Publications by authors named "Dina Medina-Vera"

6 Publications

  • Page 1 of 1

Activation of PI3K/Akt Signaling Pathway in Rat Hypothalamus Induced by an Acute Oral Administration of D-Pinitol.

Nutrients 2021 Jun 30;13(7). Epub 2021 Jun 30.

Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain.

D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.
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http://dx.doi.org/10.3390/nu13072268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308282PMC
June 2021

A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer's Disease, the 5XFAD Mouse.

Int J Mol Sci 2021 May 20;22(10). Epub 2021 May 20.

Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain.

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg), heterozygous (Tg), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg and Tg mice and increased expression of IL-1β in Tg mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg and Tg mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.
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http://dx.doi.org/10.3390/ijms22105365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161294PMC
May 2021

Imbalance of Endocannabinoid/Lysophosphatidylinositol Receptors Marks the Severity of Alzheimer's Disease in a Preclinical Model: A Therapeutic Opportunity.

Biology (Basel) 2020 Nov 5;9(11). Epub 2020 Nov 5.

Instituto de Investigación Biomédica de Málaga-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.

Alzheimer's disease (AD) is the most common form of neurodegeneration and dementia. The endocannabinoid (ECB) system has been proposed as a novel therapeutic target to treat AD. The present study explores the expression of the ECB system, the ECB-related receptor GPR55, and cognitive functions (novel object recognition; NOR) in the 5xFAD (FAD: family Alzheimer's disease) transgenic mouse model of AD. Experiments were performed on heterozygous (HTZ) and homozygous (HZ) 11 month old mice. Protein expression of ECB system components, neuroinflammation markers, and β-amyloid (Aβ) plaques were analyzed in the hippocampus. According to the NOR test, anxiety-like behavior and memory were altered in both HTZ and HZ 5xFAD mice. Furthermore, both animal groups displayed a reduction of cannabinoid (CB1) receptor expression in the hippocampus, which is related to memory dysfunction. This finding was associated with indirect markers of enhanced ECB production, resulting from the combination of impaired monoacylglycerol lipase (MAGL) degradation and increased diacylglycerol lipase (DAGL) levels, an effect observed in the HZ group. Regarding neuroinflammation, we observed increased levels of CB2 receptors in the HZ group that positively correlate with Aβ's accumulation. Moreover, HZ 5xFAD mice also exhibited increased expression of the GPR55 receptor. These results highlight the importance of the ECB signaling for the AD pathogenesis development beyond Aβ deposition.
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http://dx.doi.org/10.3390/biology9110377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694492PMC
November 2020

D-Pinitol from Is an Orally Active Natural Inositol That Reduces Pancreas Insulin Secretion and Increases Circulating Ghrelin Levels in Wistar Rats.

Nutrients 2020 Jul 8;12(7). Epub 2020 Jul 8.

Laboratorio de Medicina Regenerativa, Instituto IBIMA de Málaga, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.

To characterize the metabolic actions of D-Pinitol, a dietary inositol, in male Wistar rats, we analyzed its oral pharmacokinetics and its effects on (a) the secretion of hormones regulating metabolism (insulin, glucagon, IGF-1, ghrelin, leptin and adiponectin), (b) insulin signaling in the liver and (c) the expression of glycolytic and neoglucogenesis enzymes. Oral D-Pinitol administration (100 or 500 mg/Kg) resulted in its rapid absorption and distribution to plasma and liver compartments. Its administration reduced insulinemia and HOMA-IR, while maintaining glycaemia thanks to increased glucagon activity. In the liver, D-Pinitol reduced the key glycolytic enzyme pyruvate kinase and decreased the phosphorylation of the enzymes AKT and GSK-3. These observations were associated with an increase in ghrelin concentrations, a known inhibitor of insulin secretion. The profile of D-Pinitol suggests its potential use as a pancreatic protector decreasing insulin secretion through ghrelin upregulation, while sustaining glycaemia through the liver-based mechanisms of glycolysis control.
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http://dx.doi.org/10.3390/nu12072030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400942PMC
July 2020

Differential hepatoprotective role of the cannabinoid CB and CB receptors in paracetamol-induced liver injury.

Br J Pharmacol 2020 07 15;177(14):3309-3326. Epub 2020 Apr 15.

UGC Salud Mental, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.

Background And Purpose: Protective mechanisms of the endogenous cannabinoid system against drug-induced liver injury (DILI) are actively being investigated regarding the differential regulatory role of the cannabinoid CB and CB receptors in liver fibrogenesis and inflammation.

Experimental Approach: The 2-arachidonoylglycerol (2-AG)-related signalling receptors and enzymatic machinery, and inflammatory/fibrogenic factors were investigated in the liver of a mouse model of hepatotoxicity induced by acute and repeated overdoses (750 mg·kg ·day ) of paracetamol (acetaminophen), previously treated with selective CB (ACEA) and CB (JWH015) agonists (10 mg·kg ), or lacking CB and CB receptors.

Key Results: Acute paracetamol increased the expression of CB , ABHD6 and COX-2, while repeated paracetamol increased that of CB and COX-2 and decreased that of DAGLβ. Both acute paracetamol and repeated paracetamol decreased the liver content of acylglycerols (2-AG, 2-LG and 2-OG). Human liver samples from a patient suffering APAP hepatotoxicity confirmed CB and CB increments. Acute paracetamol-exposed CB KO mice had higher expression of the fibrogenic αSMA and the cytokine IL-6 and lower apoptotic cleaved caspase 3. CB deficiency enhanced the repeated APAP-induced increases in αSMA and cleaved caspase 3 and blocked those of CYP2E1, TNF-α, the chemokine CCL2 and the circulating γ-glutamyltransferase (γGT). Although JWH015 reduced the expression of αSMA and TNF-α in acute paracetamol, ACEA increased the expression of cleaved caspase 3 and CCL2 in repeated paracetamol.

Conclusion And Implications: The differential role of CB versus CB receptors on inflammatory/fibrogenic factors related to paracetamol-induced hepatotoxicity should be considered for designing alternative therapies against DILI.
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http://dx.doi.org/10.1111/bph.15051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312315PMC
July 2020

Adolescent binge-ethanol accelerates cognitive impairment and β-amyloid production and dysregulates endocannabinoid signaling in the hippocampus of APP/PSE mice.

Addict Biol 2021 01 11;26(1):e12883. Epub 2020 Feb 11.

Departament de Psicobiologia, Universitat de València, Valencia, Spain.

Previous research in rodents suggests that the long-term neurobehavioral disturbances induced by chronic ethanol (EtOH) exposure could be due to endocannabinoid system (ECS) alterations. Moreover, ECS failure has been proposed to mediate the cognitive impairment and β-amyloid production in Alzheimer disease (AD). Thus, in the present study, we evaluated the effects of adolescent EtOH binge drinking on the cognitive disturbances, hippocampal β-amyloid levels, and in the ECS expression on a transgenic mouse model (APP/PSEN, AZ) of AD. We exposed AZ and wild-type mice to a binge-drinking treatment during adolescence. At 6 and 12 months of age, we evaluated hippocampal-dependent learning and memory: β-amyloid concentrations and RNA and protein levels of cannabinoid type-2 receptors (CB2), diacylglycerol lipase-α (DAGLα), and monoacylglycerol lipase (MAGL) in the hippocampus. The results showed that binge-EtOH treatment worsens cognitive function and increases β-amyloid levels in AZ. At 6 months, EtOH heightens CB2 (RNA and protein) and DAGLα (RNA) expression in wild type but not in AZ. On the contrary, EtOH enhances MAGL RNA expression only in AZ. At 12 months, AZ displays increased levels of CB2 (RNA and protein) and DAGLα (protein) compared with control. Similar to what happens at 6 months, EtOH induces an increase in CB2 gene expression in wild type but not in AZ; however, it augments CB2 and DAGLα protein levels in both genotypes. Therefore, we propose that adolescent binge drinking accelerates cognitive deficits associated with aging and AD. It also accelerates hippocampal β-amyloid accumulation in AZ and affects differently the ECS response in wild type and AZ.
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http://dx.doi.org/10.1111/adb.12883DOI Listing
January 2021
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