Current Issue : January-March Volume : 2023 Issue Number : 1 Articles : 5 Articles
Lamotrigine is widely prescribed to treat bipolar neurological disorder and epilepsy. It exerts its antiepileptic action by blocking voltage-gated sodium channels in neurons. Recently, the US Food and Drug Administration issued a warning on the use of Lamotrigine after observations of conduction anomalies and Brugada syndrome patterns on the electrocardiograms of epileptic patients treated with the drug. Brugada syndrome and conduction disturbance are both associated with alterations of the cardiac sodium current (INa) kinetics and amplitude. In this study, we used the patch clamp technique on cardiomyocytes from epileptic rats to test the hypothesis that Lamotrigine also blocks INa in the heart. We found that Lamotrigine inhibited 60% of INa peak amplitude and reduced cardiac excitability in epileptic rats but had little effect in sham animals. Moreover, Lamotrigine inhibited 67% of INaL and, more importantly, prolonged the action potential refractory period in epileptic animals. Our results suggest that enhanced affinity of Lamotrigine for INa may in part explain the clinical phenotypes observed in epileptic patients....
Arrhythmia, an irregular heartbeat, might be a life-threatening condition but also a risk factor for stroke or worsen the prognosis after myocardial infarction. The limited efficacy and proarrhythmic potential of the available drugs require searching for new, more effective, and safer pharmacotherapies. Studies indicate that the blockade of α1-adrenoceptors could be effective in treating heart rhythm abnormalities. In this study, we aimed to assess the antiarrhythmic and hypotensive potential of HBK-10, a novel 2-methoxyphenylpiperazine derivative, as well as its binding to the selected adrenergic receptors. Radioligand binding studies demonstrated that HBK-10 showed a high affinity for α1 but not for α2 or β1 receptors. Next, we evaluated the ability of HBK- 10 to protect against an adrenaline-induced arrhythmia in rats. The compound showed potent prophylactic antiarrhythmic properties in this arrhythmia model. Notably, the compound did not show proarrhythmic potential in normotensive rats since it did not influence the ECG parameters at antiarrhythmic doses. Finally, the compound showed hypotensive properties in rats, which were not observed after coadministration with adrenaline, noradrenaline, or methoxamine, which suggests α1-adrenolytic properties of HBK-10. Our results confirm that compounds with a 2-methoxyphenylpiperazine group show a high affinity for α1-adrenoceptors and a significant antiarrhythmic effect. Given the promising results of our study, further evaluation of HBK-10 is necessary to unravel the mechanisms behind its pharmacological effects and evaluate the safety profile....
Tramadol overdose is frequently associated with the onset of seizures, usually considered as serotonin syndrome manifestations. Recently, the serotoninergic mechanism of tramadol-attributed seizures has been questioned. This study’s aim was to identify the mechanisms involved in tramadolinduced seizures in overdose in rats. The investigations included (1) the effects of specific pretreatments on tramadol-induced seizure onset and brain monoamine concentrations, (2) the interaction between tramadol and γ-aminobutyric acid (GABA)A receptors in vivo in the brain using positron emission tomography (PET) imaging and 11C-flumazenil. Diazepam abolished tramadol-induced seizures, in contrast to naloxone, cyproheptadine and fexofenadine pretreatments. Despite seizure abolishment, diazepam significantly enhanced tramadol-induced increase in the brain serotonin (p < 0.01), histamine (p < 0.01), dopamine (p < 0.05) and norepinephrine (p < 0.05). No displacement of 11C-flumazenil brain kinetics was observed following tramadol administration in contrast to diazepam, suggesting that the observed interaction was not related to a competitive mechanism between tramadol and flumazenil at the benzodiazepine-binding site. Our findings do not support the involvement of serotoninergic, histaminergic, dopaminergic, norepinephrine or opioidergic pathways in tramadol-induced seizures in overdose, but they strongly suggest a tramadol-induced allosteric change of the benzodiazepine-binding site of GABAA receptors. Management of tramadolpoisoned patients should take into account that tramadol-induced seizures are mainly related to a GABAergic pathway....
Adipose tissue (AT) secretes adipokines, modulators of low-grade chronic inflammation in obesity. Molecules that induce the emergence of new and functional adipocytes in AT can alleviate or prevent inflammatory and metabolic disorders. The objective of this study was to investigate the role of palmitoleic acid (n7) in 3T3-L1 and primary pre-adipocyte differentiation and AT inflammation. C57BL/6j mice were submitted to a control or high-fat diet (HFD) for 8 weeks, and treated with n7 for 4 weeks. Mice consuming a HFD presented an increase in body weight, epididymal (Epi) fat mass, and Epi adipocytes size. N7 treatment attenuated the body weight gain and completely prevented the hypertrophy of Epi adipocytes, but not the increment in Epi mass induced by the HFD, suggesting a greater adipocytes hyperplasia in animals treated with n7. It was agreed that n7 increased 3T3-L1 proliferation and differentiation, as well as the expression of genes involved in adipogenesis, such as Cebpa, Pparg, aP2, Perilipin, and Scl2a4. Furthermore, n7 decreased the inflammatory cytokines Mcp1, Tnfa, Il6, Cxcl10, and Nos2 genes in Epi vascular stromal cells, but not in the whole AT. These findings show that n7 exerts anti-hypertrophic effects in adipocytes which influence the surrounding cells by attenuating the overexpression of pro-inflammatory cytokines triggered by a HFD....
Disturbance of glucose metabolism, nerve growth factor (NGF) and m-TOR signaling have been associated with the pathophysiology of epilepsy. Pioglitazone (PGZ) is an anti-diabetic drug that shows a protective effect in neurodegenerative diseases including epilepsy; however, its exact mechanism is not fully elucidated. The present study aimed to investigate the potential neuroprotective effect of PGZ in pentylenetetrazole (PTZ) kindled seizure in mice. Swiss male albino mice were randomly distributed into four groups, each having six mice. Group 1 was considered the control. Epilepsy was induced by PTZ (35 mg/kg i.p.) thrice a week for a total of 15 injections in all other groups. Group 2 was considered the untreated PTZ group while Group 3 and Group 4 were treated by PGZ prior to PTZ injection at two dose levels (5 and 10 mg/kg p.o., respectively). Seizure activity was evaluated after each PTZ injection according to the Fischer and Kittner scoring system. At the end of the experiment, animals were sacrificed under deep anesthesia and the hippocampus was isolated for analysis of glucose transporters by RT-PCR, nerve growth factor (NGF) by ELISA and mTOR by western blotting, in addition to histopathological investigation. The PTZ-treated group showed a significant rise in seizure score, NGF and m-TOR hyperactivation, along with histological abnormalities compared to the control group. Treatment with PGZ demonstrated a significant decrease in NGF, seizure score, m-TOR, GLUT-1 and GLUT-3 in comparison to the PTZ group. In addition, improvement of histological features was observed in both PGZ treated groups. These findings suggest that PGZ provides its neuroprotective effect through modulating m-TOR signaling, glucose metabolism and NGF levels....
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