多巴胺受体激动剂在缺血性脑损伤后脑保护研究进展

doi:10.3969/j.issn.1673-5765.2024.10.015

摘要/Abstract

摘要： 缺血性脑损伤在脑损伤中占87%，常导致严重的功能障碍。多巴胺是大脑内含量最丰富的儿茶酚胺类神经递质，与自主运动、情感、睡眠、认知等功能密切相关。缺血性脑损伤后患者脑内多巴胺功能严重失调。有研究发现多巴胺受体激动剂如罗匹尼罗、普拉克索、吡贝地尔等可通过受体或非受体依赖途径减轻脑损伤，对学习、记忆、行为、意识等功能有明显改善。本文就不同多巴胺受体激动剂在缺血性脑损伤的脑保护方面可能的作用机制进行综述。

文章导读： 本文总结了多巴胺受体激动剂对缺血性脑损伤的保护作用，提出使用多巴胺受体激动剂保护脑功能的新的思路和启示。

关键词: 多巴胺受体激动剂; 缺血性脑损伤; 脑保护

Abstract: Ischemic brain injury comprises 87% of all brain injuries and typically results in severe functional impairments. Dopamine, the most abundant catecholamine neurotransmitter in the brain, is intimately linked with autonomous movement, emotion, sleep, cognition, and other critical functions. Following ischemic brain injury, patients have severe dysfunction of dopamine in the brain. Studies have demonstrated that dopamine receptor agonists, such as ropinirole, pramipexole, and piribedil, can mitigate brain injury through both receptor-dependent and non-receptor-dependent pathways. These agonists have significant improvements in functions including learning, memory, behavior, and consciousness. This article reviews the potential mechanisms of various dopamine receptor agonists in brain protection after ischemic brain injury.

Key words: Dopamine receptor agonist; Ischemic brain injury; Brain protection

中图分类号:

张琳瑶, 刘丽旭. 多巴胺受体激动剂在缺血性脑损伤后脑保护研究进展[J]. 中国卒中杂志, 2024, 19(10): 1215-1220.

ZHANG Linyao, LIU Lixu. Progress in the study of Dopamine Receptor Agonists for Brain Protection after Ischemic Brain Injury[J]. Chinese Journal of Stroke, 2024, 19(10): 1215-1220.

参考文献

[1] GRAY R，PATEL S，IVES N，et al. Long-term effectiveness of adjuvant treatment with catechol-O-methyltransferase or monoamine oxidase B inhibitors compared with dopamine agonists among patients with Parkinson disease uncontrolled by levodopa therapy：the PD MED randomized clinical trial[J]. JAMA Neurol，2022，79（2）：131-140.
[2] CINCOTTA A H. Brain dopamine-clock interactions regulate cardiometabolic physiology：mechanisms of the observed cardioprotective effects of circadian-timed bromocriptine-qr therapy in type 2 diabetes subjects
[J/OL]. Int J Mol Sci，2023，24（17）：13255[2024-01-01].
https://doi.org/10.3390/ijms241713255.
[3] CINCOTTA A H，CERSOSIMO E，ALATRACH M，et al. Bromocriptine-QR therapy reduces sympathetic tone and ameliorates a pro-oxidative/pro-inflammatory phenotype in peripheral blood mononuclear cells and plasma of type 2 diabetes subjects[J/OL]. Int J Mol Sci，2022，23（16）：8851[2024-01-01]. https://doi.org/10.3390/ijms23168851.
[4] GOSSARD T R，TROTTI L M，VIDENOVIC A，et al. Restless legs syndrome：contemporary diagnosis and treatment[J]. Neurotherapeutics，2021，18（1）：140-155.
[5] OSUGO M，WHITEHURST T，SHATALINA E，et al. Dopamine partial agonists and prodopaminergic drugs for schizophrenia：systematic review and meta-analysis of randomized controlled trials[J/OL]. Neurosci Biobehav Rev，2022，135：104568[2024-01-01].
https://doi.org/10.1016/j.neubiorev.2022.104568.
[6] HUANG S Y，LIU L，TANG X D，et al. Research progress on the role of hormones in ischemic stroke[J/OL].
Front Immunol，2022，13：1062977[2024-01-01]. https://doi.org/10.3389/fimmu.2022.1062977.
[7] CHEN H，LI J S，HUANG Z X，et al. Dopaminergic system and neurons：role in multiple neurological diseases
[J/OL]. Neuropharmacology，2024，260：110133[2024-01-01]. https://doi.org/10.1016/j.neuropharm.2024.110133.
[8] WANG Z Z，LU H Y，LI Y D，et al. Exploring the correlation between cardiovascular adverse events and antidepressant use：a retrospective pharmacovigilance analysis based on the FDA adverse event reporting system database[J/OL]. J Affect Disord，2024，367：96-108[2024-01-01]. https://doi.org/10.1016/j.jad.2024.08.161.
[9] CHOI J，HORNER K A. Dopamine agonists[M]. Treasure Island（FL）：StatPearls Publishing，2024.
[10] BEAULIEU J M，GAINETDINOV R R. The physiology，signaling，and pharmacology of dopamine receptors[J]. Pharmacol Rev，2011，63（1）：182-217.
[11] 李蓉，李文斌. 缺血性脑损伤中细胞Ca2+稳态丧失的研究进展[J]. 中国脑血管病杂志，2023，20（4）：280-289.
LI R，LI W X. Research progress of the loss of cellular calcium homeostasis in ischemic brain injury[J]. Chin J Cerebrovasc Dis，2023，20（4）：280-289.
[12] ZHANG Q，JIA M，WANG Y F，et al. Cell death mechanisms in cerebral ischemia-reperfusion injury[J]. Neurochem Res，2022，47（12）：3525-3542.
[13] JIANG XSTOCKWELL B R，CONRAD M. Ferroptosis：mechanisms，biology and role in disease[J]. Nat Rev Mol Cell Biol，2021，22（4）：266-282.
[14] LI L，SHI C L，DONG F，et al. Targeting pyroptosis to treat ischemic stroke：from molecular pathways to treatment strategy[J/OL]. Int Immunopharmacol，2024，133：112168[2024-01-01]. https://doi.org/10.1016/j.
intimp.2024.112168.
[15] GOWER A，TIBERI M. The intersection of central dopamine system and stroke：potential avenues aiming at enhancement of motor recovery[J/OL]. Front Synaptic Neurosci，2018，10：18[2024-01-01]. https://doi.org/10.3389/fnsyn.2018.00018.
[16] FAN Y，KONG X，LIU K，et al. Exercise on striatal dopamine level and anxiety-like behavior in male rats after 2-VO cerebral ischemia[J/OL]. Behav Neurol，2022，2022：2243717[2024-01-01]. https://doi.org/10.1155/2022/2243717.
[17] UZDENSKY A，DEMYANENKO S，FEDORENKO G，et al. Protein profile and morphological alterations in penumbra after focal photothrombotic infarction in the rat cerebral cortex[J]. Mol Neurobiol，2017，54（6）：4172-4188.
[18] SIEBER M W，GUENTHER M，JAENISCH N，et al. Age-specific transcriptional response to stroke[J]. Neurobiol Aging，2014，35（7）：1744-1754.
[19] FILLOUX F M，ADAIR J，NARANG N. The temporal evolution of striatal dopamine receptor binding and mRNA expression following hypoxia-ischemia in the neonatal rat[J]. Brain Res Dev Brain Res，1996，94（1）：81-91.
[20] BUCHER M L，DICENT J，DUARTE H C，et al. Neurotoxicology of dopamine：victim or assailant？[J/OL]. Neurotoxicology，2024，103：175-188[2024-01-01]. https://doi.org/10.1016/j.neuro.2024.06.001.
[21] FELSING D E，JAIN M K，ALLEN J A. Advances in dopamine D1 receptor ligands for neurotherapeutics[J]. Curr Top Med Chem，2019，19（16）：1365-1380.
[22] LE W D，JANKOVIC J，XIE W，et al. Antioxidant property of pramipexole independent of dopamine receptor activation in neuroprotection[J]. J Neural Transm（Vienna），2000，107（10）：1165-1173.
[23] BOZZI Y，BORRELLI E. Dopamine in neurotoxicity and neuroprotection：what do D2 receptors have to do with it？[J]. Trends Neurosci，2006，29（3）：167-174.
[24] WILSON S M，WURST M G，WHATLEY M F，et al. Classics in chemical neuroscience：pramipexole[J]. ACS Chem Neurosci，2020，11（17）：2506-2512.
[25] KAUSHIK P，ALI M，TABASSUM H，et al. Post-ischemic administration of dopamine D2 receptor agonist reduces cell death by activating mitochondrial pathway following ischemic stroke[J/OL]. Life Sci，2020，261：118349[2024-01-01]. https://doi.org/10.1016/j.lfs.2020.118349.
[26] MICALE V，INCOGNITO T，IGNOTO A，et al. Dopaminergic drugs may counteract behavioral and biochemical changes induced by models of brain injury[J]. Eur Neuropsychopharmacol，2006，16（3）：195-203.
[27] OHTA K，FUJINAMI A，KUNO S，et al. Cabergoline stimulates synthesis and secretion of nerve growth factor，brain-derived neurotrophic factor and glial cell
line-derived neurotrophic factor by mouse astrocytes in primary culture[J]. Pharmacology，2004，71（3）：162-168.
[28] BONO F，SAVOIA P，GUGLIELMI A，et al. Role of dopamine D2/D3 receptors in development，plasticity，and neuroprotection in human iPSC-derived midbrain dopaminergic neurons[J]. Mol Neurobiol，2018，55（2）：1054-1067.
[29] 刘丽旭，董为伟，史若飞. 脑复苏临床处理的新途径[J]. 中华医学杂志，2006，86（29）：2069-2071.
LIU L X，DONG W W，SHI R F. A new approach to the clinical management of brain resuscitation[J]. Natl Med J China，2006，86（29）：2069-2071.
[30] SAMI M B，FARUQUI R. The effectiveness of dopamine agonists for treatment of neuropsychiatric symptoms post brain injury and stroke[J]. Acta Neuropsychiatr，2015，27（6）：317-326.
[31] DAMMAVALAM V，RUPERT D，LANIO M，et al. Dementia after ischemic stroke，from molecular biomarkers to therapeutic options[J/OL]. Int J Mol Sci，2024，25（14）：7772[2024-01-01]. https://doi.org/10.3390/ijms25147772.
[32] ANDRABI S S，TABASSUM H，PARVEEN S，et al. Ropinirole induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in Wistar rats[J/OL]. Neurotoxicology，2020，77：94-104[2024-01-01]. https://doi.org/10.1016/j.neuro.2019.12.004.
[33] FATIMA S，ALI M，QUADRI S N，et al. Crafting ɣ-L-glutamyl-l-cysteine layered human serum albumin-nanoconstructs for brain targeted delivery of ropinirole to attenuate cerebral ischemia/reperfusion injury via“3A approach”[J/OL]. Biomaterials，2022，289：121805[2024-01-01]. https://doi.org/10.1016/j.
biomaterials.2022.121805.
[34] NEHA，ANWAR S，PINKY，et al. Ropinirole reverses the effects of neuroinflammation，and cellular demise by downregulating the MARK4-NFκβ signaling system in Alzheimer’s disease[J/OL]. Int J Biol Macromol，2024，271（Pt 1）：132425[2024-01-01]. https://doi.org/10.1016/j.ijbiomac.2024.132425.
[35] ANDRABI S S，ALI M，TABASSUM H，et al. Pramipexole prevents ischemic cell death via mitochondrial pathways in ischemic stroke[J/OL]. Dis Model Mech，2019，12（8）：dmm033860[2024-01-01]. https://doi.org/10.1242/dmm.033860.
[36] HUANG J P，LAN H，XIE CJ，et al. Pramipexole protects against traumatic brain injury-induced blood-brain barrier（BBB）dysfunction[J]. Neurotox Res，2022，40（4）：1020-1028.
[37] 康晓宇，刘丽旭，王文竹，等. 普拉克索联合左旋多巴对全脑缺血再灌注损伤大鼠认知能力及线粒体功能的影响[J]. 中国康复理论与实践，2023，29（5）：533-540.
KANG X Y，LIU L X，WANG W Z，et al. Effects of pramipexole combined with levodopa on cognitive and mitochondrial function of rats after global cerebral ischemia-reperfusion injury[J]. Chin J Rehabil Theory Pract，2023，29（5）：533-540.
[38] KANG X，LIU L，WANG W，et al. Effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potentials in rats with global cerebral ischemia-reperfusion injury[J/OL]. J Stroke Cerebrovasc Dis，2023，32（7）：107142[2024-01-01]. https://doi.org/10.1016/j.jstrokecerebrovasdis.2023.107142.
[39] WANG W Z，LIU L X，CHEN C，et al. Protective effects of dopamine D2/D3 receptor agonist piribedil on learning and memory of rats exposed to global cerebral ischemia-reperfusion[J/OL]. Neurosci Lett，2018，684：181-186[2024-01-01]. https://doi.org/10.1016/j.neulet.2018.08.011.
[40] CALDWELL M A，REYMANN J M，BENTUE-FERRER D，et al. The dopamine agonists lisuride and piribedil protect against behavioural and histological changes following 4-vessel occlusion in the rat[J]. Neuropsychobiology，1996，34（3）：117-124.
[41] AMIN S J，AGHAJAN Y，WEBB A J. Clinical experience with bromocriptine for central hyperthermia after brain insult[J]. Brain Inj，2024，38（8）：652-658.
[42] FORTIN J S，BENSKEY M J，LOOKINGLAND K J，et al. Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide：evidence from horses with pituitary pars intermedia dysfunction[J/OL]. BMC Vet Res，2020，16（1）：356[2024-01-01]. https://doi.org/10.1186/s12917-020-02565-3.
[43] FATIMA M，AHMAD M H，SRIVASTAV S，et al. A selective D2 dopamine receptor agonist alleviates depression through up-regulation of tyrosine hydroxylase and increased neurogenesis in hippocampus of the prenatally stressed rats[J/OL]. Neurochem Int，2020，136：104730[2024-01-01]. https://doi.org/10.1016/j.
neuint.2020.104730.
[44] O’NEILL M J，HICKS C A，WARD M A，et al. Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia[J]. Eur J Pharmacol，1998，352（1）：37-46.
[45] TIKLOVÁ K，BJÖRKLUND Å K，LAHTI L，et al. Single-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development[J/OL]. Nat Commun，2019，10（1）：581[2024-01-01]. https://doi.org/10.1038/s41467-019-08453-1.
[46] MITTAL S，ARENKIEL B R，LYONS-WARREN A M. Arcuate dopaminergic/GABAergic neurons project within the hypothalamus and to the median eminence[J]. J Neurophysiol，2024，132（3）：943-952.