“Sigma-1 receptor modulation by clemastine highlights its repurposing as neuroprotective agent against seizures and cognitive deficits in PTZ-kindled rats”

Article

作者: Zaki, Hala F ; Shokr, Mustafa M ; Elshazly, Shimaa M ; Mohamed, Ahmed F ; Badawi, Ghada A

Epilepsy is a neurological disorder characterized by recurrent spontaneous seizures alongside other neurological comorbidities. Cognitive impairment is the most frequent comorbidity secondary to progressive neurologic changes in epilepsy. Sigma 1 receptors (σ1 receptors) are involved in the neuroprotection and pathophysiology of both conditions and targeting these receptors may have the potential to modulate both seizures and comorbidities. The current research demonstrated the effect of clemastine (10 mg/kg, P.O.), a non-selective σ1 receptor agonist, on pentylenetetrazol (PTZ) (35 mg/kg, i.p., every 48 h for 14 doses)-kindling rats by acting on σ1 receptors through its anti-inflammatory/antioxidant capacity. Clemastine and phenytoin (30 mg/kg, P.O.) or their combination were given once daily. Clemastine treatment showed a significant effect on neurochemical, behavioural, and histopathological analyses through modulation of σ1 receptors. It protected the kindling animals from seizures and attenuated their cognitive impairment in the Morris water maze test by reversing the PTZ hippocampal neuroinflammation/oxidative stress state through a significant increase in inositol-requiring enzyme 1 (IRE1), x-box binding protein 1 (XBP1), along with a reduction of total reactive oxygen species (TROS) and amyloid beta protein (Aβ). The involvement of σ1 receptors in the protective effects of clemastine was confirmed by their abrogation when utilizing NE-100, a selective σ1 receptor antagonist. In light of our findings, modulating σ1 receptors emerges as a compelling therapeutic strategy for epilepsy and its associated cognitive impairments. The significant neuroprotective effects observed with clemastine underscore the potential of σ1 receptor-targeted treatments to address both the primary symptoms and comorbidities of neurological disorders.

2024-07-01·Journal of Labelled Compounds and Radiopharmaceuticals

Fully Automated Cassette‐Based Synthesis of 2‐Deoxy‐2‐[¹⁸F]Fluorocellobiose Using Trasis AllInOne Module

Article

作者: Hammoud, Dima A. ; Basuli, Falguni ; Shah, Swati ; Swenson, Rolf E. ; Shi, Jianfeng ; Lai, Jianhao

ABSTRACTDue to the continuous rise in global incidence and severity of invasive fungal infections (IFIs), particularly among immunocompromised and immunodeficient patients, there is an urgent demand for swift and accurate fungal pathogen diagnosis. Therefore, the need for fungal‐specific positron emission tomography (PET) imaging agents that can detect the infection in the early stages is increasing. Cellobiose, a disaccharide, is readily metabolized by fungal pathogens such as Aspergillus species. Recently, our group reported fluorine‐18 labeled cellobiose, 2‐deoxy‐2‐[18F]fluorocellobiose ([18F]FCB), for specific imaging of Aspergillus infection. The positive imaging findings with very low background signal on delayed imaging make this ligand a promising fungal‐specific imaging ligand. Inspired by this result, the decision was made to automate the radiolabeling procedure for better reproducibility and to facilitate clinical translation. A Trasis AllInOne (Trasis AIO) automated module was used for this purpose. The reagent vials contain commercially available 2‐deoxy‐2‐[18F]fluoroglucose ([18F]FDG), glucose‐1‐phosphate, and enzyme (cellobiose phosphorylase). A Sep‐Pak cartridge was used to purify the tracer. The overall radiochemical yield was 50%–70% (n = 6, decay corrected) in 75‐min synthesis time with a radiochemical purity of > 98%. This is a highly reliable protocol to produce current good manufacturing practice (cGMP)–compliant [18F]FCB for clinical PET imaging.

2014-09-01·Brain Research Bulletin3区 · 医学

Evidence for the gastric cytoprotective effect of centrally injected agmatine

3区 · 医学

Article

作者: Zádori, Zoltán S ; Németh, József ; Fehér, Ágnes ; Philipp, Kirsch ; Tóth, Viktória E ; Gyires, Klára

Agmatine (decarboxylated arginine) exerts cytoprotective action in several tissues, such as in the brain, heart or kidneys, but there is still controversy over the effects of agmatine on the gastric mucosa. The aim of the present study was to reveal the potential gastroprotective action of agmatine by using an acid-independent ulcer model to clarify which receptors and peripheral factors are involved in it. Gastric mucosal damage was induced by acidified ethanol. Mucosal levels of calcitonin gene-related peptide (CGRP) and somatostatin were determined by radioimmunoassay. For analysis of gastric motor activity the rubber balloon method was used. It was found that agmatine given intracerebroventricularly (i.c.v., 0.044-220 nmol/rat) significantly inhibited the development of ethanol-induced mucosal damage, while in the case of intraperitoneal injection (0.001-50mg/kg i.p.) it had only a minor effect. The central gastroprotective action of agmatine was completely antagonized by mixed alpha2-adrenoceptor and imidazoline I1 receptor antagonists (idazoxan, efaroxan), but only partially by yohimbine (selective alpha2-adrenoceptor antagonist) and AGN 192403 (selective I1 receptor ligand, putative antagonist). It was also inhibited by the non-selective opioid-receptor antagonist naloxone and the selective δ-opioid receptor antagonist naltrindole, but not by β-funaltrexamine and nor-Binaltorphimine (selective μ- and κ-opioid receptor antagonists, respectively). Furthermore, the effect of agmatine was antagonized by bilateral cervical vagotomy and by pretreatment with indomethacin and NG-nitro-l-arginine. Agmatine also reversed the ethanol-induced reduction of gastric mucosal CGRP and somatostatin content, but did not have any significant effect on gastric motor activity. These results indicate that agmatine given centrally induces gastric cytoprotection, which is mediated by central imidazoline I1 receptors, alpha2-adrenoceptors and δ-opioid receptors. Activation of these receptors induces the release of different mucosal protective factors, such as NO, prostaglandins, CGRP and somatostatin by a vagal-dependent mechanism. Alterations of gastric motility are not likely to contribute to the observed protective effect.

100 项与 [(18)F]5a(Helmholtz-Zentrum Dresden-Rossendorf e. V.) 相关的药物交易

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