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Projeto de investigação
INNOVATIVE WATER-SOLUBLE PHYTOMATERIAL INHIBITORs FOR ALZHEIMERs AND PARKINSONs DISEASES PREVENTION
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Predation stress causes excessive aggression in female mice with partial genetic inactivation of Tryptophan hydroxylase-2: evidence for altered myelination-related processes
Publication . Svirin, Evgeniy; Veniaminova, Ekaterina; Nunes, João; Gorlova, Anna; Umriukhin, Aleksei; Kalueff, Allan V.; Proshin, Andrey; Anthony, Daniel C.; Nedorubov, Andrey; Tse, Anna Chung Kwan; Walitza, Susanne; Lim, Lee Wei; Lesch, Klaus-Peter; Strekalova, Tatyana
The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 (Tph2) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant (Tph2-/-) mice. In heterozygous male mice (Tph2+/-), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2+/- mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2+/- females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a, glycogen synthase kinase-3 β (GSK-3β), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein (Mbp), proteolipid protein 1 (Plp1), myelin-associated glycoprotein (Mag), and myelin oligodendrocyte glycoprotein (Mog). The expression of the plasticity markers synaptophysin (Syp) and cAMP response element binding protein (Creb), but not AMPA receptor subunit A2 (GluA2), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2+/- mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior.
Thiamine compounds alleviate oxidative stress, over-expression of pro-inflammatory markers and behavioral abnormalities in a mouse predation model of PTSD
Publication . Strekalova, Tatyana; Gorlova, Anna; Nunes, João; Litavrin, Aleksandr; Munter, Johannes P. M. de; Lyundup, Alexei; Umriukhin, Aleksei; Proshin, Andrey; Kalueff, Allan; Grünblatt, Edna; Walitza, Susanna
Experiences of life-threatening stimuli can induce post-traumatic stress disorder (PTSD), which is associated with long-lasting behavioral and neurochemical abnormalities. Despite its increased global incidence, the current treatment options for PTSD remain limited, highlighting the need for novel therapeutic strategies. As oxidative stress and neuroinflammation contribute to PTSD, the use of powerful antioxidants such as thiamine (B1 vitamin) compounds may counteract disease development. Young C57BL/6 mice received thiamine or benfotiamine in drinking water (each at a dose of 200 mg/kg/day) for 21 days, and for the last five days, they were subjected to rat exposure. Mice were studied for anxiety-like behavior, exploration, locomotion, grooming, social interactions, pain sensitivity, brain changes in protein carbonyl (PC), total glutathione (TG), and gene expression of distress and inflammation markers. Rat exposure induced anxiety-like behavior, excessive grooming, and alteration in locomotion, along with other abnormalities. Stressed, untreated mice had elevated levels of PC and TG in the prefrontal cortex, hippocampus, amygdala, and striatum and increased expression of Il-1β, Tnf, c-Fos, Cox-1, and Cox-2. Treatment with thiamine or benfotiamine significantly ameliorated most of these changes in the stressed groups. Thus, thiamine compounds may have therapeutic potential in patients with PTSD, owing to their antioxidant and anti-inflammatory properties.
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European Commission
Programa de financiamento
H2020
Número da atribuição
101007642