Silva Brenda Rufino da, Lima Joyce Maria Ferreira Alexandre, Echeverry Marcela Bermudez, Alberto-Silva Carlos
Natural and Humanities Sciences Center (CCNH), Experimental Morphophysiology Laboratory, Federal University of ABC (UFABC), São Bernardo do Campo 09606-070, Brazil.
Center for Mathematics, Computation and Cognition (CMCC), Federal University of ABC (UFABC), São Bernardo do Campo 09606-070, Brazil.
Neurol Int. 2024 Dec 5;16(6):1731-1741. doi: 10.3390/neurolint16060125.
BACKGROUND/OBJECTIVES: Antipsychotic medicines are used to treat several psychological disorders and some symptoms caused by dementia and schizophrenia. Haloperidol (Hal) is a typical antipsychotic usually used to treat psychosis; however, its use causes motor or extrapyramidal symptoms (EPS) such as catalepsy. Hal blocks the function of presynaptic D2 receptors on cholinergic interneurons, leading to the release of acetylcholine (ACh), which is hydrolyzed by the enzyme acetylcholinesterase (AChE).
This study was designed to investigate the Hal-inhibitory effects on AChE activity in regions representative of the cholinergic system of mice and potential associations between cataleptic effects generated by Hal using therapeutic doses and their inhibitory effects on AChE.
The distribution of the AChE activity in the different regions of the brain followed the order striatum > hippocampus > (prefrontal cortex/hypothalamus/ cerebellum) > brainstem > septo-hippocampal system. In ex vivo assays, Hal inhibited AChE activity obtained from homogenate tissue of the striatum, hippocampus, and septo-hippocampal system in a concentration-dependent manner. The inhibitory concentration of 50% of enzyme activity (IC) indicated that the septo-hippocampal system required a higher concentration of Hal (IC = 202.5 µmol·L) to inhibit AChE activity compared to the striatum (IC = 162.5 µmol·L) and hippocampus (IC = 145 µmol·L). In in vivo assays, male Swiss mice treated with concentrations of Hal higher than 0.1 mg·kg induced cataleptic effects. Positive correlations with were observed only between the lack of cataleptic effect and the decreased AChE activity of the hippocampus in the mice treated with 0.01 mg·kg of Hal but not in the striatum and septo-hippocampal system.
Our results suggest that Hal could increase cholinergic effects via AChE inhibition, in addition to its dopamine antagonist effect, as an alternative approach to the treatment of behavioral disturbances associated with dementia.
背景/目的：抗精神病药物用于治疗多种心理障碍以及痴呆和精神分裂症引起的一些症状。氟哌啶醇（Hal）是一种典型的抗精神病药物，通常用于治疗精神病；然而，其使用会导致运动或锥体外系症状（EPS），如僵住症。Hal阻断胆碱能中间神经元上突触前D2受体的功能，导致乙酰胆碱（ACh）释放，而ACh会被乙酰胆碱酯酶（AChE）水解。
本研究旨在调查Hal对小鼠胆碱能系统代表性区域中AChE活性的抑制作用，以及使用治疗剂量的Hal产生的僵住效应与其对AChE的抑制作用之间的潜在关联。
大脑不同区域的AChE活性分布顺序为纹状体>海马体>（前额叶皮质/下丘脑/小脑）>脑干>隔海马系统。在体外试验中，Hal以浓度依赖性方式抑制从纹状体、海马体和隔海马系统的匀浆组织中获得的AChE活性。50%酶活性的抑制浓度（IC）表明，与纹状体（IC = 162.5 μmol·L）和海马体（IC = 145 μmol·L）相比，隔海马系统需要更高浓度的Hal（IC = 202.5 μmol·L）来抑制AChE活性。在体内试验中，用高于0.1 mg·kg浓度的Hal处理的雄性瑞士小鼠产生了僵住效应。仅在用0.01 mg·kg的Hal处理的小鼠中，未出现僵住效应与海马体AChE活性降低之间观察到正相关，而在纹状体和隔海马系统中未观察到。
我们的结果表明，除了其多巴胺拮抗剂作用外，Hal还可通过抑制AChE增加胆碱能效应，作为治疗与痴呆相关的行为障碍的替代方法。
