| 1. |
- Stam, Frida, et al.
(författare)
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Hydrogen Peroxide Induced Toxicity Is Reversed by the Macrocyclic IRAP-Inhibitor HA08 in Primary Hippocampal Cell Cultures
- 2022
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Ingår i: Current Issues in Molecular Biology. - : MDPI. - 1467-3037 .- 1467-3045. ; 44:10, s. 5000-5012
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Tidskriftsartikel (refereegranskat)abstract
- Angiotensin IV (Ang IV), a metabolite of Angiotensin II, is a bioactive hexapeptide that inhibits the insulin-regulated aminopeptidase (IRAP). This transmembrane zinc metallopeptidase with many biological functions has in recent years emerged as a new pharmacological target. IRAP is expressed in a variety of tissues and can be found in high density in the hippocampus and neocortex, brain regions associated with cognition. Ang IV is known to improve memory tasks in experimental animals. One of the most potent IRAP inhibitors known today is the macrocyclic compound HA08 that is significantly more stable than the endogenous Ang IV. HA08 combines structural elements from Ang IV and the physiological substrates oxytocin and vasopressin, and binds to the catalytic site of IRAP. In the present study we evaluate whether HA08 can restore cell viability in rat primary cells submitted to hydrogen peroxide damage. After damaging the cells with hydrogen peroxide and subsequently treating them with HA08, the conceivable restoring effects of the IRAP inhibitor were assessed. The cellular viability was determined by measuring mitochondrial activity and lactate dehydrogenase (LDH) release. The mitochondrial activity was significantly higher in primary hippocampal cells, whereas the amount of LDH was unaffected. We conclude that the cell viability can be restored in this cell type by blocking IRAP with the potent macrocyclic inhibitor HA08, although the mechanism by which HA08 exerts its effects remains unclear.
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| 2. |
- Zelleroth, Sofia, 1990-
(författare)
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Anabolic Androgenic Steroids : Neurobiological Effects of Nandrolone, Testosterone, Trenbolone, and Stanozolol
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The use of anabolic androgenic steroids (AAS) for recreational purposes is a health concern, as long-term AAS-use in supraphysiological doses is associated with severe physical and psychological adverse effects. Several behavioral and cognitive problems are reported after long-term AAS-use, and alterations in brain morphology as well as neurotransmitter systems have been reported. The AAS-induced negative impact on the brain may depend on the type of AAS used, but the rationale behind the adverse effects observed is still not clear.The aim of the present thesis was to investigate the neurobiological impact of supraphysiological doses of structurally diverse AAS; testosterone, nandrolone, stanozolol, and trenbolone, as well as of the prodrugs nandrolone decanoate, testosterone undecanoate, testosterone decanoate, and trenbolone decanoate. Wistar rats were used to study the influence on behavior, effects on the brain, and additional somatic effects. Furthermore, in vitro models of immature and mature primary rat cortical cell cultures were used to examine the potential toxic properties of the AAS administered. In the in vitro studies, nandrolone and trenbolone were identified as the most toxic of the AAS investigated, due to their adverse impact on mitochondrial function, membrane integrity, apoptosis, and neurite outgrowth. In vivo, the AAS demonstrated diverse somatic outcomes affecting body weight development, and organ weights to different degrees. In addition, nandrolone decanoate caused a reduced general activity, an effect possibly induced by increased stress vulnerability and alterations in the oxytocinergic system. Furthermore, nandrolone decanoate induced impaired memory in the novel object recognition test. Overall, nandrolone decanoate was identified as the most harmful steroid investigated due to its prominent impact on body weight development, affecting multiple organs, and being the only AAS causing impaired cognitive function. In conclusion, the structurally different AAS exerted diverse effects on cell viability, neurite development as well as regarding physical impairments and impact on behavior, suggesting that harmful physiological, neurological, and psychological outcomes may be expected after AAS-use. These findings highlight that the severity and type of adverse effects depend on the type of AAS used, which is valuable information to consider in order to provide good healthcare and treatment options to AAS-users.
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| 3. |
- Zelleroth, Sofia, 1990-, et al.
(författare)
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Nandrolone decanoate and testosterone undecanoate differently affect stress hormones, neurotransmitter systems, and general activity in the male rat
- 2022
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Ingår i: Behavioural Brain Research. - : Elsevier. - 0166-4328 .- 1872-7549. ; 432
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Tidskriftsartikel (refereegranskat)abstract
- Anabolic androgenic steroids (AAS) are frequently used to improve physical appearance and strength. AAS are known to affect muscle growth, but many AAS-users also experience psychiatric and behavioral changes after long-term use. The AAS-induced effects on the brain seem to depend on the type of steroid used, but the rationale behind the observed effect is still not clear. The present study investigated and compared the impact of nandrolone decanoate and testosterone undecanoate on body weight gain, levels of stress hormones, brain gene expression, and behavioral profiles in the male rat. The behavioral profile was determined using the multivariate concentric squared field test (MCSF-test). Blood plasma and brains were collected for further analysis using ELISA and qPCR. Nandrolone decanoate caused a reduction in body weight gain in comparison with both testosterone undecanoate and control. Rats receiving nandrolone decanoate also demonstrated decreased general activity in the MCSF. In addition, nandrolone decanoate reduced the plasma levels of ACTH in comparison with the control and increased the levels of corticosterone in comparison with testosterone undecanoate. The qPCR analysis revealed brain region-dependent changes in mRNA expression, where the hypothalamus was identified as the region most affected by the AAS. Alterations in neurotransmitter systems and stress hormones may contribute to the changes in behavior detected in the MCSF. In conclusion, both AAS affect the male rat, although, nandrolone decanoate has more pronounced impact on the physiological and the behavioral parameters measured.
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