are contributed equally to this work. AbstractDysfunction of the circadian rhythm is one of most common nonmotor symptoms in Parkinson's disease (PD), but the molecular role of the circadian rhythm in PD is unclear. We here showed that inactivation of brain and muscle ARNT-like 1 (BMAL1) in 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine (MPTP)-treated mice resulted in obvious motor functional deficit, loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc), decrease of dopamine (DA) transmitter, and increased activation of microglia and astrocytes in the striatum. Time on the rotarod or calorie consumption, and food and water intake were reduced in the Bmal1 −/− mice after MPTP treatment, suggesting that absence of Bmal1 may exacerbate circadian and PD motor function. We observed a significant reduction of DANs (~35%) in the SNpc, the tyrosine hydroxylase protein level in the striatum (~60%), the DA (~22%), and 3,4-dihydroxyphenylacetic acid content (~29%), respectively, in MPTP-treated Bmal1 −/− mice. Loss of Bmal1 aggravated the inflammatory reaction both in vivo and in vitro. These findings suggest that BMAL1 may play an essential role in the survival of DANs and maintain normal function of the DA signaling pathway via regulating microglia-mediated neuroinflammation in the brain. K E Y W O R D S circadian rhythm, dopaminergic neurons, neuroinflammation, nonmotor symptoms | 6571 LIU et aL.

Background:Colorectal cancer (CRC) is a malignant gastrointestinal tumor with a high mortality rate, including both colon and rectal cancer. In order to provide clinical guidance for the treatment of CRC, this study is conducted to investigate the correlations of intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms with susceptibility and multidrug resistance (MDR) of colorectal cancer (CRC).Methods:A total of 195 patients with CRC were selected as the observation group and 188 healthy people enrolled as the control group. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to test ICAM-1 A13848G and K469E polymorphisms. The expressions of MDR-associated protein topoisomerase II (Topo II) and P-glycoprotein (P-gp) in CRC tissues were detected by immunohistochemistry. The analysis on association of clinical indexes of CRC patients with ICAM-1 gene polymorphisms was performed.Results:The frequencies of KK genotype and K allele of K469E in the observation group were significantly higher than that in the control group. KE + EE genotype and E allele might be protective factors for CRC. The distribution of genotypes, K469E KK and KE+EE, was highly correlated with histologic grade of tumor differentiation. Compared with adjacent normal tissues, positive rates of Topo II and P-gp expression were significantly increased in CRC tissues. Topo II expression in CRC patients was positively associated with lymph node metastasis and depth of tumor invasion, whereas P-gp expression was only associated with depth of tumor invasion. Higher positive rates of Topo II and P-gp expression were observed in ICAM-1 K469E KK genotype carriers, indicating that ICAM-1 K469E KK genotype might be related to MDR in CRC.Conclusion:These findings in the current study suggested that ICAM-1 K469E polymorphism is highly correlated with susceptibility and MDR in CRC.

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor healthrelated quality of life. However, classic therapeutic drugs supplying dopamine have limited therapeutic effect on PD related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study has demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-HT) contents in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been con rmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most researches have shown that 5-HT1A receptor and 5-HT3 receptor played a key role in pain transmission in the spinal cord. Thus, we hypothesize that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons and the functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 µmol/L), but not 5-HT3 receptor agonist M-CPBG (30 µmol/L), 5-HT1A receptor antagonist 8-OH DPAT (10 µmol/L)and agonist WAY-100635 (10 µmol/L). Intrathecal injection with ondansetron (0.1 mg/kg) but not M-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg) and WAY-100635 (0.1 mg/kg) signi cantly attenuated the mechanical hyperalgesia and thermal hyperalgesia of 6-OHDA rats. Therefore, the present study suggests that inhibition of 5-HT3 receptor relieves hyperalgesia in PD rats by reducing the excitability of SDH neurons. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

Pain in Parkinson’s disease (PD) is increasingly recognized as a major factor associated with poor health-related quality of life. However, classic therapeutic drugs supplying dopamine have limited therapeutic effect on PD related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study has demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-HT) contents in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most researches have shown that 5-HT1A receptor and 5-HT3 receptor played a key role in pain transmission in the spinal cord. Thus, we hypothesize that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons and the functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 µmol/L), but not 5-HT3 receptor agonist M-CPBG (30 µmol/L), 5-HT1A receptor antagonist 8-OH DPAT (10 µmol/L)and agonist WAY-100635 (10 µmol/L). Intrathecal injection with ondansetron (0.1 mg/kg) but not M-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg) and WAY-100635 (0.1 mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia of 6-OHDA rats. Therefore, the present study suggests that inhibition of 5-HT3 receptor relieves hyperalgesia in PD rats by reducing the excitability of SDH neurons. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.