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    Blood levels of cytokines in children with idiopathic partial and generalized epilepsy
    (W B Saunders Co Ltd, 2013) Sonmez, Fatma Mujgan; Serin, Hepsen Mine; Alver, Ahmet; Aliyazicioglu, Rezzan; Cansu, Ali; Cane, Gamze; Zaman, Dilek
    Purpose: Antiepileptic drugs have been reported to reduce the levels of serum immunoglobulins and affect the production and levels of certain cytokines. We investigated the effects of valproic acid (VPA) and topiramate (TPM) on the blood levels of interleukin (IL)-alpha, IL-1 beta, IL-6, IL-10, and TNF-alpha in children with idiopathic generalized and partial epilepsy. Methods: Forty prepubertal children aged 6-12 (mean 8.3 +/- 1.7) years, 19/40 (47.5%) female and 21/40 (52.5%) male, with idiopathic generalized or partial epilepsy diagnosed in the child neurology outpatient clinic were included. The patients were divided into two treatment groups: 20 were treated with VPA and 20 with TPM. The plasma levels of IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF-alpha were measured using ELISA method before the initiation of treatment and at the 6th and 12th months of the treatment. The Chi-square test was used to compare qualitative data. To compare the periods, recurrence measurements were done using variance analysis and Freidman 2-sided variance analysis. p < 0.05 was considered as statistically significant. Results: In the VPA group, the levels of IL-1 alpha significantly increased at 12 months while the levels of IL-10 decreased at 6 months of treatment compared to values before treatment (p < 0.05). There was no significant difference in levels of IL-1 beta, IL-6, TNF-alpha (p > 0.05). In the TPM group, lower levels of IL-10 were observed at 6th and 12th months compared to the onset of treatment (p < 0.05). Conclusion: The results of this study demonstrated that VPA and TPM might lead to changes in the levels of cytokines in epileptic patients. The next step would be to investigate the relation of these findings to the outcome of epilepsy and response to treatment. (C) 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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    Brain-Derived Neurotrophic Factor Deficiency Exacerbates Innate Immune Responses by Enhancing NLRP3 Inflammasome Activation and GSDMD-Mediated Pyroptosis in Mice
    (Mdpi, 2026) Erdem, Seniz; Saglam, Neslihan; Sahin, Elif; Erdem, Mehmet; Abidin, Ismail; Alver, Ahmet
    Background and Objectives: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a key innate immune complex, and its aberrant activation contributes to metabolic and neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with anti-inflammatory and metabolic regulatory functions, but its role in NLRP3 inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis remains unclear. The aim of this study was to investigate the effects of BDNF deficiency on LPS- and nigericin-induced NLRP3 inflammasome activation and GSDMD-mediated pyroptosis in vivo, and to elucidate the involvement of NF-kappa B signaling, autophagy, and ESCRT-III-dependent plasma membrane repair in this process. Materials and Methods: In this in vivo study, male Bdnf +/+ and Bdnf +/- mice were subjected to lipopolysaccharide (LPS) plus nigericin-induced NLRP3 inflammasome activation. Serum and hippocampus, cortex, liver, epididymal adipose, and muscle tissues were collected 24 h after stimulation for analysis of inflammasome-related, autophagy-related, and membrane repair-related proteins by Western blotting and of serum BDNF, interleukin-1 beta (IL-1 beta), and interleukin-18 (IL-18) by ELISA. Results: Bdnf +/- mice displayed significantly reduced circulating BDNF levels and exhibited exaggerated LPS plus nigericin-induced increases in IL-1 beta and IL-18 compared with Bdnf +/+ mice. Across all tissues, BDNF deficiency enhanced NF-kappa B p65, NLRP3, active caspase-1 p20, and GSDMD expression, indicating amplified inflammasome activation and pyroptosis. Conversely, LC3B and SQSTM1/p62 levels were decreased, and VPS4A expression, a key component of the ESCRT-III membrane repair machinery, was suppressed in Bdnf +/- mice, suggesting impaired selective autophagy, autophagosome formation, and plasma membrane repair. Conclusions: Together, these findings indicate that BDNF restrains NLRP3 inflammasome activation and GSDMD-mediated pyroptosis through inhibition of NF-kappa B signaling and coordinated activation of autophagy and ESCRT-III-dependent membrane repair. BDNF thus emerges as an endogenous negative regulator of inflammasome activity and a potential therapeutic target for conditions characterized by aberrant NLRP3-driven inflammation.
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    R 2-adrenoceptor agonist formoterol attenuates NLRP3 inflammasome activation and GSDMD-mediated pyroptosis in microglia through enhancing IκBα/NF-κB κ B α /NF- κ B inhibition, SQSTM1/p62-dependent selective autophagy and ESCRT-III-mediated plasma membrane repair
    (Academic Press Inc Elsevier Science, 2024) Erdem, Mehmet; Erdem, Seniz; Alver, Ahmet; Kiran, Tugba Raika; Karahan, Sueleyman Caner
    Microglia are immune cells that play important roles in the formation of the innate immune response within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiple protein complex that is crucial for innate immunity, and excessive activation of the inflammasome for various reasons contributes to the pathogenesis of neurodegenerative diseases (NDs). R2-adrenoceptor 2-adrenoceptor agonists have become the focus of attention in studies on NDs due to the high synthesis of R2-adrenoceptors 2-adrenoceptors in the central nervous system (CNS). Promising results have been obtained from these studies targeting antiinflammatory and neuroprotective effects. Formoterol is an effective, safe for long-term use, and FDA- approved R2-adrenoceptor 2-adrenoceptor agonist with demonstrated anti-inflammatory features in the CNS. In this study, we researched the effects of formoterol on LPS/ATP-stimulated NLRP3 inflammasome activation, pyroptosis, NF-kappa B, autophagy, and ESCRT-III-mediated plasma membrane repair pathways in the N9 microglia cells. The results showed that formoterol, through the I kappa B alpha/NF-kappa B axis, significantly inhibited NLRP3 inflammasome activation, reduced the level of active caspase-1, secretion of IL-1R and IL-18 proinflammatory cytokine levels, and the levels of pyroptosis. Additionally, we showed that formoterol activates autophagy, autophagosome formation, and ESCRT-III-mediated plasma membrane repair, which are significant pathways in the inhibition of NLRP3 inflammasome activation and pyroptosis. Our study suggests that formoterol efficaciously prevents the NLRP3 inflammasome activation and pyroptosis in microglial cells regulation through I kappa B alpha/NF-kappa B, autophagy, autophagosome formation, and ESCRT-III-mediated plasma membrane repair.
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    The brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone mitigates NLRP3 inflammasome activation and GSDMD-mediated pyroptosis and enhances the negative regulatory pathways of pyroptosis in microglia
    (Elsevier, 2025) Erdem, Mehmet; Erdem, Seniz; Karahan, Suleyman Caner; Alver, Ahmet; Karabulut, Soner; Yildiz, Gokhan
    Microglia are resident immune cells of brain, which serves as a driver of the innate immunity within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that is critical component of the innate immunity and hyperactivation of inflammasome under various conditions contributing to the pathogenesis of neurodegenerative diseases (NDs). 7,8-Dihydroxyflavone (7,8-DHF) have become the focus of attention in studies on NDs due to exert its neurotrophic effects in the CNS. Recent studies have shown encouraging outcomes targeting immune regulatory and neuroprotective properties. 7,8-DHF is a specific tropomyosin-related kinase receptor B (TrkB) agonist and bioavailable brainderived neurotrophic factor (BDNF) mimetic, which has immunomodulator properties in the CNS. In the present study, we researched the effects of BDNF mimetic 7,8-DHF on NLRP3 inflammasome activation, GSDMDmediated pyroptosis, NF-kappa B signaling, ESCRT-III-dependent plasma membrane repair, and selective autophagy in LPS plus ATP-induced murine N9 microglial cells. These findings demonstrated that BDNF mimetic 7,8-DHF significantly reduced NLRP3 inflammasome activation, decreased active caspase-1 the levels, inhibited secretion of proinflammatory cytokine IL-1 beta and IL-18 levels through the I kappa B alpha/NF-kappa B axis. Furthermore, we showed that BDNF mimetic 7,8-DHF activated selective autophagy and ESCRT-III-dependent plasma membrane repair, both of which play crucial roles in the negative regulation of NLRP3 inflammasome activation. Our study reveals that BDNF mimetic 7,8-DHF effectively prevents microglial NLRP3 inflammasome activation and GSDMD-mediated pyroptosis by inhibiting I kappa B alpha/NF-kappa B, promoting ESCRT-III-dependent plasma membrane repair and enhancing selective autophagy.