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Opioid addiction causes some molecular alterations in the brain reward pathway, such as changes in gene expression that may be transferred to the next generation via epigenetic mechanisms such as histone acetylation. This study aimed to evaluate the effect of theophylline as an HDAC (Histone deacetylases) activator on D1 and D2 dopamine receptor expression in the nucleus accumbens (NAc) and anxiety behavior in the offspring of morphine-dependent female rats. Female rats were exposed to escalating doses of morphine for six days and were then treated with theophylline (20 mg/kg) or saline for 10 days before mating with normal male rats. Male and female offspring were tested for anxiety behavior using an elevated plus maze apparatus. Besides, the expression of D1 and D2 dopamine receptors in the NAc was evaluated by real-time PCR (polymerase chain reaction). Results showed that offspring of morphine-dependent female rats had increased expression of both D1 and D2 receptors in the NAc, as well as decreased anxiety behavior, compared to control offspring. However, the mentioned effects were returned to normal levels in the offspring whose morphine-dependent mothers had received theophylline for 10 days before mating. It is concluded that theophylline may be therapeutically effective in minimizing the adverse consequences of maternal morphine dependence on offspring behavior by restoring normal dopamine receptor expression levels and modulating anxiety. To completely comprehend the underlying mechanisms of this phenomenon, more research is required., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The unstable response to bevacizumab is a big dilemma in the antiangiogenic therapy of high-grade glioma that appears to be linked to an increase in the post-treatment intratumor levels of hypoxia-inducible factor 1 α (HIF1α) and active AKT. Particularly, a selective phosphodiesterase IV (PDE4) inhibitor, rolipram is capable of inhibiting HIF1α and AKT in cancer cells. Here, the effect of bevacizumab alone and in presence of rolipram on therapeutic efficacy, intratumor hypoxia levels, angiogenesis, apoptosis and proliferation mechanisms were evaluated. BALB/c mice bearing C6 glioma were received bevacizumab and rolipram either alone or combined for 30 days (n = 11/group). At the last day of treatments, apoptosis, proliferation and microvessel density, in xenografts (3/group) were detected by TUNEL staining, Ki67 and CD31 markers, respectively. Relative expression of target proteins was measured using western blotting. Bevacizumab initially hindered the tumor progression but its antitumor effect was weakened later despite the vascular regression and apoptosis induction. Unpredictably, bevacizumab-treated tumors exhibited the highest cell proliferation coupled with PDE4A, HIF1α and AKT upregulation and p53 downregulation and reversed by co-treatment with rolipram. Unlike a similar antivascular pattern to bevacizumab, rolipram consistently led to a more tumor growth suppression and proapoptotic effect versus bevacizumab. Co-treatment maximally hampered the tumor progression and elongated survival along with the major vascular regression, hypoxia, apoptosis induction, p53 and caspase activities. In conclusion, superior and persistent therapeutic efficacy of co-treatment provides a new insight into antiangiogenic therapy of malignant gliomas, suggesting to be a potential substitute in selected patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The dynorphin (DYN)/kappa opioid receptor (KOR) system plays an important role in the development of addiction, and dysregulation of this system could lead to abnormal activity in the reward pathway. It has been reported that the expression state of the neurotransmitters and their receptors in the brain is reflected in peripheral blood lymphocytes (PBLs)., Methods: We have evaluated the PBLs and plasma samples of four groups: 1) subjects with severe opioid use disorder (SOD), 2) methadone-maintenance treated (MMT) individuals, 3) long-term abstinent subjects having former SOD, and 4) healthy control subjects (n = 20 in each group). The mRNA expression level of preprodynorphin (pPDYN) and KOR in PBLs has been evaluated by real-time PCR. Peptide expression of PDYN in PBLs has been studied by western blot, and DYN concentration in plasma has been measured by ELISA., Results: The relative expression level of the pPDYN mRNA and PDYN peptide in PBLs were significantly up-regulated in SOD, MMT, and abstinent groups compared to control subjects. No significant difference was found in the plasma DYN concentration between study groups. The expression level of the KOR mRNA in PBLs was significantly decreased in all three study groups compared to the control subjects., Conclusion: the expression changes in the DYN/KOR system after chronic exposure to opioids, including methadone, seems to be stable and does not return to normal levels even after 12 months abstinence. These long-time and permanent changes in PBLs may serve as a biomarker and footprint of SOD development in the periphery., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Glioblastoma cancer stem-like cells (GCSCs) promote themselves proliferation by secreting the vascular endothelial growth factor A (VEGF A ) in an autocrine manner, positively regulated by phosphodiesterase IV (PDE4). In the current study, we investigated the putative cytotoxic effect of bevacizumab, a VEGF A blocker, alone and in combination with a specific inhibitor of PDE4 called rolipram on GCSCs isolated from human surgical tumor specimen with a focus on PI3K/AKT pathway., Main Methods: CD133+/CD15+ GCSCs were characterized by flow cytometry and expanded in a serum-free primary culture system. The cell survival, apoptosis, and protein expression values were measured using MTT assay, TUNEL staining and western blot, successively. Intracellular cAMP and free secreted VEGF A levels were assessed by cAMP enzyme immunoassay and ELISA, respectively., Key Findings: Bevacizumab suppressed GCSCs survival with IC 50 ~6.5μg/ml and enhanced the levels of apoptosis, p53 and cleaved-caspase3 along with a decrease in free VEGF A levels and ERKs activation. However, there was no significant modulation of AKT phosphorylation on serine 473, the intracellular PDE4A, VEGF A and cAMP levels. More cytotoxicity in co-treated cells coupled with a more substantial decline in the free VEGF A levels and a greater increase in the quantities of p53 and cleaved-caspase3 compared to those treated with bevacizumab alone. Co-treatment reduced phospho-AKT, endogenous VEGF A and PDE4A values but elevated cAMP levels., Significance: This study highlighted a booster cytotoxic effect of combined rolipram and bevacizumab treatment on the GCSCs primary culture, suggesting that this approach is warranted in treatment of GBMs overexpressing VEGF A and PDE4A., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Hemolytic kernicterus, an indirect bilirubin-induced brain dysfunction, is associated with hyper-bilirubinemia in mammalian neonates. In this study, a new model of kernicterus has been developed using intra-peritoneal injections of phenyl hydrazine and subcutaneous injections of sulfisoxazole. These drugs can potentially induce kernicterus in neonatal through changes in hemolysis and hypo-albumin., Methods: For this purpose, 7-day-old male Wistar rats (n=72; mean weight 11±1g) were used. The animals have been divided into six different groups which received the drugs alone and their combination, and the drugs' solvents and their combination. Biochemical parameters, brain iron and bilirubin, behavioural performance, auditory function and apoptosis were measured using auto-analyser instruments; atomic absorption spectroscopy, Sawasaki, footprint, auditory brainstem response (ABR) and TUNEL test, respectively., Result: The drug-injected groups showed a significant reduction in serum haematocrit and an increase in the concentration of brain bilirubin, total and indirect bilirubin as well as TUNEL positive cells in basal ganglia. In addition, the obtained results showed that there was a significant increase in behavioural disturbance and auditory dysfunction in the group injected with the combination of two drugs., Conclusion: This kernicterus-induced rat model could perfectly mimic the common conditions of the hyperbilirubinemia in human neonates. This study offers an easy technique to develop more stable models for follow-up studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)