Baclofen治疗脊髓损伤后痉挛的疗效观察

目的观察脊髓损伤性痉挛患者口服Baclofen的解痉效果。方法136例患者连续服药2个月。采用改良Ashworth评分进行评定。结果改良Ashworth评分降低超过1级的131例(96.3%)。结论该药对不同年龄、性别、损伤部位、损伤程度和损伤时间的患者均有明显的解痉效果,长期服药对肝肾功能无影响。

Baclofen治疗脊髓损伤性痉挛的初步报告

Baclofen常译为贝克洛酚或巴氯酚.商品名称是力奥来素(Lioresal),是目前最有效、副作用最小的骨骼肌松驰剂,自70年代以来,国外一直广泛应用于脊髓损伤性痉挛患者的治疗.我科在国内率先将此药应用于脊髓损伤合并痉挛的临床治疗,取得较好效果.1 资料与方法1.1 对象 患者18例,男14例,女4例;年龄21～61岁,平均33岁;受伤时间4月～16年,平均1年:四肢瘫8例,截瘫10例;完全性损伤9例,不完全性损伤9例.1.2 Baclofen作用机制 Baclofen抑制单突触和多突触反射传递,它可刺激GABA_B受体。

Baclofen对慢性神经痛大鼠镇痛效果的影响

目的 研究GABAB 受体激动剂baclofen对慢性神经痛大鼠痛阈的影响以及对脊髓c fos表达的影响 ,探讨脊髓GABA能系统在神经痛调节中的可能机制。方法 结扎大鼠左侧L5脊神经根建立慢性神经痛模型。SD大鼠 2 4只随机等分成 (1)假手术 +baclofen组 :大鼠背部假手术而未行神经根结扎 ,术后 2 8至 34d每天腹腔注射baclofen 10mg/kg两次 ;(2 )假手术组 :背部假手术后2 8至 34d每天腹腔注射 0 9%NaCl 2ml两次 ;(3)L5结扎 +baclofen组 :实施L5神经根结扎 ,术后2 8至 34d每天腹腔注射baclofen 10mg/kg两次 ;(4)L5结扎组 :实施L5神经根结扎 ,术后 2 8至 34d每天腹腔注射 0 9%NaCl 2ml两次。术后 1、3、7、10、14、2 1、2 8、35d测大鼠双后肢光热刺激性痛阈。术后 35d处死大鼠取出腰段脊髓 ,冰冻切片 ,免疫组化法检测c fos免疫阳性细胞。结果 (1)术后 7～ 2 8d ,左L5脊神经结扎大鼠较假手术大鼠痛阈明显降低 (P <0 0 1)。术后 35d ,使用与不使用baclofen大鼠的假手术大鼠左后肢痛阈无显著变化 (P >0 0 5 ) ,双侧脊髓深层 (Ⅲ Ⅹ层 )FLI细胞无显著差异 (P >0 0 5 ) ;(2 )术后 35d ,使用baclofen的L5结扎大鼠的左后肢痛觉显著低于未使用baclofen的L5结扎大鼠 (P <0 0 1) ,前者脊髓深层 (Ⅲ Ⅹ层 )FLI细胞显著?

Baclofen对大鼠新鲜分离DRG神经元GABA和NMDA激活电流的抑制作用

用全细胞膜片箝技术在大鼠新鲜分离的背根神经节 (DRG)细胞上观察到baclofen对GABA和NMDA激活电流有调制作用。单独给予DRG细胞baclofen (1～ 10 0 μmol/L)未记录到可测的电流改变 ,但预加baclofen对GABA和NMDA激活电流具有明显的抑制作用 ,且呈剂量依赖性。 10 0 μmol/Lbaclofen对GABA和NMDA激活电流分别抑制(5 1.2± 10 .9) % (X±SE ,n=8,P <0 .0 1)和 (6 4 .1± 2 1.1) % (X±SE ,n=6 ,P <0 .0 1) ,此抑制作用是可逆的 ,可被GABAB 受体拮抗剂saclofen(10 0 μmol/L ) 所取消 (n =4 )。

Baclofen对成年大鼠和猫背根神经节神经元电活动的影响

药理学研究表明哺乳类动物脊髓背角中的GABA受体亚型（GABAA和GABAB）参与介导脊髓初级传入末梢的突触前抑制．本研究应用细胞内记录技术探讨GABAB受体激活对背根神经节（dorsalrootganglion，DRG）细胞膜电特性的作用．实验标本取自SD成年大鼠（120-190g，n＝58）DRG（L4-L6）和猫（n＝8）在体L6-L7DRRG,当灌流液加入GABAB受体激活剂baclofen（10-4-10-6mol／L）时，在DRG的98个细胞中，约58％的细胞（n＝57）无反应．部分A类和C类细胞的膜电位出现超极化（n＝37）和去极化（n＝14）反应．A传入（n＝71）和C传入（n＝27）激活的反应没有明显的差异．Baclofen引起的DRG细胞的去极化和超极化反应可被GABAB受体选择性拮抗剂saclofen（103-105mo1／L）阻断．一些对baclofen反应的细胞也可被GABAA受体激动剂muscimol去极化．在所记录的细胞中，baclofen对动作电位时程（APD50）没有明显的影响．上述结果提示，在部分细胞中，baclofen激活的GABAB受体介导细胞膜电位去极化和超级化反应,GABAA和GABAB这二种受体不仅在慢传速的Aδ和C类细胞中共存，同样也共存于快传速的Aα和Aβ的细胞膜上．

Baclofen对大鼠脊髓薄片胶状质神经元的抑制作用

用脊髓薄片全细胞电压钳法观察激活γ 氨基丁酸B亚型受体 (GABABR)对大鼠脊髓背角胶状质(SG)神经元活动的影响。选择性GABABR激动剂baclofen减少所有被记录SG神经元 (n =15)的微小兴奋性突触后电流 (mEPSCs)的发放频率 ,同时引起一缓慢的抑制性 (外向 )膜电流并伴有膜电导增加。细胞内电泳G蛋白偶联受体抑制剂 (GDP β S)抑制被钳制神经元的G蛋白偶联受体后 ,baclofen引起的缓慢外向电流被抑制 ,但对mEPSC频率的减低作用依然存在。结果提示脊髓内baclofen敏感的GABAB

Therapeutic efficacy of baclofen in refractory gastroesophageal reflux-induced chronic cough

AIM:To evaluate the efficacy and safety of baclofen for treatment of refractory gastroesophageal reflux-induced chronic cough (GERC) unresponsive to standard anti-reflux therapy. METHODS:Sixteen patients with refractory GERC were given an 8-wk course of baclofen 20 mg three times a day as an add-on therapy to omeprazole. Changes in the cough symptom score, cough threshold to capsaicin, reflux symptom score and possible adverse effects were determined after treatment. The variables of multi-channel intraluminal impedance combined with pH monitoring were compared between responders and non-responders to baclofen. RESULTS:Twelve of 16 patients completed treatment. Cough disappeared or improved in 56.3% (9/16)of patients, including 6 patients with acid refluxinduced cough (66.7%) and 3 patients with non-acid reflux-induced cough (33.3%). With baclofen treatment, the cough symptom score began to decrease at week 2, was clearly decreased at week 6 and reached a minimum at week 8. At the end of therapy, the lowest concentration of capsaicin required for induction of ≥ 2 and ≥ 5 coughs increased from 0.98 (1.46) to 1.95 (6.82) μmol/L (Z = -2.281, P = 0.024) and from 1.95 (7.31) to 7.8 (13.65) μmol/L (Z = -2.433, P = 0.014), respectively, and the reflux symptom score decreased from 8.0 ± 1.6 to 6.8 ± 0.8 (t = 2.454, P = 0.023). The number of acid reflux episodes was significantly lower in responders than in non-responders. The main adverse effects were somnolence, dizziness and fatigue. CONCLUSION:Baclofen is a useful, but suboptimal treatment option for refractory GERC.

Baclofen与异搏停治疗脊髓损伤后痉挛性膀胱的对比研究

目的 :观察Baclofen与异搏停治疗脊髓完全性损伤后痉挛性膀胱的疗效并进行比较分析。方法 :将 32例脊髓损伤后痉挛性膀胱患者按随机抽样法分为Baclofen组和异搏停组 ,分别于用药后 2、4、8周观察膀胱功能变化 ,并进行尿流动力学检测。结果 :两组患者用药后排尿间隔延长、排尿量增加、尿道压力降低 ,膀胱贮尿及排尿功能均较用药前明显提高 ,Baclofen组优于异搏停组。结论 :Baclofen与异搏停治疗脊髓损伤后痉挛性膀胱疗效显著 ,Ba clofen可做为首选用药。

Comparison of Baclofen and Tizanidine in Reducing Spasticity in Cerebral Palsy: A Randomized Control Trial

Background: Cerebral palsy is the most common chronic motor disability that begins in childhood with the predominant motor abnormality that is spasticity. Objective: The purpose of the present study was to compare the efficacy of oral baclofen and oral tizanidine in reducing spasticity in cerebral palsy patients. Methodology: This randomized controlled trial was conducted from January 2010 to December 2011 and it was carried out in the Out Patient Department (OPD) of Pediatrics at Dhaka Medical College Hospital (DMCH), Dhaka, Bangladesh and Center for Neurodevelopment and Autism in Children (CNAC) of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Results: A total number of 70 cerebral palsy children were recruited for this study of which 35 patients were in Tizanidine group and 35 patients were in baclofen group. Furthermore, 70 cerebral palsy children were taken as control who were treated with placebo. Tizanidine had superior efficacy in reducing tone in spastic cerebral palsy over baclofen measured by using Modified Ashworth scale in different time periods from AS score-3 to score-2 (p < 0.05). Tizanidine was also superior in joint angle improvement in spastic cerebral palsy measured by physician rating scale from AS score-3 to score-2 (crouch p < 0.0001) and foot contact from AS score-3 to score-2 (p < 0.0001);but no statistically significant improvement in gross motor function. Adverse effect was more in baclofen group. Conclusion: For reducing generalized spasticity with regards to muscle tone, joint angle and improvement in gait in cerebral palsy patients, tizanidine has superior efficacy and less adverse effects than baclofen.

不对称氢转移合成R-(-)-Baclofen

以外消旋的β-羟基酮酸酯为原料,通过不对称氢转移的方法,高效的合成了光学活性的手性中间体β-羟基酮酸酯,光学纯度达到98%,然后通过亲核取代反应生成了光学活性的β-氰基丙酮酸酯,最后还原生成R-(-)-Baclofen。

Effect of baclofen combined with neural facilitation technique on the reduction of muscular spasm in patients with spinal cord injury

BACKGROUND： Recent researches have demonstrated that baclofen is a commonly central anti-spasm drug. In addition, neural facilitation technique based on nerve development and neurophysiology is widely used for rehabilitation training of motor disorder after central nerve injury. However, whether baclofen combining with neural facilitation technique can relieve muscular spasm after spinal cord injury needs further studies. OBJECTIVE： To observe the effect of baclofen combining with neural facilitation technique on decreasing muscular tension in two lower extremities after spinal cord injury. DESIGN： Randomized controlled study. SETTING- Departments of Rehabilitation and Orthopaedics, the Third Affiliated Hospital of Guangzhou Medical College. PARTICIPANTS： A total of 28 patients with spinal cord injury, including 17 males and 11 females, whose age ranged from 31 to 71 years, were selected from Departments of Rehabilitation and Orthopaedics, the Third Affiliated Hospital of Guangzhou Medical College from March 2005 to September 2006. The illness course ranged from 22 to 54 days and the mean course was （38±8） days. All patients were diagnosed as the fLrst onset and the increase of extensor muscular tension in two lower extremities after thoracic vertebra injury by using spine MR or CT examination. Informed consents were obtained from all the patients. METHODS： All 28 patients who had upper motor neuronal paralysis in two lower extremities after spinal cord injury in thoracic vertebra region were randomly divided into treatment group and control group with 14 cases in each group. Patients in both groups received routine therapy, while those in the treatment group were treated with oral baclofen （the beginning dosage： 5 rag/time; three times per day, 5 mg was increased every three days; the maximal dosage was 60 mg/day; 6 weeks in total） （made in Weicai Pharmaceutical Co., Ltd.; tablet; batch number： HC20040029） combining with neural facilitation technique, which accorded to Rood technique （slight joint extrusion, slow and persistent stretch, etc.）, Brunnstrom technique （non-symmetric cervical reflex： head turning to one side promoting contralateral flexuosity in both upper and lower extremities） and Bobath technique （reflective inhibition, such as reducing supine position; increasing lateral recumbent position, rolling in bed and posture transfer; controlling key sites; 6 weeks in total）. MAIN OUTCOME MEASURES： At 6 weeks after treatment, modified Ashworth grading method and Barthel Index were used to detect extensor muscular tension in two lower extremities and activities of daily living （ADL） of patients in both groups. RESULTS： ①Grade of muscular tension in two lower extremities： At 6 weeks after treatment, muscular tension in the treatment group was classified into grade I （n =12）, gradeII （n =2） and grade III（n =0）, which was markedly improved as compared with that in the control group [grade Ⅰ （n =6）, grade Ⅱ （n =4） and grade Ⅲ （n =4）]. In addition, there was significant difference between the two groups （P 〈 0.05）. ②ADL ability： Barthel Index of patients with complete and incomplete spinal cord injury in the treatment group was higher than that in the control group at 6 weeks after treatment, and there was significant difference between them （P 〈 0.05）. CONCLUSION： Baclofen combining with neural facilitation technique can not only remarkably relieve muscular tension of upper motor neuronal paralysis after spinal cord injury, but also obviously accelerate recoveries of motor functional and ADL ability.

Intrathecal Baclofen Facilitated Postanesthetic Tracheal Extubation in a Dystonic Patient Associated with Neurodegeneration of Brain Iron Accumulation (Hallervorden-Spatz Disease)

Patients with Hallervorden-Spatz disease may be confronted by invasive procedure, like gastrostomy and thalamotomy for care of the status of extreme dystonia and rigidity. This rare disorder possesses potential perioperative risks, such as difficult airway management, aspiration pneumonia, hyperpyrexia, dehydration, acute renal failure, and postoperative pulmonary insufficiency. As patients were usually in the state of uncontrollable dystonia and rigidity, delayed endotracheal extubation had been suggested by several previous case reports. We report the anesthetic management of a 34-year-old Hallervorden-Spatz disease woman scheduled for intrathecal baclofen pump implantation under general anesthesia. Preoperatively she had suffered from severe dystonia, confusion and repeated attacks of respiratory insufficiency and pneumonia requiring mechanical ventilation and critical care. Anesthesia was induced uneventfully and the catheter of the pump reached the CSF via T2 interspace. Intraoperative intrathecal baclofen injection mildly relieved her severe dystonia and rigidity. Hemodynamics and arterial blood gas were improved than preoperative. She was extubated after consciousness was regained. Postanesthetic visit demonstrated a fair outcome. Whether this treatment applies to every case confronted by general anesthesia needs to be elucidated. Nevertheless, we suggest intrathecal baclofen may help postanesthetic pulmonary care by attenuating dystonia and rigidity and can be an adjuvant for anesthesia care in patients with Hallervorden-Spatz disease.

The Importance of Adjuvant Agents in Acute Intrathecal Baclofen Withdrawal: Case Report and Review of the Literature

Objective: Baclofen (β-p-chlorophenyl-GABA) selectively activates the GABAB subtype of γ-aminobutyric acid (GABA) receptors, a group of receptors known to provide inhibitory neurotransmission in the central nervous system. Available for over thirty years in oral form for the treatment of skeletal muscle spasticity, its availability now includes continuous intrathecal infusion via an internally implanted pump. While ideal for long-term attenuation of symptoms, this treatment modality can also become disastrous should the pump empty and withdrawal subsequently ensue. Case Report: A 48-year-old male with a past medical history of T8 spinal cord injury from a motor vehicle crash originally presented with altered mental status. Because of resultant paraplegia and spasticity from his injuries, a neurosurgeon implanted an intrathecal baclofen pump three years prior to presentation with symptomatic relief. Further exploration revealed that he had missed his scheduled pump refill appointment and interrogation of his pump confirmed a completely empty reservoir. The patient endured a protracted hospital course that included rhabdomyolysis, acute renal failure, lactic acidosis, respiratory failure, and systemic inflammatory response syndrome. Treatment included benzodiazepines, dantrolene, aggressive hydration, opiates, and refill of his intrathecal baclofen pump. His mentation and ventilatory status improved with recovery from his critical illness and eventual discharge. Conclusions: Treatment of intrathecal baclofen withdrawal should focus on restoration of previous intrathecal baclofen levels by refill of the intrathecal pump. Adjuvant medications such as benzodiazepines, propofol, cyproheptadine, dantrolene, tizanidine, and opiates may prove crucial in helping with muscle spasticity while these levels are reestablished. A high index of suspicion, leading to timely initiation of proper treatment, may serve as the most important factor in successful recovery from this life-threatening syndrome.

Long-term effect of intrathecal baclofen treatment on bone health and body composition after spinal cord injury:A case matched report

BACKGROUND Severe spasticity may negatively impact functionality and quality of life after spinal cord injury(SCI).Intrathecal baclofen treatment(IBT)is effectively used to manage severe spasticity and reduce comorbidities.However,long-term IBT may have a negative effect on bone mineral content(BMC),bone mineral density(BMD)and body composition(such as percentage fat mass and lean body mass).We demonstrated the negative effects of long-term IBT use in a single case compared with two non-IBT users.CASE SUMMARY A 46-year old Caucasian male Veteran(case)with a 21 year history of complete tetraplegia(complete C6 SCI)was implanted with IBT for 20 years.The case was matched to two participants with different time since injuries[2(match 1)and 13(match 2)years]without IBT.Knee BMC and BMD at the epiphysis and metaphysis of the distal femur and proximal tibia were evaluated using dual knee and the dual femur modules of GE Lunar iDXA software.Total and leg body composition assessments were also conducted for the three participants.Potential effect of long-term IBT was demonstrated by changes in BMD,consistent with bone demineralization,at the distal femur and proximal tibia and changes in percentage fat mass and lean mass of legs.The case showed 113%lower BMD at the distal femur,and 78.1%lower at the proximal tibia compared to match 1,moreover the case showed 45%lower BMD at the distal femur,and no observed changes at the proximal tibia compared to match 2.The case had 27.1%and 16.5%greater leg%fat mass compared to match 1 and match 2,respectively.Furthermore,the case had 17.4%and 11.8%lower%leg lean mass compared to match 1 and match 2,respectively.CONCLUSION Long-term IBT may impact bone health and body composition parameters in persons with complete SCI.It may be prudent to encourage regular screening of individuals on long-term IBT considering the prevalence of osteoporosis related fractures,cardiovascular diseases,and metabolic disorders in this population.

Baclofen对机械分离的大鼠海马锥体细胞GABA-激活电流的抑制作用

在机械分离的海马锥体细胞上,应用全细胞膜片钳技术。证明大多数细胞(88.5％,46／52)对GABA敏感。10-5-10-3mol／L的GABA引起一剂量依赖性、有明显去敏感作用的内向电流。预加3×10-5mol／L baclofen(GABAB受体的特异性激动剂)30 s后再加GABA,84.8％(39／46)的细胞GABA-激活电流被抑制,其中仅有一个细胞(2.2％,1／46)GABA-激活电流幅值增强,13％(6／46)的细胞GABA-激活电流幅值无变化。预加baclofen后,GABA-激活电流量-效曲线明显下移。预加baclofen前后IGABA量效曲线的Kd值非常接近(1.0×10-4 vsl.4×10-4 mol／L)。经saclofen预处理可消除baclofen对GABA-激活电流的抑制。这与我室以往在外周神经元上的研究结果一致。本文结果不仅证明了GABAA和GABAB受体在海马锥体细胞上的共存,而且也证明了GABAB受体激活后对GABAA受体功能抑制这一现象无论在外周或中枢神经系统均具有普遍性。

巴氯芬过量致晚期直肠癌患者昏迷1例并文献复习

呃逆是临床常见病症,在肿瘤患者中发生率可能更高,一般可通过去除诱因、药物治疗及物理疗法缓解。巴氯芬是治疗顽固性呃逆的有效药物,但不良反应较多。本文介绍了1例不合理应用巴氯芬致严重不良反应的病例,以期为临床工作提供一定参考。

Differential effects of aging on EEG after baclofen administration

Baclofen is a selective gamma-aminobutyric acid (GABA) type B agonist that may have important medicinal uses,such as in analgesics and drug addiction treatment.In addition,evidence is accumulating that suggests GABAergic-mediated neurotransmission is altered during aging.This study investigated whether baclofen administration (5 mg kg 1) induces differential effects on cortical electrical activity with age.Electroencephalograms (EEGs) were recorded from young (3-4 months) and aged (15-17 months) rats,and both the absolute and relative powers in five frequency bands (delta:2-4 Hz;theta:4-8 Hz;alpha:8-12 Hz;beta:12-20 Hz;gamma:20-100 Hz) were analyzed.Before administration of baclofen,we found that the EEG relative power in the beta band was higher in the aged than that in the young rats.After administration of baclofen,there was a slower increase in the relative power in the delta band in the aged than that in the young rats.Moreover,there was no significant difference between the two age groups in absolute power in any frequency band.These findings indicate that baclofen treatment appears to differentially modify cortical EEG activity as a function of age.Our data further elucidate the relationship between GABA B receptor-mediated neurotransmission and aging.

巴氯芬联合中医疗法用于顽固性呃逆的病例分享及思考

顽固性呃逆虽不直接致命,但严重影响患者生活质量,病程迁延日久亦可能引起诸多不良后果,临床治疗颇为棘手。此文主要以临床具体病例的形式,介绍巴氯芬联合中医疗法对顽固性呃逆的效果,文中简要提及该病的分类、治疗手段及中医的病因病机、治疗方法,并着重分析治疗经过及处方用药;同时,提出自己的思考,认为本病为顽疾,在治疗过程中,需注意病情的发展,及时调整思路及治疗用药;注意中西医结合,辨病辨证施治;注意内服、外用等多种手段并用。希望为临床同道在治疗该病的时候,提供一定的思路。

巴氯芬联合早期神经肌肉电刺激对脑卒中患者高肌张力的临床疗效研究

目的探讨巴氯芬联合早期神经肌肉电刺激对脑卒中患者高肌张力的临床疗效。方法选取上海市嘉定区安亭医院2021年1月~2023年1月收治的106例脑卒中后高肌张力患者,随机数表法分为联合组和电刺激组,各53例。电刺激组给予常规治疗并实施早期神经肌肉电刺激,联合组加用巴氯芬片,连续治疗4周。评估两组患者治疗前后肢体痉挛状况、肌张力情况、运动功能以及患者日常生活能力;观察两组患者血清炎症指标变化;统计两组患者治疗效果和不良反应。结果联合组患者总有效率为96.23%,高于电刺激组83.02%,差异有统计学意义(χ^(2)=4.970,P<0.05)。治疗后,两组患者临床痉挛指数(CSI)、Ashworth评分明显降低,Fugl-Meyer评分(FMA)、改良Barthel指数(mBI)升高,且联合组治疗后CSI、Ashworth评分低于电刺激组,FMA、mBI则高于电刺激组[(4.65±1.12)分vs.(7.73±1.63)分、(1.38±0.53)分vs.(1.81±0.46)分、(71.47±7.65)分vs.(68.08±6.44)分、(68.92±7.46)分vs.(64.89±7.09)分],差异有统计学意义(t=11.376、2.070、2.634、2.860,P<0.05)。治疗后,两组患者血清白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、高迁移率族蛋白B1(HMGB1)水平显著降低,且联合组治疗后血清IL-1β、TNF-α、HMGB1水平显著低于电刺激组[(4.63±0.85)pg ml vs.(5.29±0.91)pg ml、(9.58±2.58)pg ml vs.(12.35±3.13)pg ml、(4.51±1.24)μg L vs.(5.68±1.51)μg L],差异有统计学意义(t=3.927、4.921、4.288,P<0.05)。两组患者不良反应发生率相当(16.98%vs.7.55%),差异无统计学意义(χ2=2.192,P>0.05)。结论巴氯芬联合早期神经肌肉电刺激治疗脑卒中患者高肌张力的疗效良好,可有效降低肢体高肌张力状况,提高患肢运动功能,抑制体内炎症反应水平。

γ-aminobutyric acid B2 receptor:A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus

BACKGROUND The association between diabetes mellitus(DM)and the increased risk and progression of cholangiocarcinoma(CCA)has been reported with unclear underlying mechanisms.Previous studies showed thatγ-aminobutyric acid(GABA)B2 receptor(GABBR2)was upregulated in CCA cells cultured in high glucose(HG)conditions.Roles of GABA receptors in CCA progression have also been studied,but their association with DM and hyperglycemia in CCA remains unclarified.AIM To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target.METHODS CCA cells,KKU-055 and KKU-213A,were cultured in Dulbecco Modified Eagle’s Medium supplemented with 5.6 mmol/L(normal glucose,NG)or 25 mmol/L(HG)glucose and assigned as NG and HG cells,respectively.GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot.Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence.GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry,and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis.Effects of baclofen,a GABA-B receptor agonist,on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays.Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment,and the candidate signaling molecules were validated using the public transcriptomic data and western blot.RESULTS GABBR2 expression in CCA cells was induced by HG in a dose-and time-dependent manner.CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia(P<0.01).High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors(P<0.05).HG cells of both tested CCA cell lines were more sensitive to baclofen treatment.Baclofen significantly suppressed the proliferation and clonogenicity of CCA cells in both NG and HG conditions(P<0.05).Phospho-kinase arrays suggested glycogen synthase kinase 3(GSK3),β-catenin,and the signal transducer and activator of transcription 3(STAT3)as candidate signaling molecules under the regulation of GABBR2,which were verified in NG and HG cells of the individual CCA cell lines.Cyclin D1 and c-Myc,the common downstream targets of GSK3/β-catenin and STAT3 involving cell proliferation,were accordingly downregulated after baclofen treatment.CONCLUSION GABBR2 is upregulated by HG and holds a promising role as a therapeutic target for CCA regardless of the glucose condition.