以大鼠大腦微透析模式探討尼古丁對MPTP/TIQ通過血腦屏障(BBB)影響之研究

Abstract

Parkinson’s disease (PD) is an age-related neurodegeneration disorder resulting in bradykinesia, resting tremor, postural instability and muscle rigidity. Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic neurotoxin, causes a Parkinson-like syndrome. In this regard, MPTP is used to establish suitable animal models to study neurodegenerative and neuroprotective processes in PD. Epidemiological researches have shown a negative association between cigarette smoking and incidences of PD. In order to investigate the effect of nicotine, one of major cigarette constituents, on blood-brain barrier (BBB) transfer of PD-induced agents, a brain microdialysis technique was used to collect dialysates in the striatum of male Wistar rats treated by MPTP with or without nicotine pretreatment. Saline or single dose of nicotine (0.3, 0.6, 2.0 and 4.0 mg/ kg) was given to rats by intraperitoneal injection 30 min prior to the femoral administration of MPTP (10 mg/ kg, i.v.). Dialysates were collected in a 30-min interval for 150 min. Concentrations of MPTP and MPP+ were quantified by a HPLC method using an ODS-column coupled with a UV-Vis and a fluorescence detector. The results showed that MPTP in 0~30 min interval in brain extracellular fluid can be significantly reduced by nicotine (666.31±65.53 ng/ mL, 561.50±12.11 ng/ mL, 493.23±35.46 ng/ mL, 375.94±76.24 ng/ mL and 329.35±55.14 ng/ mL for control and 0.3, 0.6, 2.0, 4.0 mg/ kg nicotine-pretreatment group, respectively). We also monitored nicotine concentrations in the brain and blood of nicotine at a concentration of 0.6 mg/ kg. The results showed that nicotine concentration in the brain and blood dialysates were 136.8±16.6 ng/ mL and 233.1±9.2 ng/ mL, respectively, in 30~60 min interval. There was no significant difference between a single-dose nicotine treatment and a multi-dose nicotine treatment. In addition, we also investigated whether the inhibitory effects of nicotine on MPTP is gender dependant. As the result, we found that the effect of nicotine showed no significant difference between male and female. Given that tetrahydroisoquinoline (TIQ) is a MPTP-like substance, we also investigated the effect of nicotine on BBB transfer of TIQ. The result indicated TIQ in brain extracellular fluid can not be significantly reduced by nicotine (0.6 and 2.0 mg/ kg). In conclusion, these data indicate that nicotine can reduce the transfer of MPTP into the brain. However, nicotine can not reduce the transfer of TIQ across BBB. The mechanism of lower incidence of PD associated with smoking needs to be confirmed in the future.