Frost Emma D, Shi Swanny X, Byroju Vishnu V, Pitton Rissardo Jamir, Donlon Jack, Vigilante Nicholas, Murray Briana P, Walker Ian M, McGarry Andrew, Ferraro Thomas N, Hanafy Khalid A, Echeverria Valentina, Mitrev Ludmil, Kling Mitchel A, Krishnaiah Balaji, Lovejoy David B, Rahman Shafiqur, Stone Trevor W, Koola Maju Mathew
Cooper Neurological Institute, Cooper University Health Care, Camden, NJ 08103, USA.
Department of Neurology, Montefiore Medical Center, Bronx, NY 10467, USA.
Brain Sci. 2024 Nov 21;14(12):1163. doi: 10.3390/brainsci14121163.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 1% of population over age 60. It is defined by motor and nonmotor symptoms including a spectrum of cognitive impairments known as Parkinson's disease dementia (PDD). Currently, the only US Food and Drug Administration-approved treatment for PDD is rivastigmine, which inhibits acetylcholinesterase and butyrylcholinesterase increasing the level of acetylcholine in the brain. Due to its limited efficacy and side effect profile, rivastigmine is often not prescribed, leaving patients with no treatment options. PD has several derangements in neurotransmitter pathways (dopaminergic neurons in the nigrostriatal pathway, kynurenine pathway (KP), acetylcholine, α7 nicotinic receptor, and N-methyl-D-aspartate (NMDA) receptors) and rivastigmine is only partially effective as it only targets one pathway. Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, affects the pathophysiology of PDD in multiple ways. Both galantamine (α7 nicotinic receptor) and memantine (antagonist of the NMDA subtype of the glutamate receptor) are KYNA modulators. When used in combination, they target multiple pathways. While randomized controlled trials (RCTs) with each drug alone for PD have failed, the combination of galantamine and memantine has demonstrated a synergistic effect on cognitive enhancement in animal models. It has therapeutic potential that has not been adequately assessed, warranting future randomized controlled trials. In this review, we summarize the KYNA-centric model for PD pathophysiology and discuss how this treatment combination is promising in improving cognitive function in patients with PDD through its action on KYNA.
帕金森病（PD）是一种进行性神经退行性疾病，影响着超过1%的60岁以上人群。它由运动和非运动症状定义，包括一系列被称为帕金森病痴呆（PDD）的认知障碍。目前，美国食品药品监督管理局唯一批准用于治疗PDD的药物是 rivastigmine，它抑制乙酰胆碱酯酶和丁酰胆碱酯酶，从而提高大脑中的乙酰胆碱水平。由于其疗效有限且有副作用，rivastigmine常常不被处方，导致患者没有治疗选择。PD在神经递质途径中有多种紊乱（黑质纹状体途径中的多巴胺能神经元、犬尿氨酸途径（KP）、乙酰胆碱、α7烟碱受体和N-甲基-D-天冬氨酸（NMDA）受体），而rivastigmine仅部分有效，因为它只针对一条途径。犬尿喹啉酸（KYNA）是色氨酸代谢的一种代谢产物，以多种方式影响PDD的病理生理学。加兰他敏（α7烟碱受体）和美金刚（谷氨酸受体NMDA亚型的拮抗剂）都是KYNA调节剂。当联合使用时，它们针对多种途径。虽然单独使用每种药物治疗PD的随机对照试验（RCT）都失败了，但加兰他敏和美金刚的联合使用在动物模型中已显示出对认知增强的协同作用。其治疗潜力尚未得到充分评估，值得未来进行随机对照试验。在这篇综述中，我们总结了以KYNA为中心的PD病理生理学模型，并讨论了这种联合治疗如何通过对KYNA的作用有望改善PDD患者的认知功能。
