The effect of WIN 55,212-2 suggests a cannabinoid-sensitive component in the early toxicity induced by organic acids accumulating in glutaric acidemia type I and in related disorders of propionate metabolism in rat brain synaptosomes

Colín-González, Ana Laura; Paz-Loyola, A.L.; Serratos, Iris N.; Seminotti, Bianca; Ribeiro, César Augusto João; Leipnitz, Guilhian; Souza, Diogo O.; Santamarı́a, Abel

doi:10.1016/j.neuroscience.2015.09.043

Cited by 13 publications

(12 citation statements)

References 58 publications

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“…Noteworthy, in recent reports, and in further support to this study, we have characterized a cannabinoid component involved in the in vitro toxic events elicited by other toxic organic acids, including glutaric acid, 3-hydroxyglutaric acid, MMA and PA, that are found at higher concentrations in the corresponding organic acidurias [17]. In such report, we collected evidence demonstrating that the synthetic control (29 % below; P < 0.05).…”

Section: The Toxic Synergism Induced By 3mga and Quin Was Prevented Asupporting

confidence: 76%

“…On the other hand, we have recently shown that modulation of the endocannabinoid system (ECS) by cannabinoid receptor (CBr) agonists can be beneficial against some harmful actions of these toxic organic acids related to organic acidemias [17]. Thus, the aim of this study was to investigate the effects of 3MGA on different endpoints of toxicity (mitochondrial dysfunction and lipid peroxidation) in isolated synaptic terminals from the rat brain.…”

Section: Introductionmentioning

confidence: 99%

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Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging Mechanisms

et al. 2016

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3-Methylglutaric acid (3MGA) is an organic acid that accumulates in various organic acidemias whose patients present neurodegeneration events in children coursing with metabolic acidurias. Limited evidence describes the toxic mechanisms elicited by 3MGA in the brain. Herein, we explored the effects of 3MGA on different toxic endpoints in synaptosomal and mitochondrial-enriched fractions of adult rat brains to provide novel information on early mechanisms evoked by this metabolite. At 1 and 5 mM concentration, 3MGA increased lipid peroxidation, but decreased mitochondrial function only at 5 mM concentration. Despite less intense effects were obtained at 1 mM concentration, its co-administration with the kynurenine pathway (KP) metabolite and N-methyl-D-aspartate receptor (NMDAr) agonist, quinolinic acid (QUIN, 50 and 100 µM), produced toxic synergism on markers of oxidative stress and mitochondrial function. The toxicity of 3MGA per se (5 mM) was prevented by the cannabinoid receptor agonist WIN55,212-2 and the NMDAr antagonist kynurenic acid (KYNA), suggesting cannabinoid and glutamatergic components in the 3MGA pattern of toxicity. The synergic model (3MGA + QUIN) was also sensitive to KYNA and the antioxidant S-allylcysteine, but not to the nitric oxide synthase inhibitor L-nitroarginine methyl ester. These findings suggest various underlying mechanisms involved in the neurotoxicity of 3MGA that may possibly contribute to the neurodegeneration observed in acidemias.

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Section: The Toxic Synergism Induced By 3mga and Quin Was Prevented Asupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging Mechanisms

et al. 2016

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“…It has also been used—with varying effects—in MMA patients with optic atrophy and in Mut −/− mice with renal failure (TT#13). Other explored anti‐oxidants are CB agonist WIN and S‐allylcysteine, glutathione, GM1 ganglioside, melatonin, mitoQ and resveratrol, tiron and trolox, in most cases resulting in a partial or complete reduction of the induced phenotype (TT#15). Methylene blue, an electron transfer mediator, is successfully used in methylmalonic acid‐induced seizures …”

Section: Therapy Targets and Treatment Strategiesmentioning

confidence: 99%

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

Haijes

Hasselt

Jans

et al. 2019

J of Inher Metab Disea

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Despite realizing increased survival rates for propionic acidemia (PA) and methylmalonic acidemia (MMA) patients, the current therapeutic regimen is inadequate for preventing or treating the devastating complications that still can occur. The elucidation of pathophysiology of these complications allows us to evaluate and rethink treatment strategies. In this review we display and discuss potential therapy targets and we give a systematic overview on current, experimental and unexplored treatment strategies in order to provide insight in what we have to offer PA and MMA patients, now and in the future. Evidence on the effectiveness of treatment strategies is often scarce, since none were tested in randomized clinical trials. This raises concerns, since even the current consensus on best practice treatment for PA and MMA is not without controversy. To attain substantial improvements in overall outcome, gene, mRNA or enzyme replacement therapy is most promising since permanent reduction of toxic metabolites allows for a less strict therapeutic regime. Hereby, both mitochondrial‐associated and therapy induced complications can theoretically be prevented. However, the road from bench to bedside is long, as it is challenging to design a drug that is delivered to the mitochondria of all tissues that require enzymatic activity, including the brain, without inducing any off‐target effects. To improve survival rate and quality of life of PA and MMA patients, there is a need for systematic (re‐)evaluation of accepted and potential treatment strategies, so that we can better determine who will benefit when and how from which treatment strategy.

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“…57,81 This setup qualifies diseases from degenerative contexts such as AD, PD, and HD as ideal targets for experimental approaches but also reflects in disorders of low incidence-and rising awareness-such as OAs (GA-I, PAcidemia, MMAcidemia, etc). 85 Particular effects evoked after CB activation have attracted interest due to its advantageous applications. One of the most prominent is the antinociceptive response produced by CBs, which are mainly exerted through CB1 receptors.…”

Section: Possible Neuroprotective Mechanisms Of Cbs In the Brainmentioning

confidence: 99%

Potential Therapeutic Targets of the Endocannabinoid System in Common Neurodegenerative Disorders and Organic Acidemias

Aguilera

Santamarı́a

2017

Journal of Inborn Errors of Metabolism and Screening

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The cannabinoid chemistry is currently being addressed in preclinical approaches as a viable therapeutic alternative for the management of a wide range of signs, symptoms, and some biochemical hallmarks of many neurological pathologies (such as neuroinflammation and neurodegeneration). This clinical orientation is grounded on the consistent promissory profile that cannabinoid compounds have shown, and the great necessity of feasible options to undergo such disorders. Even though at early research stages, metabolic disorders are starting to rise as potential targets of cannabinoid alternatives; approaches in this term could, in turn, aim to modulate the endocannabinoid response for therapeutic purposes. This review recalls the pathologic scenarios endured in the course of neurological diseases of high occurrence and the most typical metabolic disorders, while discussing the neuroprotective mechanisms of cannabinoid agonists in the central nervous system, and the potential targets of the endocannabinoid system and metabolic disorders.

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The effect of WIN 55,212-2 suggests a cannabinoid-sensitive component in the early toxicity induced by organic acids accumulating in glutaric acidemia type I and in related disorders of propionate metabolism in rat brain synaptosomes

Cited by 13 publications

References 58 publications

Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging Mechanisms

Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging Mechanisms

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

Potential Therapeutic Targets of the Endocannabinoid System in Common Neurodegenerative Disorders and Organic Acidemias

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