N-Acetyl-L-Methionyl-L-Dopa-Methyl Ester as a dual acting drug that relieves L-Dopa-induced oxidative toxicity

Minelli, Alba; Conte, Carmela; Prudenzi, Elvira; Cacciatore, Ivana; Cornacchia, Catia; Taha, Elena; Pinnen, Francesco

doi:10.1016/j.freeradbiomed.2010.03.011

Cited by 17 publications

(6 citation statements)

References 44 publications

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“…Taking into account that drugs with two or more useful biological activities for the same pathology may represent an important pharmacological advance, we are currently interested in multifunctional drugs that combine potent antioxidant, chelant, and neuroprotective properties in a single molecule for the treatment of PD and AD [13,14,15,16]. For this purpose, to design a novel class of compounds with a multimodal mechanism of action, we selected the hydroxyquinoline (HQ) scaffold as a privileged structure since it is a clinically relevant bioactive metal chelator.…”

Section: Introductionmentioning

confidence: 99%

A Potent (R)-alpha-bis-lipoyl Derivative Containing 8-Hydroxyquinoline Scaffold: Synthesis and Biological Evaluation of Its Neuroprotective Capabilities in SH-SY5Y Human Neuroblastoma Cells

et al. 2013

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A novel bis-lipoyl derivative containing 8-hydroxyquinoline scaffold (LA-HQ-LA, 5) was synthesized as a new multifunctional drug candidate with antioxidant, chelant, and neuroprotective properties for the treatment of neurodegenerative diseases. We have investigated the potential effectiveness of LA-HQ-LA against the cytotoxicity induced by 6-OHDA and H2O2 on human neuroblastoma SH-SY5Y cell line. Our outcomes showed that LA-HQ-LA resulted in significant neuroprotective and antioxidant effects against H2O2- and 6-OHDA-induced neurotoxicity in human neuroblastoma SH-SY5Y cells, as assessed by MTT assay. In particular, it showed potent neuroprotective effects against 6-OHDA in RA/PMA differentiated cells at all the tested concentrations.

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Section: Introductionmentioning

confidence: 99%

A Potent (R)-alpha-bis-lipoyl Derivative Containing 8-Hydroxyquinoline Scaffold: Synthesis and Biological Evaluation of Its Neuroprotective Capabilities in SH-SY5Y Human Neuroblastoma Cells

et al. 2013

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“…In addition, Minelli et al [84] showed that administration of codrug 11 to mice treated with Z-ILeu-Glu(OtBu)-Ala-Leu-CHO (PSI), used as a PD model, resulted in a reduction in dopaminergic neuronal death and a significant raise in GSH levels. In particular, codrug 11 could control the LD-induced oxidative stress in primary mesencephalic cultures and in newborn mice pups since in both cases GSH content results increased.…”

Section: Medicinal-chemistry-based Strategies To Increase Gsh Levelsmentioning

confidence: 99%

“…In particular, codrug 11 could control the LD-induced oxidative stress in primary mesencephalic cultures and in newborn mice pups since in both cases GSH content results increased. Using newborn mice pups, characterized by incomplete formation of BBB, Minelli et al [84] found that buthionine-[S,R]-sulfoximine-(BSO-) mediated GSH depletion prevented the increase of GSH levels promoted by codrug 11 , supporting the role of GSH for codrug- 11 -induced protection. To investigate whether heme oxygenase (HO) activity was related to GSH levels, ZnPPIX was used as HO inhibitor.…”

Section: Medicinal-chemistry-based Strategies To Increase Gsh Levelsmentioning

confidence: 99%

“…Codrug 11 exhibited in vivo protective effect against LD-induced stress through a mechanism via Nrf2 activation leading to a decrease in ROS generation and an increase in GSH. Therefore, this codrug might offer benefits in the treatment of PD and provide a potential alternative to LD therapy by avoiding nigrostriatal oxidative degeneration [84]. …”

Section: Medicinal-chemistry-based Strategies To Increase Gsh Levelsmentioning

confidence: 99%

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Recent Advances in the Treatment of Neurodegenerative Diseases Based on GSH Delivery Systems

Cacciatore

Baldassarre

Fornasari

et al. 2012

Oxidative Medicine and Cellular Longevity

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Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease(AD), are a group of pathologies characterized by a progressive and specific loss of certain brain cell populations. Oxidative stress, mitochondrial dysfunction, and apoptosis play interrelated roles in these disorders. It is well documented that free radical oxidative damage, particularly on neuronal lipids, proteins, DNA, and RNA, is extensive in PD and AD brains. Moreover, alterations of glutathione (GSH) metabolism in brain have been implicated in oxidative stress and neurodegenerative diseases. As a consequence, the reduced GSH levels observed in these pathologies have stimulated a number of researchers to find new potential approaches for maintaining or restoring GSH levels. Unfortunately, GSH delivery to the central nervous system (CNS) is limited due to a poor stability and low bioavailability. Medicinal-chemistry- and technology-based approaches are commonly used to improve physicochemical, biopharmaceutical, and drug delivery properties of therapeutic agents. This paper will focus primarily on these approaches used in order to replenish intracellular GSH levels, which are reduced in neurodegenerative diseases. Here, we discuss the beneficial properties of these approaches and their potential implications for the future treatment of patients suffering from neurodegenerative diseases, and more specifically from PD and AD.

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“…The bioavailability of the new compounds was evaluated by comparing neostriatal LD and DA levels after oral administration by intragastric tube: codrugs 110 and 113 were able to induce sustained delivery of both LD and DA in the rat striatum with respect to equimolar doses of LD; furthermore, the levels of DA in the striatum of rats injected intracerebroventricularly with codrug 112 were higher than those of the LDtreated groups, indicating that this compound has a longer half-life in brain. Afterwards, basing on these results, codrugs 110-112 have been assayed for their ability to relieve LD-induced oxidative toxicity [83]. In more details, the effects of the treatment with codrug 112 have been investigated in vitro using primary mesencephalic neuron cultures and in vivo using proteasome inhibitor treated mice as PD animal model.…”

Section: Codrugs Of Ldmentioning

confidence: 99%

L-Dopa Prodrugs: An Overview of Trends for Improving Parkinsons Disease Treatment

Stefano

Sozio²,

Cerasa³

et al. 2011

CPD

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L-Dopa is the mainstay of Parkinson's disease therapy; this drug is usually administered orally, but it is extensively metabolized in the gastrointestinal tract, so that relatively little arrives in the bloodstream as intact L-Dopa. The peripheral conversion of L-Dopa by amino acid decarboxylase to dopamine is responsible for the typical gastrointestinal and cardiovascular side effects. To minimize the conversion to dopamine outside the central nervous system, L-Dopa is usually given in combination with peripheral inhibitors of amino acid decarboxylase. In spite of that, other central nervous side effects such as dyskinesia, on-off phenomenon and end-of-dose deterioration still remain. The main factors responsible for the poor bioavailability are the drug's physical-chemical properties: low water and lipid solubility, resulting in unfavorable partition, and the high susceptibility to chemical and enzymatic degradation. Starting from these considerations the prodrug approach has been applied to L-Dopa in order to overcome its metabolism problems and to improve its bioavailability. The goal of this paper is to provide the reader with a critical overview on L-Dopa prodrugs here classified according to the nature of the main chemical modification on L-Dopa backbone that led to the formation of the desired derivative.

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N-Acetyl-L-Methionyl-L-Dopa-Methyl Ester as a dual acting drug that relieves L-Dopa-induced oxidative toxicity

Cited by 17 publications

References 44 publications

A Potent (R)-alpha-bis-lipoyl Derivative Containing 8-Hydroxyquinoline Scaffold: Synthesis and Biological Evaluation of Its Neuroprotective Capabilities in SH-SY5Y Human Neuroblastoma Cells

A Potent (R)-alpha-bis-lipoyl Derivative Containing 8-Hydroxyquinoline Scaffold: Synthesis and Biological Evaluation of Its Neuroprotective Capabilities in SH-SY5Y Human Neuroblastoma Cells

Recent Advances in the Treatment of Neurodegenerative Diseases Based on GSH Delivery Systems

L-Dopa Prodrugs: An Overview of Trends for Improving Parkinsons Disease Treatment

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