Motor Function Impairment In Obstructive Jaundice And Electrophysiology Mechanisms

Obstructive jaundice, which is biliary excretion disorder caused by obstruction ofintrahepatic or extrahepatic bile ducts, can be accompanied by two symptoms of fatigueand pruritus reflecting extrahepatic manifestations of the underlying disease andconsiderably reducing the quality of life. In particular, patients often complain of "fatigue",as it is not a specific symptom, which is usually ignored. In recent years, more and morestudies focused on the fatigue in patients with cholestatic disease and fatiguequestionnaires are developed. As a gradual and cumulative process, fatigue reflectsvigilance decrement and decreased capacity to perform, along with subjective states thatare associated with this decreased performance. The performance scales, not the verbalfatigue questionnaires, are believed to reflect fatigue objectively in clinic. Therefore, in thisclinical study, paper-pencil tests including Number connection test A, Line-tracing test,Serial dotting test and Digit-symbol test were used to assess psychomotor performance,especially fine motor function alternation in obstructive jaundice patients. Control groupcontains the non-obstructive jaundice patients with gender, age and education matched.There is clinical and experimental evidence suggesting that fatigue in cholestaticpatients probably related with alterations including neurotransmitters and receptors innervous system. Increased levels of both peripheral and central endogenous opioidergictone are observed in cholestatic patients and rodents. In addition, the serotoninneurotransmitter system has been implicated in the genesis of fatigue in patients withcholestasis. Therefore, we questioned that: Were there other neurotransmitters in CNSinvolved in the regulation mechanisms of motor fatigue in cholestasis? Sinceneurotransmitters alternation can be induced by general anesthetics, did general anestheticsexacerbate motor impairment in cholestatic patients who need surgery?To answer these questions, bile duct ligation (BDL) rats were used to investigate themotor impairment in cholestasis. Open field test and Rotarod test were used to assessmotor deficit. Movement distance in open field test was measured for spontaneouslocomotor activity. The mean latency to fall off the rotarod was recorded to reflect motorcoordination and balance. We hypothesized that GABA neurotransmitter system wasinvolved in the motor impairment of BDL rats. Flumazenil, a non-subtype-specific centralGABA-benzodiazepine receptor complex antagonist, was injected intraperitoneally toinvestigate the motor function alternation in BDL rats. Sevoflurane exposure was also used for the evaluation of general anesthetics on motor function in BDL rats.In addition, in vivo electrophysiological recording was applied in BDL rats3weeksafter surgery. Spontaneous firing of the medial prefrontal cortex (mPFC) pyramidalneurons was observed. Both Flumazenil and sevoflurane was injected intraperitoneally andrespectively to investigate the firing changes in BDL rats.Results:1. Clinical study: Jaundice patients had significantly decreased scores compared withnon-jaundice patients in the paper-pencil psychometric tests: Number connectiontest A, Line-tracing test, Serial dotting test and Digit-symbol test.2. Animal behavior experiments: Compared with Sham rats, BDL rats showeddecreased movement distance in open field test and decreased mean latency to falloff the rotarod in rotarod test. During10to20min after administration offlumazenil (1mg/kg, i.p.), increased movement distance was observed. Moreover,increased mean latency to fall off the rotarod was also observed during30min afteradministration. Sevoflurane exposure did not exacerbate motor impairment in BDLrats by observation of rotarod test.3. Electrophysiology recording: Compared with Sham group，BDL rats showeddecreased average active cell per track and decreased firing rate and increased interspike interval in mPFC pyramidal neurons. However, no significant difference ofmode was observed. After administration of flumazenil (1mg/kg, i.p.), increasedfiring rate was observed. After administration of emulsified sevoflurane, BDL ratsexhibited increased firing rate.Conclusions:1. Patients with obstructive jaundice exhibited motor function impairment and paper-pencil tests can be used for the easy and objective assessment.2. BDL rat model mimics the clinical motor impairment in patients with obstructivejaundice.3. Administration of flumazenil relieved motor function impairment in BDL rats,suggesting that GABAergic transmission involved in the mechanisms.4. Sevoflurane exposure did not exacerbate motor impairment in BDL rats.5. Decreased mPFC pyramidal neurons activity in BDL rats can be one of the reasonsof motor function impairment in BDL rats.