Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

Scaini, Giselli; Jeremias, Gabriela C.; Furlanetto, Camila B.; Dominguini, Diogo; Comim, Clarissa M.; Quevedo, João; Schuck, Patrícia Fernanda; Ferreira, Gustavo C.; Streck, Emílio L.

doi:10.1007/8904_2013_274

Cited by 14 publications

(9 citation statements)

References 72 publications

(84 reference statements)

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“…Thus, we hypothesized that chronic exposure to an HFD could raise plasma BCAA concentrations sufficiently to limit the uptake of tryptophan into the brain as a result of the competition between amino acids, and thereby reduce neuronal 5-HT synthesis and release from nerve terminals. This is consistent with findings reporting that supplementation in BCAAs reduced brain 5-HT content in rats (Choi et al, 2013) and induced depressive-like symptoms in rodents such as anxiety (Coppola et al, 2013) or anhedonia (Scaini et al, 2014). By attenuating circulating BCAA levels, Met could favor tryptophan availability in the brain and thereby positively reverberate on central 5-HT tone.…”

Section: Discussionsupporting

confidence: 91%

“…Indeed, elevated circulating BCAA levels predict the severity of IR (Newgard et al, 2009;Gannon et al, 2018) while limiting the uptake of tryptophan into the brain through the blood-brain barrier (BBB) by the large neutral amino acid transporter 1 (LAT1; Pardridge, 1998). Thus, the rate of 5-HT production may be affected by BCAAs, thereby leading to anxiodepressive symptoms, as shown in clinical (Fellendorf et al, 2018) and preclinical studies (Coppola et al, 2013;Scaini et al, 2014;Asor et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

et al. 2019

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Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic-and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic-and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

et al. 2019

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“…It is well known that MSUD patients present behavioral alterations, with an increased risk of developing anxiety and depression, appearently caused by high levels of MSUD neurotoxic metabolites (Muelly et al, 2013; Strauss and Morton, 2003; Walterfang et al, 2013). Previously, we suggested the link between MSUD and depression in rats (Scaini et al, 2013). Specifically, we demonstrated that rats submitted to chronic administration of BCAA during development present depressive‐like behavior and depression features, such as anhedonia, immobility during the forced swimming test and decreased adrenal gland weight (Scaini et al, 2013).…”

Section: Introductionmentioning

confidence: 91%

“…Previously, we suggested the link between MSUD and depression in rats (Scaini et al, 2013). Specifically, we demonstrated that rats submitted to chronic administration of BCAA during development present depressive‐like behavior and depression features, such as anhedonia, immobility during the forced swimming test and decreased adrenal gland weight (Scaini et al, 2013).…”

Section: Introductionmentioning

confidence: 91%

“…Several animal models of MSUD are used to mimic the damage caused by increased of BCAA, whether genetic or non‐genetic. We and other research groups have extensively used a model that induces MSUD chemically in rats, which allowed the study of many disease aspects (Bridi et al, 2006; Scaini et al, 2012, 2013). Moreover, Friedrich et al (2012) described a new model using zebrafish morpholinos with E2 gene mutation, with similar characteristics of MSUD individuals.…”

Section: Introductionmentioning

confidence: 99%

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Acute exposure to leucine modifies behavioral parameters and cholinergic activity in zebrafish

Wessler

Farias

Ronsani

et al. 2019

Intl J of Devlp Neuroscience

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Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder, caused by a deficiency on branched chain α-ketoacid dehydrogenase complex activity, resulting in accumulation of branched-chain amino acids (BCAA) (e.g. leucine). The treatment of MSDU patients increases survival time and quality of life. Thus, nowadays there are a crescent number of adolescents and adults with MSUD. Relevant studies have been reported behavioral alterations in these patients, i.e. high risk of chronic neuropsychiatric problems, such as attention deficit disorder, depression and anxiety. Moreover, MSUD is associated to neurotransmitters deficiency. Herein, we aimed to investigate whether the toxicity of leucine is associated to anxiety-like behavioral, using zebrafish acutely exposed to leucine as experimental model of MSUD. In addition, we evaluated the effects of high levels of leucine in the acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activities, components of cholinergic neurotransmission system. Young zebrafish were exposed to 2 mM and 5 mM concentration of leucine for 24 h. After that, the animals were submitted to the Novel Tank test, having the brain collected to enzymatic determination. The exposure to both concentrations of leucine caused behavioral and brain cholinergic activity alterations in young zebrafish, indicating an anxiety-like behavior and cholinergic dysfunction. Therefore, this animal could be considered a promising organism to study the BCAA neurotoxic effects, which could help to a better comprehension of the behavioral and neurochemical alterations present in patients with MSUD.

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Antioxidants reverse the changes in energy metabolism of rat brain after chronic administration of L.-tyrosine

et al. 2016

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Tyrosinemia type II is a rare autosomal recessive disease caused by deficiency of hepatic tyrosine aminotransferase and is associated with neurologic and development difficulties in numerous patients. Considering that the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly known and that high concentrations of tyrosine provoke mitochondrial dysfunction and oxidative stress, in the present study we investigated the in vivo influence of antioxidants (N-acetylcysteine, NAC; and deferoxamine, DFX) administration on the inhibitory effects on parameters of energy metabolism in cerebral cortex, hippocampus and striatum of rats, provoked by chronic administration of L.-tyrosine. Our results showed that chronic administration of L.-tyrosine results in a marked decrease in the activity of citrate synthase in all the analyzed structures and succinate dehydrogenase activities in hippocampus and striatum, and that antioxidants administration can prevent this inhibition in hippocampus and striatum. Moreover, chronic administration of L.-tyrosine inhibited the activity of complex I, II-III and IV in the striatum, which can be prevented by antioxidant treatment. However, the co-administration of NAC plus DFX could not prevent the inhibition of creatine kinase activity in the striatum. In conclusion, the present study demonstrates that the administration of antioxidants NAC and DFX attenuates the L.-tyrosine effects on enzymes of the Krebs cycle and the mitochondrial respiratory chain, suggesting that impairment of energy metabolism can be involved with oxidative stress. These results also indicate a possible neuroprotective role for NAC and DFX as a potential adjuvant therapy to the patients with Tyrosinemia type II.

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Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

Cited by 14 publications

References 72 publications

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

Acute exposure to leucine modifies behavioral parameters and cholinergic activity in zebrafish

Antioxidants reverse the changes in energy metabolism of rat brain after chronic administration of L.-tyrosine

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