Comparison Between 5-Aminosalicylic Acid (5-ASA) and Para-Aminosalicylic Acid (4-PAS) as Potential Protectors Against Mn-Induced Neurotoxicity

Santos, D.; Batoréu, M.C.; Aschner, Michael; Santos, A.P. Marreilha dos

doi:10.1007/s12011-012-9597-0

Cited by 9 publications

(4 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAS has been proven to be an effective agent for the treatment of Mn-induced neurotoxicity in brain cells [20] , in experimental animals [13,16,18,19] , and in humans [11,12,14,15,17] . However, the mechanisms by which PAS and its metabolite AcPAS are transported across the BBB remained unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence has also been provided regarding the effective removal of Mn from the CSF and brain tissues in rats following PAS treatment [18] . More recently, Santos and colleagues reported that PAS is effective in reducing brain Mn burden [19,20] . The authors further suggest that in addition to its role in metal chelation, the anti-inflammatory property of PAS allows it to reduce the level of prostaglandin E 2 (PGE 2 ), which is crucial for the development of neuroinflammation [19] .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain

Hong

O’Neal

et al. 2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Para-aminosalicylic acid (PAS) is effective in the treatment of manganism-induced neurotoxicity (manganism). In this study we investigated the roles of P-glycoprotein (MDR1a) and multidrug resistance protein (MRP) in transporting PAS and its N-acetylated metabolite AcPAS through blood-brain barrier. Methods: MDR1a-null or wild-type mice were intravenously injected with PAS (200 mg/kg). Thirty minutes after the injection, blood samples and brains were collected, and the concentrations of PAS and AcPAS in brain capillaries and parenchyma were measured using HPLC. Both MDCK-MDR1 and MDCK-MRP1 cells that overexpressed P-gp and MRP1, respectively, were used in two-chamber Transwell transport studies in vitro. Results: After injection of PAS, the brain concentration of PAS was substantially higher in MDR1a-null mice than in wild-type mice, but the brain concentration of AcPAS had no significant difference between MDR1a-null mice and wild-type mice. Concomitant injection of PAS with the MRP-specific inhibitor MK-571 (50 mg/kg) further increased the brain concentration of PAS in MDR1a-null mice, and increased the brain concentration of AcPAS in both MDR1a-null mice and wild-type mice. Two-chamber Transwell studies with MDCK-MDR1 cells demonstrated that PAS was not only a substrate but also a competitive inhibitor of P-gp, while AcPAS was not a substrate of P-gp. Two-chamber Transwell studies with the MDCK-MRP1 cells showed that MRP1 had the ability to transport both PAS and AcPAS across the BBB. Conclusion: P-gp plays a major role in the efflux of PAS from brain parenchyma into blood in mice, while MRP1 is involved in both PAS and AcPAS transport in the brain.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain

Hong

O’Neal

et al. 2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…Thus efflux of Mn by this transporter would seem to be very effective however more research needs to be done if such therapy will prove beneficial [20]. Similarly, synthetic compounds like ibuprofen, 5 aminosalicylic acids, and para-aminosalicylic acid were shown to protect against mitochondrial damage and apoptosis in vivo and invitro [47,48]. Recently raloxifene, a selective estrogen receptor modulator (SERM) enhanced the expression of Glutamate Aspartate Transporter (GLAST) and glutamate transporter (GLT 1) which take up most of the glutamate from the synaptic cleft to prevent excitotoxic neuronal death.…”

Section: Conventional Approachmentioning

confidence: 99%

Manganese, a Likely Cause of 'Parkinson's in Cirrhosis', a Unique Clinical Entity of Acquired Hepatocerebral Degeneration

Mehkari

Mohammed

Javed

et al. 2020

Cureus

View full text Add to dashboard Cite

With idiopathic Parkinson's disease being a common entity, parkinsonism in acquired hepatocerebral degeneration (AHD) in the context of Manganese (Mn) has gained importance in recent years. An insight into the pathomechanisms behind this disease has been put forth. How can Mn as a divalent metal exert its effect in leading to chronic neurodegenerative disorder? Secondary to decreased excretion in liver cirrhosis, Mn significantly alters the striatal dopaminergic system. Management of this debilitating disease also focuses on different aspects where Mn has been involved in the pathogenesis. We have put forth the details behind Mn effects in Parkinson's, which will be a guide for better understanding and management of this disease. A literature search was performed using PubMed as a sole database, and all the articles were peer-reviewed. The author tried to follow the PRISMA guidelines. Inclusion criteria were set for 10 years, with most studies with in the last seven years. All types of study designs were included relevant to the topic, clearly delineating the pathomechanisms of Mn in the disease and also its management. After extensive research, through the PubMed database, we found that Parkinson's disease is one of the neurological complications in advanced liver cirrhosis. Mn is an essential element behind its pathogenesis; it works at different cellular levels to promote neurotoxicity. From its influx to its effects on dopamine transporters (DAT), where it disrupts dopamine homeostasis also altering postsynaptic dopamine (D2) receptors, it disrupts mitochondria and the endoplasmic reticulum (ER) promotes oxidative stress and neuroinflammation. Misfolding of alpha-synuclein (α-Syn) is promoted on chronic exposure to Mn where α-Syn from being neuroprotective becomes neurotoxic. It also alters glutaminergic and gabaergic neurotransmission. In a nutshell, the diversity of its effect on nigrostriatal denervation is challenging. The importance of neuroimaging and various approaches to management is also discussed. AHD, an uncommon entity in advanced liver cirrhosis, needs more awareness so that it can be diagnosed earlier and better therapeutic options can be sought. Our study highlighted Mn mechanisms behind this clinical entity, putting forth grounds for a better understanding of this disease. Advanced research targeting Mn for managing this disease will be revolutionary.

show abstract

“…Of note, anti-inflammatory agents have been reported to decrease Mn neurotoxicity in vitro and after in vivo exposure. For instance, Santos et al (2013) demonstrated in vitro that 5- aminosalicylic acid (5-ASA) and para-aminosalicylic acid (4-PAS) increased mitochondrial and cell viability following Mn exposure [205]. Ibuprofen, a nonsteroidal anti-inflammatory drug, protected striatal neurons from dendritic atrophy and spine loss in rats treated for 2 weeks with the drug prior to Mn exposure [184].…”

Section: Main Textmentioning

confidence: 99%

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

Peres

Schettinger

Chen

et al. 2016

BMC Pharmacol Toxicol

Self Cite

294

183

View full text Add to dashboard Cite

Manganese (Mn) is an essential heavy metal. However, Mn’s nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson’s disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

show abstract

Comparison Between 5-Aminosalicylic Acid (5-ASA) and Para-Aminosalicylic Acid (4-PAS) as Potential Protectors Against Mn-Induced Neurotoxicity

Cited by 9 publications

References 28 publications

Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain

Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain

Manganese, a Likely Cause of 'Parkinson's in Cirrhosis', a Unique Clinical Entity of Acquired Hepatocerebral Degeneration

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

Contact Info

Product

Resources

About