Metabolic alterations in plasma from patients with familial and idiopathic Parkinson’s disease

Yakhine-Diop, Sokhna M. S.; Morales-García, José A.; Niso-Santano, Mireia; González‐Polo, Rosa A.; Uribe-Carretero, Elisabet; Martínez-Chacón, Guadalupe; Durand, Sylvère; Maiuri, Maria Chiara; Aiastui, Ana; Zulaica, Miren; Ruíz‐Martínez, Javier; Munáin, Adolfo López de; Pérez‐Tur, Jordi; Pérez-Castillo, Ana; Kroemer, Guido; Pedro, José Manuel Bravo-San; Fuentes, José

doi:10.18632/aging.103992

Cited by 40 publications

(40 citation statements)

References 63 publications

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“…Our analysis also revealed decreased purine metabolism in the CMA group. Plasma levels of hypoxanthine and adenosine were significantly reduced in the CMA group, consistent with a recent clinical study showing increased hypoxanthine levels in PD 73 . Furthermore, our findings of decreased peripheral levels of hypoxanthine could also be interpreted as increased CNS bioavailability of hypoxanthine considering its high blood-brain barrier permeability and adenosine triphosphate (ATP)-enhancing role under energy crisis conditions.…”

Section: Discussionsupporting

confidence: 90%

Combined Metabolic Activators Improve Cognitive Functions without Altering Motor Scores in Parkinson’s Disease

Yuluğ¹,

Altay

et al. 2021

Preprint

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The neuropathologic hallmarks of Parkinson's disease (PD) are associated with mitochondrial dysfunction and metabolic abnormalities. We have reported that the Combined Metabolic Activators (CMA), consisting of L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate can be used in treating metabolic abnormalities. These metabolic activators are the precursors of nicotinamide adenine dinucleotide (NAD+) and glutathione (GSH) and used in activation of mitochondrial and global metabolism. We have performed a placebo-controlled, phase-2 study in Alzheimer's disease (AD) patients and reported that the cognitive functions in AD patients is significantly improved 29% in the CMA group whereas it is improved only 14% in the placebo group after 84 days of CMA administration. Here, we designed a randomized, double-blinded, placebo-controlled, phase-2 study in PD patients with CMA administration. We found that the cognitive functions in PD patients is significantly improved 21% in the CMA group, whereas it is improved only 11% in the placebo group after 84 days of CMA administration. We also found that the administration of CMA did not affect motor functions in PD patients. We performed a comprehensive multi-omics analysis of plasma proteins and metabolites, and revealed the molecular mechanism associated with the treatment of the patients. In conclusion, our results show that treating PD patients with CMAs leads to enhanced cognitive function, as recently reported in AD patients.

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Section: Discussionsupporting

confidence: 90%

Combined Metabolic Activators Improve Cognitive Functions without Altering Motor Scores in Parkinson’s Disease

Yuluğ¹,

Altay

et al. 2021

Preprint

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“…They suggested that ROT disrupts the functioning of mitochondria in cells; in other words, it creates conditions similar to those in the brain neurons of patients with PD. On the other hand, Yakhine-Diop, et al [19] observed an increase in the levels of both hypoxanthine and xanthine in the serum of mice with PD caused by 6-OHDA, similar to the results obtained in patients with PD. All these data show that an increase in the content of xanthine l.Ya.…”

Section: Resultssupporting

confidence: 62%

Corrective effects of benzodiazepine derivative – diazepinone on purine and lipid metabolism in the liver of rats with Parkinson’s disease

Shtanova¹,

Yanchuk²,

Veselsky³

et al. 2021

Fiziol Zh

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The cause of PD is not fully understood, and effective treatments still do not exist. It is believed that oxidative stress, mitochondrial dysfunction, and impaired lipid metabolism may underlie the pathogenesis of PD. Bile contains the breakdown products of various compounds that form in hepatocytes. This study aimed to evaluate the effect of a new benzodiazepine derivative - diazepinone (DP) on purine and lipid metabolism in the liver of rats with PD caused by rotenone (ROT) by studying the composition of bile. The concentration of ATP, ADP, AMP, xanthine, hypoxanthine, phospholipids (PL), cholesterol (CHOL), cholesterol esters (ECHOL), free fatty acids (FFA), and triglycerides (TG) was quantified in bile samples by thin-layer chromatography. Our findings suggested that the ratio of AMP/ ATP in bile increased almost threefold under the influence of ROT, and with DP, it exceeded the norm by only 1.6 times. ROT also increased the content of xanthine and hypoxanthine by 28.6% and 66.7%, respectively. DP did not affect the increased xanthine content relative to control but significantly reduced the level of hypoxanthine (up to 22.2%, above normal). In addition, ROT reduced the content of bile PL, CHOL, ECHOL, TG by 23.9%, 38.6%, 47.5%, 39.2 %, respectively. Under the influence of the DP, all the above indicators returned to the level of control. Thus, diazepinone improves both the metabolism of purines and lipids in the liver of rats with ROT-simulated PD. This drug may become a therapeutic agent for treating PD and possibly other neurodegenerative diseases in the future.

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“…In patients with PD, a metabolomic study in plasma showed the bile acid biosynthesis pathway was dysregulated in patients with PD, together with other lipid metabolic pathways (glycerolphospholipids, fatty acids), and considering the essential role of bile acids on lipid homeostasis [42], the authors suggested that abnormalities in bile acid may cause disturbances in all lipid metabolism [43]. These findings were supported by another recent study, which reported a significant metabolic change in the bile acids pathway, both in a murine model of PD and in patients with PD [20]. Also, another study proposed that abnormalities in bile acids biosynthesis in patients with PD caused by intestinal dysbiosis, which is common in PD, may dysregulate lipid metabolism [44].…”

Section: Discussionmentioning

confidence: 88%

“…Previous studies have mostly explored metabolomics in blood and CSF of patients with PD, and a broad number of metabolic pathway dysfunctions have been associated with the disease [15–18]. Also, PD progression could be estimated based on a panel of metabolites discovered by metabolomic analysis [19], and no difference was seen in the metabolic profile of genetic forms of PD [20]. About metabolomic studies in LID, a previous study showed no association between dyskinesias and the kynurenine pathway in plasma [21], even though another study reported a specific metabolite signature based on kynurenine products in plasma and CSF on LID [22].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Profile in Plasma and CSF of Levodopa-Induced Dyskinesia of Parkinson’s Disease

Gardinassi

Bortolanza

et al. 2020

Preprint

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Structured AbstractBackgroundThe existence of few biomarkers and the lack of a better understanding of the pathophysiology of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD) require new approaches, as the metabolomic analysis, for discoveries.ObjectivesWe aimed to identify a metabolic profile associated with LID in patients with PD in an original cohort, and to confirm the results in an external cohort (BioFIND).MethodsIn the original cohort, plasma and CSF were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. LC-MS/MS and metabolomics data analysis were used to perform untargeted metabolomics. Untargeted metabolomics data from the BioFIND cohort were analyzed.ResultsWe identified a metabolic profile associated with LID in PD, composed of multiple metabolic pathways. In particular, the dysregulation of glycosphingolipids metabolic pathway was more related to LID and was strongly associated with the severity of dyskinetic movements. Further, bile acid biosynthesis and C21-steroid hormone biosynthesis metabolites simultaneously found in plasma and CSF have distinguished patients with LID from other participants. Levels of cortisol and cortisone were reduced in patients with PD and LID compared to patients with PD without LID. Data from the BioFIND cohort confirmed dysregulation in plasma metabolites from the bile acid biosynthesis and C21-steroid hormone biosynthesis pathways.ConclusionThere is a distinct metabolic profile associated with LID in PD, both in plasma and CSF, which may be associated with the dysregulation of lipid metabolism and neuroinflammation.

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Metabolic alterations in plasma from patients with familial and idiopathic Parkinson’s disease

Cited by 40 publications

References 63 publications

Combined Metabolic Activators Improve Cognitive Functions without Altering Motor Scores in Parkinson’s Disease

Combined Metabolic Activators Improve Cognitive Functions without Altering Motor Scores in Parkinson’s Disease

Corrective effects of benzodiazepine derivative – diazepinone on purine and lipid metabolism in the liver of rats with Parkinson’s disease

Metabolic Profile in Plasma and CSF of Levodopa-Induced Dyskinesia of Parkinson’s Disease

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