodegeneration, these data lend support to translational approaches targeting the EP2 receptor to reduce inflammation and neuronal injury that occur after stroke.
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http://dx.doi.org/10.1073/pnas.1818544116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525498PMC
May 2019

Acupuncture Improves the Facial Muscular Function in a Case of Facioscapulohumeral Muscular Dystrophy.

J Acupunct Meridian Stud 2019 Apr 1;12(2):73-76. Epub 2018 Dec 1.

Department of Neurology and Neurological Sciences, Stanford University, Stanford, USA. Electronic address:

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disorder in which muscles of the face, shoulder blades, and upper arms develop gradual and progressive weakness. There is no effective pharmacological treatment currently available for this disorder so far. We had an opportunity to treat a patient with FSHD using acupuncture. The patient was a 62-year-old female, who presented to us with symptoms such as weakness in her eyes, mouth, shoulder, and upper and lower limbs. Muscle atrophy could be found in multiple areas in her body including her face, shoulder, arm, chest, and lower limbs. Her diagnosis of FSHD muscular dystrophy was established a few years ago and was later genetically confirmed. After a long treatment course of about 10 months with acupuncture, this patient showed a significant restoration of her facial muscle function. However, acupuncture did not improve the function of other muscle groups. The potential mechanism that acupuncture improved the facial function but not the other muscles needs to be further investigated.
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http://dx.doi.org/10.1016/j.jams.2018.11.001DOI Listing
April 2019

Engineered stem cell mimics to enhance stroke recovery.

Biomaterials 2018 09 14;178:63-72. Epub 2018 Jun 14.

Department of Neurology and the Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA; Stanford Stroke Center and Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Currently, no medical therapies exist to augment stroke recovery. Stem cells are an intriguing treatment option being evaluated, but cell-based therapies have several challenges including developing a stable cell product with long term reproducibility. Since much of the improvement observed from cellular therapeutics is believed to result from trophic factors the stem cells release over time, biomaterials are well-positioned to deliver these important molecules in a similar fashion. Here we show that essential trophic factors secreted from stem cells can be effectively released from a multi-component hydrogel system into the post-stroke environment. Using our polymeric system to deliver VEGF-A and MMP-9, we improved recovery after stroke to an equivalent degree as observed with traditional stem cell treatment in a rodent model. While VEGF-A and MMP-9 have many unique mechanisms of action, connective tissue growth factor (CTGF) interacts with both VEGF-A and MMP-9. With our hydrogel system as well as with stem cell delivery, the CTGF pathway is shown to be downregulated with improved stroke recovery.
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http://dx.doi.org/10.1016/j.biomaterials.2018.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063531PMC
September 2018

Gpr124 is essential for blood-brain barrier integrity in central nervous system disease.

Nat Med 2017 Apr 13;23(4):450-460. Epub 2017 Mar 13.

Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.
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http://dx.doi.org/10.1038/nm.4309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559385PMC
April 2017

Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice.

Brain 2016 07 13;139(Pt 7):2063-81. Epub 2016 May 13.

1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA

Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers.
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http://dx.doi.org/10.1093/brain/aww117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939702PMC
July 2016

Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.

Brain 2016 Feb 18;139(Pt 2):468-80. Epub 2015 Dec 18.

1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA 3 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA

Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery.
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http://dx.doi.org/10.1093/brain/awv360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805083PMC
February 2016

Electroacupuncture remediates glial dysfunction and ameliorates neurodegeneration in the astrocytic α-synuclein mutant mouse model.

J Neuroinflammation 2015 May 28;12:103. Epub 2015 May 28.

Departments of Neurobiology and Physiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Beijing Key Laboratory for Parkinson's Disease, Capital Medical University; Beijing Institute for Brain Disorders, Beijing, 100069, China.

Background: The acupuncture or electroacupuncture (EA) shows the therapeutic effect on various neurodegenerative diseases. This effect was thought to be partially achieved by its ability to alleviate existing neuroinflammation and glial dysfunction. In this study, we systematically investigated the effect of EA on abnormal neurochemical changes and motor symptoms in a mouse neurodegenerative disease model.

Methods: The transgenic mouse which expresses a mutant α-synuclein (α-syn) protein, A53T α-syn, in brain astrocytic cells was used. These mice exhibit extensive neuroinflammatory and motor phenotypes of neurodegenerative disorders. In this study, the effects of EA on these phenotypic changes were examined in these mice.

Results: EA improved the movement detected in multiple motor tests in A53T mutant mice. At the cellular level, EA significantly reduced the activation of microglia and prevented the loss of dopaminergic neurons in the midbrain and motor neurons in the spinal cord. At the molecular level, EA suppressed the abnormal elevation of proinflammatory factors (tumor necrosis factor-α and interleukin-1β) in the striatum and midbrain of A53T mice. In contrast, EA increased striatal and midbrain expression of a transcription factor, nuclear factor E2-related factor 2, and its downstream antioxidants (heme oxygenase-1 and glutamate-cysteine ligase modifier subunits).

Conclusions: These results suggest that EA possesses the ability to ameliorate mutant α-syn-induced motor abnormalities. This ability may be due to that EA enhances both anti-inflammatory and antioxidant activities and suppresses aberrant glial activation in the diseased sites of brains.
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http://dx.doi.org/10.1186/s12974-015-0302-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449593PMC
May 2015

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models.

J Clin Invest 2015 Jan 8;125(1):350-64. Epub 2014 Dec 8.

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.
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http://dx.doi.org/10.1172/JCI77487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382270PMC
January 2015

Relation between microPET imaging and rotational behavior in a parkinsonian rat model induced by medial forebrain bundle axotomy.

Behav Brain Res 2014 May 15;265:148-54. Epub 2014 Feb 15.

Department of Neurobiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, PR China. Electronic address:

The purpose of the current study was to examine the relation between apomorphine (APO) induced rotational behavior and the pre- and post-synaptic dopaminergic function in a parkinsonian rat model induced by medial forebrain bundle (MFB) axotomy. The brains of these rats were unilaterally lesioned by mechanical transection of the nigrostriatal dopamine pathway at the MFB. Behavioral studies were carried out by APO challenge prior to and 1, 3, and 5 weeks after MFB axotomy. MicroPET scans with [(11)C]CFT and [(11)C]raclopride were performed 2 days after the behavioral test. The two PET scans were separated by an interval of 24-48 h. Immunohistochemistry was conducted 4 days after the last PET scan. Our data showed that [(11)C]CFT binding decreased progressively 1, 3, and 5 weeks postlesion, and there was a significant nonlinear correlation between [(11)C]CFT uptake ratio (right/left) and APO induced rotations. In contrast, [(11)C]raclopride binding only increased significantly 3 weeks postlesion, and there was a positive linear correlation between [(11)C]raclopride uptake ratio (right/left) and APO induced rotations. Postmortem immunohistochemical studies confirmed the loss of both striatal dopamine fibers and nigral neurons on the lesioned side. These findings not only demonstrate the relation between APO induced rotational behavior and the pre- and post-synaptic dopamine function but also indicate the utility and validity of in vivo PET imaging in understanding disease mechanisms and progression, which should in turn lead to development of new therapies.
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http://dx.doi.org/10.1016/j.bbr.2014.02.008DOI Listing
May 2014

Efficacy of percutaneous laser disc decompression on lumbar spinal stenosis.

Lasers Med Sci 2014 May 31;29(3):921-3. Epub 2013 Aug 31.

Department of Orthopaedics, Beijing Chuiyangliu Hospital, Beijing, 100022, People's Republic of China,

The objective of this study is to observe the effect of percutaneous laser disc decompression (PLDD) on lumbar spinal stenosis (LSS). Thirty-two LSS patients were treated using pulsed Nd: YAG laser, of which 21 cases (11 males and 10 females with an average age of 64 years old) were followed up for 2 years. All of the 21 patients had intermittent claudication with negative straight leg raising test results. Fifteen patients suffered from anterior central disc herniation which often compressed the cauda equina but seldom compressed the posterior part; six patients suffered from posterior ligamentum flavum hypertrophy which often compressed the cauda equina but seldom compressed the anterior part. The efficacy was evaluated 1, 3, 6, 12 and 24 months after surgery on 21 patients using the performance evaluation criteria of the lumbago treatment by the Japanese Orthopaedic Association (JOA 29 scores). The fineness (i.e. excellent and good treatment outcome) rate 1, 3, 6, 12 and 24 months after the operation were 46.7%, 66.7%, 66.7%, 66.7% and 66.7%, respectively, in patients with severe anterior compression and 16.7%, 33.3%, 33.3%, 33.3% and 33.3%, respectively, in patients with severe posterior compression. PLDD had certain positive efficacy on the treatment of lumbar spinal stenosis, which was more significant on LSS dominated by the anterior compression than that by the posterior compression.
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http://dx.doi.org/10.1007/s10103-013-1429-8DOI Listing
May 2014

Electro-acupuncture stimulation improves spontaneous locomotor hyperactivity in MPTP intoxicated mice.

PLoS One 2013 30;8(5):e64403. Epub 2013 May 30.

Neuroscience Research Institute, Peking University, Key Laboratory for Neuroscience of the Ministry of Education, Beijing, PR China.

Bradykinesia is one of the major clinical symptoms of Parkinson`s disease (PD) for which treatment is sought. In most mouse models of PD, decreased locomotor activity can be reflected in an open field behavioral test. Therefore the open field test provides a useful tool to study the clinic symptoms of PD patients. Our previous work demonstrated that 100 Hz electro-acupuncture (EA) stimulation at ZUSANLI and SANYINJIAO protected the dopaminergic nigrostriatal system of C57BL/6 mice from MPTP toxicity, indicating that acupuncture might be an effective therapy for PD sufferers. In the present study, we investigated the effects of 100 Hz EA stimulation on the spontaneous locomotor activity in MPTP injured mice. Here we found that, in MPTP treated mice, the total movements significantly decreased and the movement time, velocity and distance dramatically increased, although the dopaminergic nigrostriatal system was devastated, revealed by immunohistochemistry and HPLC-ECD. After 12 sessions of 100 Hz EA stimulation, the total movements elevated and the movement time, velocity and distance decreased, in MPTP mice. 100 Hz EA increased striatal dopamine content in MPTP mice by 35.9%, but decreased its striatal dopamine turnover. We assumed that the injury of other regions in the brain, such as the A11 group in diencephalon, might be involved in the hypermotility in MPTP mice. The effects of 100 Hz EA on spontaneous locomotor activity in MPTP mice might not relate with the striatal dopamine, but with its neuroprotective and regulatory effects on motor circuits in the brain. Our study suggests that EA might be a promising treatment for neurological disorders including PD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064403PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667805PMC
January 2014

Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer disease.

Ann Neurol 2012 Nov 22;72(5):788-98. Epub 2012 Aug 22.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.

Objective: There is significant evidence for a central role of inflammation in the development of Alzheimer disease (AD). Epidemiological studies indicate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the preclinical development of AD. Here, we investigate the function of prostaglandin E(2) (PGE(2) ) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide.

Methods: The function of PGE(2) signaling through its EP3 receptor was examined in vivo in a model of subacute neuroinflammation induced by administration of Aβ(42) peptides. Our findings were then confirmed in young adult APPSwe-PS1ΔE9 transgenic mice.

Results: Deletion of the PGE(2) EP3 receptor in a model of Aβ(42) peptide-induced neuroinflammation reduced proinflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1ΔE9 model of familial AD, deletion of the EP3 receptor blocked induction of proinflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were β-secretase and β C-terminal fragment levels, suggesting that generation of Aβ peptides may be increased as a result of proinflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in presynaptic proteins seen in APPSwe-PS1ΔE9 mice.

Interpretation: Our findings identify the PGE(2) EP3 receptor as a novel proinflammatory, proamyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE(2) -EP3 signaling in the development of AD.
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http://dx.doi.org/10.1002/ana.23677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509238PMC
November 2012

Signaling via the prostaglandin E₂ receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia.

J Clin Invest 2011 Nov 3;121(11):4362-71. Epub 2011 Oct 3.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.

Stroke is the third leading cause of death in the United States. Fewer than 5% of patients benefit from the only intervention approved to treat stroke. Thus, there is an enormous need to identify new therapeutic targets. The role of inducible cyclooxygenase (COX-2) activity in stroke and other neurologic diseases is complex, as both activation and sustained inhibition can engender cerebral injury. Whether COX-2 induces cerebroprotective or injurious effects is probably dependent on which downstream prostaglandin receptors are activated. Here, we investigated the function of the PGE2 receptor EP4 in a mouse model of cerebral ischemia. Systemic administration of a selective EP4 agonist after ischemia reduced infarct volume and ameliorated long-term behavioral deficits. Expression of EP4 was robust in neurons and markedly induced in endothelial cells after ischemia-reperfusion, suggesting that neuronal and/or endothelial EP4 signaling imparts cerebroprotection. Conditional genetic inactivation of neuronal EP4 worsened stroke outcome, consistent with an endogenous protective role of neuronal EP4 signaling in vivo. However, endothelial deletion of EP4 also worsened stroke injury and decreased cerebral reperfusion. Systemic administration of an EP4 agonist increased levels of activated eNOS in cerebral microvessels, an effect that was abolished with conditional deletion of endothelial EP4. Thus, our data support the concept of targeting protective prostaglandin receptors therapeutically after stroke.
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http://dx.doi.org/10.1172/JCI46279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204834PMC
November 2011

The antioxidative effect of electro-acupuncture in a mouse model of Parkinson's disease.

PLoS One 2011 23;6(5):e19790. Epub 2011 May 23.

Neuroscience Research Institute, Peking University, Beijing, People's Republic of China.

Accumulating evidence indicates that oxidative stress plays a critical role in Parkinson's disease (PD). Our previous work has shown that 100 Hz electro-acupuncture (EA) stimulation at ZUSANLI (ST36) and SANYINJIAO (SP6) protects neurons in the substantia nigra pars compacta from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in male C57BL/6 mice, a model of PD. In the present study we administered 100 Hz EA stimulation at the two acupoints to MPTP-lesioned mice for 12 sessions starting from the day prior to the first MPTP injection. We found that in the striatum of MPTP treated mice 100 Hz EA stimulation effectively inhibited the production of hydrogen peroxide and malonaldehyde, and increased glutathione concentration and total superoxide dismutase activity through biochemical methods. However, it decreased glutathione peroxidase activity via biochemical analysis and did not affect the level of 1-methyl-4-phenylpyridinium in the striatum revealed by high performance liquid chromatography with ultraviolet detection. These data suggest that 100 Hz EA stimulation at ST36 and SP6 has antioxidative effects in the MPTP model of PD. This data, along with our previous work, indicates that 100 Hz EA stimulation at ST36 and SP6 protects the nigrostriatal system by multiple mechanisms including antioxidation and antiapoptosis, and suggests that EA stimulation is a promising therapy for treating PD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100295PMC
November 2011

The prostaglandin E2 EP2 receptor accelerates disease progression and inflammation in a model of amyotrophic lateral sclerosis.

Ann Neurol 2008 Sep;64(3):304-14

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Objective: Inflammation has emerged as an important factor in disease progression in human and transgenic models of amyotrophic lateral sclerosis (ALS). Recent studies demonstrate that the prostaglandin E(2) EP2 receptor is a major regulator of inflammatory oxidative injury in innate immunity. We tested whether EP2 signaling participated in disease pathogenesis in the G93A superoxide dismutase (SOD) model of familial ALS.

Methods: We examined the phenotype of G93A SOD mice lacking the EP2 receptor and performed immunocytochemistry, quantitative reverse transcriptase polymerase chain reaction, and Western analyses to determine the mechanism of EP2 toxicity in this model.

Results: EP2 receptor is significantly induced in G93A SOD mice in astrocytes and microglia in parallel with increases in expression of proinflammatory enzymes and lipid peroxidation. In human ALS, EP2 receptor immunoreactivity was upregulated in astrocytes in ventral spinal cord. In aging G93A SOD mice, genetic deletion of the prostaglandin E(2)EP2 receptor improved motor strength and extended survival. Deletion of the EP2 receptor in G93A SOD mice resulted in significant reductions in levels of proinflammatory effectors, including cyclooxygenase-1, cyclooxygenase-2, inducible nitric oxide synthase, and components of the NADPH oxidase complex. In alternate models of inflammation, including the lipopolysaccharide model of innate immunity and the APPSwe-PS1DeltaE9 model of amyloidosis, deletion of EP2 also reduced expression of proinflammatory genes.

Interpretation: These data suggest that prostaglandin E(2) signaling via the EP2 receptor functions in the mutant SOD model and more broadly in inflammatory neurodegeneration to regulate expression of a cassette of proinflammatory genes. Inhibition of EP2 signaling may represent a novel strategy to downregulate the inflammatory response in neurodegenerative disease.
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http://dx.doi.org/10.1002/ana.21437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766522PMC
September 2008

Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia.

Neurosci Lett 2008 Jun 20;438(2):210-5. Epub 2008 Apr 20.

Department of Neurology and Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, United States.

Induction of COX-2 activity in cerebral ischemia results in increased neuronal injury and infarct size. Recent studies investigating neurotoxic mechanisms of COX-2 demonstrate both toxic and paradoxically protective effects of downstream prostaglandin receptor signaling pathways. We tested whether misoprostol, a PGE(2) receptor agonist that is utilized clinically as an anti-ulcer agent and signals through the protective PGE(2) EP2, EP3, and EP4 receptors, would reduce brain injury in the murine middle cerebral artery occlusion-reperfusion (MCAO-RP) model. Administration of misoprostol, at the time of MCAO or 2h after MCAO, resulted in significant rescue of infarct volume at 24 and 72h. Immunocytochemistry demonstrated dynamic regulation of the EP2 and EP4 receptors during reperfusion in neurons and endothelial cells of cerebral cortex and striatum, with limited expression of EP3 receptor. EP3-/- mice had no significant changes in infarct volume compared to control littermates. Moreover, administration of misoprostol to EP3+/+ and EP3-/- mice showed similar levels of infarct rescue, indicating that misoprostol protection was not mediated through the EP3 receptor. Taken together, these findings suggest a novel function for misoprostol as a protective agent in cerebral ischemia acting via the PGE(2) EP2 and/or EP4 receptors.
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http://dx.doi.org/10.1016/j.neulet.2008.04.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2621308PMC
June 2008

Divergent effects of prostaglandin receptor signaling on neuronal survival.

Neurosci Lett 2007 Jun 7;421(3):253-8. Epub 2007 Jun 7.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.

Induction of cyclooxygenase-2 (COX-2) with production of prostaglandins occurs in a wide spectrum of acute and chronic neurodegenerative diseases and is associated with neuronal death. Inhibition of the COX-2 pathway and downstream production of prostaglandins protect neurons in rodent models of cerebral ischemia and neurodegeneration. Recent studies investigating the functions of selected prostaglandin receptor pathways in mediating COX-2 neurotoxicity have demonstrated both toxic and paradoxically neuroprotective effects of several receptors in models of excitotoxicity. In this study, we investigate the functions of additional prostaglandin receptors not previously characterized in organotypic models of glutamate excitotoxicity. We find that PGD(2), PGI(2), and PGF(2alpha) receptors protect motor neurons in an organotypic spinal cord model of amyotrophic lateral sclerosis (ALS). In addition, PGI(2) and TXA(2) receptors rescue CA1 neurons in an organotypic hippocampal model of N-methyl-d-aspartate excitotoxicity. However, in a model of inflammation induced by lipopolysaccharide, prostaglandin receptors previously found to be protective in excitotoxicity now cause CA1 neuronal death. Taken together, these studies identify novel eicosanoid receptor signaling pathways that mediate neuronal protection in excitotoxic paradigms; these data also support the emerging hypothesis that the toxic/protective effects of eicosanoid signaling on neuronal viability diverge significantly depending on whether excitotoxicity or inflammation predominates as the underlying toxic stimulus.
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http://dx.doi.org/10.1016/j.neulet.2007.05.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680717PMC
June 2007

Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer's disease.

J Neurosci 2005 Nov;25(44):10180-7

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E2 (PGE2) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE2 EP2 receptor in the APPSwe-PS1DeltaE9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid-beta (Abeta) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1DeltaE9 mice lacking the EP2 receptor harbor lower levels of beta C-terminal fragments, the product of beta-site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased Abeta peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.
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http://dx.doi.org/10.1523/JNEUROSCI.3591-05.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6725803PMC
November 2005

Prostaglandin D2 mediates neuronal protection via the DP1 receptor.

J Neurochem 2005 Feb;92(3):477-86

Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21205, USA.

Cyclo-oxygenases (COXs) catalyze the first committed step in the synthesis of the prostaglandins PGE(2), PGD(2), PGF(2alpha), PGI(2) and thomboxane A(2). Expression and enzymatic activity of COX-2, the inducible isoform of COX, are observed in several neurological diseases and result in significant neuronal injury. The neurotoxic effect of COX-2 is believed to occur through downstream effects of its prostaglandin products. In this study, we examined the function of PGD(2) and its two receptors DP1 and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) (DP2) in neuronal survival. PGD(2) is the most abundant prostaglandin in brain and regulates sleep, temperature and nociception. It signals through two distinct G protein-coupled receptors, DP1 and DP2, that have opposing effects on cyclic AMP (cAMP) production. Physiological concentrations of PGD(2) potently and unexpectedly rescued neurons in paradigms of glutamate toxicity in cultured hippocampal neurons and organotypic slices. This effect was mimicked by the DP1-selective agonist BW245C but not by the PGD(2) metabolite 15d-PGJ(2), suggesting that neuroprotection was mediated by the DP1 receptor. Conversely, activation of the DP2 receptor promoted neuronal loss. The protein kinase A inhibitors H89 and KT5720 reversed the protective effect of PGD(2), indicating that PGD(2)-mediated neuroprotection was dependent on cAMP signaling. These studies indicate that activation of the PGD(2) DP1 receptor protects against excitotoxic injury in a cAMP-dependent manner, consistent with recent studies of PGE(2) receptors that also suggest a neuroprotective effect of prostaglandin receptors. Taken together, these data support an emerging and paradoxical neuroprotective role of prostaglandins in the CNS.
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http://dx.doi.org/10.1111/j.1471-4159.2004.02870.xDOI Listing
February 2005

Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia.

J Neurosci 2004 Jan;24(1):257-68

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE2, a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein-coupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMP-dependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE2 receptor subtype in brain that may provide a target for therapeutic intervention.
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http://dx.doi.org/10.1523/JNEUROSCI.4485-03.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729582PMC
January 2004