Convulsions induced by methylmalonic acid are associated with glutamic acid decarboxylase inhibition in rats: A role for GABA in the seizures presented by methylmalonic acidemic patients?

Malfatti, Carlos Ricardo Maneck; Perry, Marcos Luiz Santos; Schweigert, Ingrid Dalira; Müller, Alexandre Pastoris; Paquetti, L.; Rigo, Flávia Karine; Fighera, Michele Rechia; Garrido-Sanabria, Emilio R.; Mello, Carlos Fernando

doi:10.1016/j.neuroscience.2007.03.022

Cited by 20 publications

(19 citation statements)

References 65 publications

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“…On the other hand, it is unlikely that reactive nitrogen species were responsible for the induction of lipid peroxidation in synaptosomes used in the present investigation since the classical inhibitor of nitric oxide synthase L-NAME did not reduce the increase of TBA-RS levels provoked by MMA. Furthermore, the protective effects of the NMDA antagonist MK-801 support the involvement of these glutamate receptors in MMA effects, as previously observed (de Mello et al 1996;Kölker et al 2000;Brusque et al 2001;Malfatti et al 2007). MMA also provoked a moderate protein oxidative damage, as observed by the increase of carbonyl formation in synaptosomes elicited at a high concentration and by the mild enhancement of sulfhydryl oxidation after intrastriatal administration.…”

Section: Discussionsupporting

confidence: 75%

Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

et al. 2011

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Methylmalonic acidemia and propionic acidemia are organic acidemias biochemically characterized by predominant tissue accumulation of methylmalonic acid (MMA) and propionic acid (PA), respectively. Affected patients present predominantly neurological symptoms, whose pathogenesis is not yet fully established. In the present study we investigated the in vitro effects of MMA and PA on important parameters of lipid and protein oxidative damage and on the production of reactive species in synaptosomes from cerebrum of developing rats. Synaptosomes correspond to nerve terminals that have been used to investigate toxic properties of compounds on neuronal cells. The in vivo effects of intrastriatal injection of MMA and PA on the same parameters and on enzymatic antioxidant defenses, were also studied. MMA-induced in vitro and in vivo lipid peroxidation and protein oxidative damage. Furthermore, the lipid oxidative damage was attenuated or prevented, pending on the doses utilized, by the free radical scavengers α-tocopherol, melatonin and by the NMDA glutamate receptor antagonist MK-801, implying the involvement of reactive species and glutamate receptor activation in these effects. In addition, 2',7'-dichlorofluorescein diacetate oxidation was significantly increased in synaptosomes by MMA, reinforcing that reactive species generation is elicited by this organic acid. We also verified that glutathione peroxidase activity was inhibited by intrastriatal MMA injection. In contrast, PA did not induce any significant effect on all parameters examined in vitro and in vivo, implying a selective action for MMA. The present data demonstrate that oxidative stress is induced by MMA in vitro in nerve terminals and in vivo in striatum, suggesting the participation of neuronal cells in MMA-elicited oxidative damage.

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Section: Discussionsupporting

confidence: 75%

Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

et al. 2011

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“…Kynurenic acid, a direct NMDA‐receptor antagonist is investigated for neuroprotection in propionic and methylmalonic acid‐induced, and NMDA‐receptor agonist co‐induced ROS formation, lipid peroxidation and mitochondrial failure, leading to a partial reduction . MK‐801, also a direct NMDA‐receptor antagonist successfully reversed methylmalonic acid and propionic acid‐induced seizures and methylmalonic acid and propionic acid‐induced ROS formation, but it had no effect on methylmalonic acid‐induced cognitive problems …”

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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“…The improvements on EEG and brain imaging after LDLT were thus clearly more closely associated with changes in propionate metabolism than with the resolution of severe hyperammonemia. In methylmalonic acidemia, an organic acidemia related to PA, Malfatti et al [16] showed that activation of the N-methyl D-aspartate (NMDA) receptor and GABAergic mechanisms triggers the evolution of seizures. Rigo et al [17] observed the induction of seizures in rats injected with propionic acid into the striatum; electrodischarges were detected in the EEG.…”

Section: Discussionmentioning

confidence: 99%

Improved neurologic prognosis for a patient with propionic acidemia who received early living donor liver transplantation

Nagao¹,

Tanaka²,

Morii³

et al. 2013

Molecular Genetics and Metabolism

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Convulsions induced by methylmalonic acid are associated with glutamic acid decarboxylase inhibition in rats: A role for GABA in the seizures presented by methylmalonic acidemic patients?

Cited by 20 publications

References 65 publications

Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

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

Improved neurologic prognosis for a patient with propionic acidemia who received early living donor liver transplantation

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