| 1. |
- Bohman, Hannes, 1965-, et al.
(author)
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Preclinical atherosclerosis in adolescents with psychotic or bipolar disorders investigated with carotid high-frequency ultrasound.
- 2020
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In: Brain and Behavior. - : Wiley. - 2162-3279 .- 2162-3279. ; 10:12
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Early-onset psychosis (EOP) and bipolar disorder (EOBP) (at <18 years of age), are associated with an increased future risk of cardiovascular disease (CVD) and premature death. Yet it is unknown whether the arteries show visible signs of atherosclerosis in EOP and EOBP. This study investigated whether having EOP or EOBP was associated with detectable signs of preclinical atherosclerosis.METHOD: By using 22 MHz high-frequency ultrasound, different layers of the arterial wall of the left common carotid artery (LCCA) were assessed in 77 individuals with EOP (n = 25), EOBP (n = 22), and in age-matched healthy controls (n = 30). Conventional CVD confounders were included in the analyses.RESULTS: Adolescents with EOP and EOBP, compared to controls, had a significantly thicker LCCA intima thickness (0.132 vs. 0.095 mm, p < .001) and intima/media ratio (0.24 vs. 0.17 p < .001). There was a nonsignificant intima difference between EOP and EOBP. Conventional CVD risk factors did not explain the association between EOP/EOBP and intima thickness. In the group of EOP/EOBP, there was a significant correlation between the dose of current antipsychotic medication and intima thickness; however, the correlation was attenuated to a nonsignificant level when adjusted for global function.CONCLUSIONS: Adolescents with EOP or EOBP had an increased LCCA intima thickness, interpreted as a sign of preclinical atherosclerosis. Global function of the disorders was the strongest determinant of intima thickness. The findings, if replicated, might have implications for long-term treatment of EOP and EOBP in order to reduce a future risk of CVD.
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| 2. |
- Darsalia, Vladimer, et al.
(author)
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Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats
- 2012
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In: Clinical Science. - : Portland Press. - 0143-5221 .- 1470-8736. ; 122:9-10, s. 473-483
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Journal article (peer-reviewed)abstract
- Diabetes is a strong risk factor for premature and severe stroke. The GLP-IR (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto-Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 mu g/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2-4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-IR agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.
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| 3. |
- Lundberg, Mathias, et al.
(author)
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Clozapine protects adult neural stem cells from ketamine-induced cell death in correlation with decreased apoptosis and autophagy
- 2020
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In: Bioscience Reports. - : Portland Press Ltd.. - 0144-8463 .- 1573-4935. ; 40:1
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Journal article (peer-reviewed)abstract
- Adult neurogenesis, the production of newborn neurons from neural stem cells (NSCs) has been suggested to be decreased in patients with schizophrenia. A similar finding was observed in an animal model of schizophrenia, as indicated by decreased bromodeoxyuridine (BrdU) labelling cells in response to a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist. The antipsychotic drug clozapine was shown to counteract the observed decrease in BrdU-labelled cells in hippocampal dentate gyrus (DG). However, phenotypic determination by immunohistochemistry analysis could not reveal whether BrdU-positive cells were indeed NSCs. Using a previously established cell model for analysing NSC protection in vitro, we investigated a protective effect of clozapine on NSCs.Primary NSCs were isolated from the mouse subventricular zone (SVZ), we show that clozapine had a NSC protective activity alone, as evident by employing an ATP cell viability assay. In contrast, haloperidol did not show any NSC protective properties. Subsequently, cells were exposed to the non-competitive NMDA-receptor antagonist ketamine. Clozapine, but not haloperidol, had a NSC protective/anti-apoptotic activity against ketamine-induced cytotoxicity. The observed NSC protective activity of clozapine was associated with increased expression of the anti-apoptotic marker Bcl-2, decreased expression of the pro-apoptotic cleaved form of caspase-3 and associated with decreased expression of the autophagosome marker 1A/1B-light chain 3 (LC3-II).Collectively, our findings suggest that clozapine may have a protective/anti-apoptotic effect on NSCs, supporting previous in vivo observations, indicating a neurogenesis-promoting activity for clozapine. If the data are further confirmed in vivo, the results may encourage an expanded use of clozapine to restore impaired neurogenesis in schizophrenia.
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| 4. |
- Lundberg, Mathias, et al.
(author)
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Development of an ELISA displaying similar reactivity with reduced and oxidized human Thioredoxin-1 (Trx1) : The plasma level of Trx1 in early onset psychosis disorders
- 2022
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In: JIM - Journal of Immunological Methods. - : Elsevier. - 0022-1759 .- 1872-7905. ; 510
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Journal article (peer-reviewed)abstract
- The plasma level of human thioredoxin-1 (Trx1) has been shown to be increased in various somatic diseases and psychiatric disorders. However, when comparing the reported plasma levels of Trx1, a great inter-study vari-ability, as well as variability in study outcomes of differences between patients and control subjects has been observed, ultimately limiting the possibility to make comparative analyses. Trx1 is a highly redox active protein prone to form various redox forms, e.g. dimers, oligomers or Trx1-protein complexes. We have recently shown that ELISA systems may vary in reactivity to various Trx1 redox forms. The primary aim of the present study was to develop an ELISA system with similar reactivity to various Trx1 redox forms. By evaluating a panel of novel monoclonal antibodies (mAbs), in various paired combinations, three ELISA systems were generated, with observed large variability in reactivity to various Trx1 redox forms. Importantly, an ELISA system (capture mAb MT17R6 and detection mAb MT13X3-biotin), was identified that displayed similar reactivity to oxidized and DTT reduced Trx1. The ELISA system (MT17R6/MT13X3-biotin), was subsequently used to analyze the level of Trx1 in plasma from patients (< 18 years) with early onset psychosis disorders (EOP). However, no significant (p > 0.7) difference in plasma Trx1 levels between patients with EOP (n = 23) and healthy age matched controls (HC) (n = 20) were observed. Furthermore, reliable measurement was shown to be dependent on the estab-lishment of platelet poor plasma samples, enabled by rigorous blood sample centrifugation and by efficient blocking of potentially interfering heterophilic antibodies. In conclusion, we report the design and character-ization of a Trx1 ELISA system with similar reactivity to various Trx1 redox forms. Importantly, data indicated that generated ELISA systems show large variability in reactivity to various redox forms with ultimate impact on measured levels of Trx1. Overall, results from this study suggests that future studies may be strongly improved by the use of Trx1 ELISA systems with characterized specificity to various redox forms.
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| 5. |
- Mansouri, Shiva
(author)
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Development of therapeutics for the treatment of diabetic brain complications
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Type-2 diabetes (T2D) is characterized by hyperglycemia and hyperlipidemia, resulting in impaired insulin production and insulin resistance in peripheral tissues. Several studies have demonstrated an association between diabetes and central nervous system complications such as stroke and Alzheimer’s disease. Due to the fact that T2D is one of the fastest growing chronic illnesses, there is an urgent need to improve our knowledge on the pathogenic mechanisms to why diabetes leads to brain complications as well as to identify novel drugable targets for therapeutic use. Project 1: studies I-II Pre-clinical studies have shown that adult neurogenesis is impaired in diabetic animal models. We hypothesized that diabetes leading to neurogenesis impairment plays a role in the development of neurological complications. If so, normalizing neurogenesis in diabetes/obesity could be therapeutically useful in counteracting neurological dysfunction. The aim of studies I-II was to establish an in vitro system where to study the effect of a diabetic milieu on adult neurogenesis. Furthermore, we determined the potential role of pituitary adenylate cyclase-activating polypeptide (PACAP) and galanin to protect adult neural stem cells (NSCs) from these diabetic-like conditions. Moreover, we determined whether apoptosis and the unfolded protein response (UPR) were induced by diabetic-like conditions and whether their regulation was involved in the PACAP/galanin-mediated protective effect. Finally, we studied the potential regulation of PACAP and galanin receptors in NSCs in response to diabetic-like conditions in vitro and ex vivo. The viability of NSCs isolated from the mouse brain subventricular zone (SVZ) was assessed in presence of a diabetic milieu, as mimicked by high palmitate and glucose, which characterize diabetic glucolipotoxicity. The results show that high palmitate and glucose impair NSC viability in correlation to increased apoptosis (Bcl-2, cleaved caspase-3) and UPR signaling (CHOP, BIP, XBP1, JNK phosphorylation). We also show that PACAP and galanin counteract glucolipotoxicity via PAC1 receptor and GalR3 activation, respectively. Furthermore, we also report that PACAP and galanin receptors are regulated by diabetes in NSCs in vitro and in the SVZ ex vivo. Project 2: study III T2D is a strong risk factor for stroke and no therapy based on neuroprotection is currently available. Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist in clinical use for the treatment of T2D, which has also been shown to mediate neuroprotection against stroke pre-clinically. However, the applicability of a therapy based on Ex-4 has not been investigated in a pre-clinical setting with clinical relevance. The aim of this study was to determine the potential efficacy of Ex-4 against stroke in T2D rats by using a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Moreover, we investigated inflammation and neurogenesis as potential cellular mechanisms at the basis of Ex-4 efficacy. T2D Goto-Kakizaki (GK) rats were treated peripherally for 4 weeks with daily clinical doses of Ex-4 (0.1, 1, 5 !g/kg body weight) before inducing stroke by transient middle cerebral artery occlusion. The Ex-4 treatment was continued for 2-4 weeks thereafter. The severity of ischemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. Evaluation of stroke-induced inflammation, stem cell proliferation and neurogenesis was also quantitatively assessed by immunohistochemistry. We show that peripheral administration of Ex-4 counteracts ischemic brain damage in T2D GK rats. The results also show that Ex-4 decreased microglia infiltration and increased stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4 treatment. Together, our data in project 1 show that we have established an in vitro assay where to study the molecular mechanism on how diabetes impact adult neurogenesis. Furthermore, our results show that this assay has the potential to be developed into a screening platform for the identification of molecules that can regulate adult neurogenesis under diabetes. In project 2, we show neuroprotective efficacy against stroke by Ex-4 in a T2D rat model, by using a pre-clinical setting with clinical relevance. Ex-4 is an anti-diabetic drug in clinical use that has been reported to show limited side effects. Thus, at least in theory stroke patients should be able to easily receive this treatment, probably with minimal risks.
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| 6. |
- Mansouri, Shiva, et al.
(author)
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GalR3 activation promotes adult neural stem cell survival in response to a diabetic milieu
- 2013
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In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 127:2, s. 209-220
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Journal article (peer-reviewed)abstract
- Type 2 diabetes impairs adult neurogenesis which could play a role in the CNS complications of this serious disease. The goal of this study was to determine the potential role of galanin in protecting adult neural stem cells (NSCs) from glucolipotoxicity and to analyze whether apoptosis and the unfolded protein response were involved in the galanin-mediated effect. We also studied the regulation of galanin and its receptor subtypes under diabetes in NSCs in vitro and in the subventricular zone (SVZ) in vivo. The viability of mouse SVZ-derived NSCs and the involvement of apoptosis (Bcl-2, cleaved caspase-3) and unfolded protein response [C/EBP homologous protein (CHOP) Glucose-regulated protein 78/immunoglobulin heavy-chain binding protein (GRP78/BiP), spliced X-box binding protein 1 (XBP1), c-Jun N-terminal kinases (JNK) phosphorylation] were assessed in the presence of glucolipotoxic conditions after 24h. The effect of diabetes on the regulation of galanin and its receptor subtypes was assessed on NSCs in vitro and in SVZ tissues isolated from normal and type 2 diabetes ob/ob mice. We show increased NSC viability following galanin receptor (GalR)3 activation. This protective effect correlated with decreased apoptosis and CHOP levels. We also report how galanin and its receptors are regulated by diabetes in vitro and in vivo. This study shows GalR3-mediated neuroprotection, supporting a potential future therapeutic development, based on GalR3 activation, for the treatment of brain disorders.
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| 7. |
- Abbafati, Cristiana, et al.
(author)
-
- 2020
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Journal article (peer-reviewed)
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