Review
Multidisciplinary Sciences
Iman Imtiyaz Ahmed Juvale, Azzmer Azzar Abdul Hamid, Khairul Bariyyah Abd Halim, Ahmad Tarmizi Che Has
Summary: The multidrug resistance phenomenon poses a significant threat to the pharmaceutical industry and is mediated by multidrug transporters like P-glycoprotein. P-glycoprotein, with its versatile binding sites, accommodates various compounds and plays crucial roles in both multidrug resistant diseases and physiological functions in the human body.
Article
Clinical Neurology
Elena Pasini, Patrizia Riguzzi, Roberto Michelucci
Summary: This study reports two cases of focal pharmacoresistant epilepsy accompanied by ictal asystole during treatment with carbamazepine and phenytoin. The clear relationship between ictal arrhythmia and sodium channels blockers may be due to their negative effects on cardiac function. Ictal asystole can worsen falls in epileptic populations and requires prompt therapeutic decisions.
JOURNAL OF THE NEUROLOGICAL SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Sweilem B. Al Rihani, Lucy I. Darakjian, Malavika Deodhar, Pamela Dow, Jacques Turgeon, Veronique Michaud
Summary: The blood-brain barrier is crucial for regulating homeostasis in the central nervous system by controlling the entry of substances and supplying nutrients to the brain. Drug transporters at the BBB play a key role in determining drug distribution to the brain, and their expression and functionality can be influenced by inflammatory conditions and diseases. This can impact the efficacy and toxicity of drugs used to treat conditions such as Alzheimer's disease, epilepsy, and stroke.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Yuying Cen, Yuheng Shan, Jiahua Zhao, Xiaojiao Xu, Zhiyong Nie, Jiatang Zhang
Summary: This study aimed to investigate the impact of major transporters at the blood-brain barrier and blood-cerebrospinal fluid barrier on the pharmacokinetics of levofloxacin in rats. The results showed that the efflux of levofloxacin from the central nervous system involves multi-drug resistance-associated proteins, breast cancer resistance protein, and organic anion transporters. The concentrations of levofloxacin in cerebrospinal fluid can be used as a surrogate to predict the concentrations inside the brain parenchyma.
CNS NEUROSCIENCE & THERAPEUTICS
(2023)
Article
Clinical Neurology
Ricardo Blanco-Castaneda, Yessica Zapata-Vazquez, Blanca P. Lazalde-Ramos, Daniel Enriquez-Mendiola, Ismael Lares-Asseff, Carlos Galaviz-Hernandez, Gerardo Martinez, Martha Sosa-Macias
Summary: This study aimed to assess the effect of LEV exposure on the mRNA expression of placental transporters and found that LEV exposure led to decreased weight, height, and width of fetuses and altered expression of certain placental transporters. However, no correlation was found between serum LEV concentrations and gene expression levels.
Review
Pharmacology & Pharmacy
Chukwunonso K. Nwabufo, Reina Bendayan
Summary: The development of clinically effective drugs to complement existing vaccines is crucial for reducing the impact of COVID-19. This study examines how drug metabolism, transport, and inflammatory response may affect the efficacy of COVID-19 drugs, and provides expert opinions on strategies to improve their effectiveness.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Casey-Tyler Berezin, Nikolas Bergum, Glenda M. Torres Lopez, Jozsef Vigh
Summary: Opioids are effective analgesics, but their dangerous side effects need to be considered. Research on opioid pharmacokinetics provides crucial information on drug effects. This study found that morphine accumulates in the mouse retina at higher concentrations than in the brain and that reduced P-gp expression may be the cause. P-gp was identified as the main opioid transporter at the blood-retina barrier, and its expression correlated with morphine concentration in the retina.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Nikola Pastvova, Petr Dolezel, Petr Mlejnek
Summary: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with complex genetic alterations and protection from the blood-brain barrier (BBB). The study found that heat shock protein 90 (HSP90) inhibitors, GDN and 17-AAG, induced extensive cell death with apoptotic characteristics in glioma cell lines, regardless of genetic alterations. These inhibitors were weak substrates of ABCB1 and ABCG2, suggesting potential benefits for GBM patients.
Review
Pharmacology & Pharmacy
Huilong Luo, Lucie Chevillard, Frank Bellivier, Bruno Megarbane, Bruno Etain, Salvatore Cisternino, Xavier Decleves
Summary: This article discusses the key role of brain barriers in the neuropharmacokinetics of lithium, revealing the heterogenous distribution of lithium in the brain and the variability in transport mechanisms through brain barriers, which may improve the understanding of PK-PD of lithium and its interindividual variability in drug response.
PHARMACOLOGICAL RESEARCH
(2021)
Review
Pharmacology & Pharmacy
Md Masud Parvez, Armin Sadighi, Yeseul Ahn, Steve F. Keller, Julius O. Enoru
Summary: Uptake drug transporters in the brain play a significant role in drug metabolism, and understanding their contribution to drug entry into the central nervous system is crucial for clinical translation and drug development. However, species differences may affect the translation between humans and animals.
Article
Neurosciences
Lisa Welzel, David H. Bergin, Alina Schidlitzki, Friederike Twele, Marie Johne, Pavel Klein, Wolfgang Loescher
Summary: The authors proposed a novel approach involving multiple targets and networks, combining drugs to prevent the onset of epilepsy, and provided initial evidence of its effectiveness.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Clinical Neurology
Makihiko Nagano, Takashi Tagami, Junya Kaneko, Masayoshi Kondo, Mio Hotta, Minoru Kubota, Kazutoshi Sugaya, Hisamitsu Takase, Masamune Kuno, Kyoko Unemoto
Summary: This study aimed to evaluate the blood concentration of levetiracetam in patients with status epilepticus in an emergency clinical setting. The results showed that levetiracetam reached therapeutic levels in patients with early-stage status epilepticus after a bolus administration of 2500 mg, with positive effects observed in secondary outcomes.
SEIZURE-EUROPEAN JOURNAL OF EPILEPSY
(2021)
Article
Chemistry, Multidisciplinary
Ryuta Jomura, Shin-ichi Akanuma, Bjorn Bauer, Yukiko Yoshida, Yoshiyuki Kubo, Ken-ichi Hosoya
Summary: The study investigated the transport of phenytoin across the blood-brain barrier (BBB), identifying that MCT8 participates in the efflux of phenytoin from the brain to the blood. Meanwhile, P-gp did not affect the efflux of phenytoin from the brain.
PHARMACEUTICAL RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Sebastien Goutal, Anthony Novell, Sarah Leterrier, Louise Breuil, Erwan Selingue, Matthieu Gerstenmayer, Solene Marie, Bruno Saubamea, Fabien Caille, Oliver Langer, Charles Truillet, Benoit Larrat, Nicolas Tournier
Summary: In this study, the impact of focused ultrasound on P-gp function was investigated using positron emission tomography imaging. The results showed that the function of P-gp is associated with the integrity of the blood-brain barrier, and the down-regulation of P-gp function induced by focused ultrasound can be detected.
JOURNAL OF CONTROLLED RELEASE
(2023)
Article
Veterinary Sciences
Erez Hanael, Shelly Baruch, Orit Chai, Zohar Nir, Kira Rapoport, Marco Ruggeri, Itzhak Eizenberg, Dana Peery, Alon Friedman, Merav H. Shamir
Summary: The study found that the permeability of the blood-brain barrier in dogs is associated with the occurrence of seizures in dogs with meningoencephalitis of unknown origin (MUO).
JOURNAL OF VETERINARY INTERNAL MEDICINE
(2022)
Article
Clinical Neurology
Marie Johne, Kerstin Roemermann, Philip Hampel, Bjoern Gailus, Wiebke Theilmann, Tommi Ala-Kurikka, Kai Kaila, Wolfgang Loescher
Summary: The study evaluated the effect of bumetanide as an adjunct to phenobarbital on neonatal seizures, showing that bumetanide does not increase the efficacy of phenobarbital in a model of birth asphyxia.
Article
Behavioral Sciences
Philip Hampel, Kerstin Roemermann, Martina Gramer, Wolfgang Loescher
Summary: Bumetanide, azosemide, and torasemide all inhibit NKCC1 activity, but their distribution in the brain is limited, possibly due to efflux transport at the blood-brain barrier. Despite low levels of free fractions in plasma and brain, the free brain concentrations of bumetanide and torasemide fall within the NKCC1 inhibitory range, while azosemide is slightly below this range.
EPILEPSY & BEHAVIOR
(2021)
Article
Clinical Neurology
Wolfgang Loescher, Graeme J. Sills, H. Steve White
Summary: Alkyl-carbamates have been developed for the treatment of anxiety and epilepsy since 1955, with varying levels of success. These drugs share the ability to enhance inhibitory neurotransmission through modulation of the GABA(A) receptor, but also have different mechanisms of action and adverse events. Cenobamate stands out for its unique efficacy in treating seizures, but is also associated with serious rash and low tolerability at higher doses, suggesting the need for further safety studies and clinical experience.
Article
Neurosciences
Lisa Welzel, David H. Bergin, Alina Schidlitzki, Friederike Twele, Marie Johne, Pavel Klein, Wolfgang Loescher
Summary: The authors proposed a novel approach involving multiple targets and networks, combining drugs to prevent the onset of epilepsy, and provided initial evidence of its effectiveness.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Neurosciences
Philip Hampel, Kerstin Roemermann, Bjoern Gailus, Marie Johne, Birthe Gericke, Edith Kaczmarek, Wolfgang Loescher
Summary: NKCC1 is found in various cell types, with increased expression in neurons linked to brain disorders. Bumetanide's efficacy is uncertain, while azosemide shows promise as an alternative. Inhibiting NKCC1 with loop diuretics may not effectively increase seizure thresholds in adult epilepsy.
Review
Clinical Neurology
Wolfgang Loescher, Kai Kaila
Summary: This response corrects the inaccurate descriptions of the model and data in a recent study on the pharmacology of neonatal seizures in a novel rat model of birth asphyxia by Ben-Ari and Delpire. The authors also address the implications of bumetanide actions on neurons in other brain disorders due to its poor brain penetration and wide cellular expression patterns of the target protein NKCC1.
Article
Clinical Neurology
Marie Johne, Christopher Kaeufer, Kerstin Roemermann, Bjoern Gailus, Birthe Gericke, Wolfgang Loescher
Summary: Bumetanide failed to enhance the inhibitory effect of phenobarbital on neonatal seizures, but the combination of DIMAEB and bumepamine showed promising results in suppressing seizures, indicating potential for further development as more effective lead compounds for clinical trials.
Editorial Material
Clinical Neurology
Kai Kaila, Wolfgang Loescher
Summary: This article responds to Kevin Staley's critique of our research, explaining that our study was conducted on an asphyxia model, not just hypercarbia; clinically relevant doses of bumetanide lead to significantly lower concentrations in the brain than what is needed for any direct effect on neuronal functions; furthermore, bumetanide's molecular target in the brain has vital functions that make specifically targeting the depolarizing and excitatory actions of gamma-aminobutyric acid in neonatal seizures difficult.
Article
Cell Biology
Birthe Gericke, Inka Wienboeker, Gudrun Brandes, Wolfgang Loescher
Summary: This study investigated the localization and function of P-glycoprotein (Pgp) in intracellular compartments using biochemical and ultrastructural methods. The results showed that Pgp is rarely or not expressed at the limiting membrane of endolysosomes (ELs), but is present in early endosomes and intraluminal vesicles.
Article
Clinical Neurology
Bjorn Welzel, Ricardo Schmidt, Marie Johne, Wolfgang Loescher
Summary: In a rat model of birth asphyxia, midazolam not only prevented seizures but also reduced neuroinflammation, behavioral and cognitive abnormalities, and neurodegeneration following asphyxia. These findings suggest that midazolam has potential as an intervention to improve the treatment and outcome of birth asphyxia.
ANNALS OF NEUROLOGY
(2023)
Review
Clinical Neurology
Wolfgang Loescher, Carl E. Stafstrom
Summary: Epilepsy is associated with neurobehavioral comorbidities and a bidirectional relationship. Rodent models provide valuable insights into shared mechanisms and potential treatments for epilepsy and its comorbidities.
Article
Clinical Neurology
Chris Rundfeldt, Pavel Klein, Detlev Boison, Alexander Rotenberg, Raimondo D'Ambrosio, Cliff Eastman, Benton Purnell, Madhuvika Murugan, Howard P. Goodkin, Wolfgang Loescher
Summary: This study presents a novel meglumine-based solution of topiramate (TPM) that may be well suited for clinical development. Meglumine significantly enhances the aqueous solubility of TPM and can be used to prepare drug cocktails with other antiseizure medications. Tolerability studies demonstrate excellent tolerability of the novel drug solutions.
Review
Clinical Neurology
Wolfgang Loescher
Summary: Ivermectin is a potent antiparasitic drug, but it is not suitable for the treatment of epilepsy due to its limited penetration into the mammalian brain, non-selective activation of multiple receptors, equivocal preclinical evidence for antiseizure effects, and lack of direct antiseizure effect in clinical studies.
Review
Cell Biology
Wolfgang Loescher, H. Steve White
Summary: In the past 30 years, many new anti-seizure medicines have been developed for epilepsy treatment, but drug-resistant epilepsy (DRE) still affects a significant percentage of patients. Current approaches to discovering new DRE treatments involve testing drugs in preclinical models that show varying degrees of drug resistance. Recent efforts have been made to include more relevant models in the evaluation of investigational drugs, to better understand DRE mechanisms and test new therapies. This review discusses the pharmacology of different epilepsy models and the challenges in identifying novel treatments.
Article
Behavioral Sciences
Ricardo Schmidt, Bjorn Welzel, Wolfgang Loescher
Summary: Neonatal seizures are common after birth asphyxia, occurring more frequently in males. Stress and circadian rhythms also affect seizure characteristics.
EPILEPSY & BEHAVIOR
(2023)
Correction
Neurosciences
Lucia Privitera, Ellen L. Hogg, Matthias Gaestel, Mark J. Wall, Sonia A. L. Correa
Article
Neurosciences
Li-Ya Jiang, Guan-Hao Wang, Jing-Jiao Xu, Xiao-Li Li, Xiao-Yan Lin, Xiang Fang, Hong-Xu Zhang, Mei Feng, Chun-Ming Jiang
Summary: This study reveals the importance of LINC00473 in regulating temozolomide (TMZ) resistance in glioblastoma (GB) and its potential mechanism. By regulating the expression of CEBP alpha and MGMT, LINC00473 promotes the formation of chemoresistance. Furthermore, LINC00473 can transfer chemoresistance to adjacent sensitive cells through exosomes.
Article
Neurosciences
Olga Kopach, Tetyana Pivneva, Nataliya Fedirko, Nana Voitenko
Summary: This study found that diabetic animals exhibit severe xerostomia characterized by reduced saliva flow rate, diminished total protein content, and decreased amylase activity. The impaired saliva production in diabetes is associated with reduced and delayed intracellular Ca2+ signals in submandibular acinar cells, caused by malfunctioning mitochondria. Targeting malfunctioning mitochondria may be a potential strategy for the treatment of diabetic xerostomia.
Article
Neurosciences
Nicholas M. Timme, Cherish E. Ardinger, Seth D. C. Weir, Rachel Zelaya-Escobar, Rachel Kruger, Christopher C. Lapish
Summary: This study aimed to assess aversion-resistant drinking behavior in head-fixed mice and explore the relationship between non-consummatory behaviors and aversion-resistant drinking. The results showed that head-fixed mice exhibited heterogenous levels of aversion-resistant drinking and non-consummatory behaviors were related to the intensity of this behavior.
Article
Neurosciences
David R. Maguire, Charles P. France
Summary: Methocinnamox (MCAM) is a novel, long-acting opioid receptor antagonist that effectively decreases fentanyl self-administration and prevents opioid overdose in monkeys. The study demonstrates the potential therapeutic utility of MCAM in the treatment of opioid use disorder.
Article
Neurosciences
Xiang Li, Dan Feng, Shenglu Ma, Mingxing Li, Shulei Zhao, Man Tang
Summary: This study investigated the effects of fluoxetine on neurochemical, neurobiological, and neurobehavioral changes in different subregions of the hippocampus. The results showed that fluoxetine increased dialysate 5-HT, decreased membrane 5-HTT protein, and increased cytoplasmic fraction. Additionally, fluoxetine reduced immobility times in behavioral tests, with greater effects observed in the ventral subregion compared to the dorsal subregion.
Article
Neurosciences
Alexander V. Zholos, Mariia I. Melnyk, Dariia O. Dryn
Summary: Acetylcholine is an important neurotransmitter in visceral smooth muscles, activating M2 and M3 muscarinic receptors to cause smooth muscle excitation and contraction. This review focuses on the cellular and molecular mechanisms underlying acetylcholine-induced depolarisation and smooth muscle contraction, as well as the effects of anticholinergic drugs on gastrointestinal motility. The knowledge gained from recent studies has greatly expanded our understanding of these processes.
Article
Neurosciences
Zhenlong Li, Hsien-Yu Peng, Chau-Shoun Lee, Tzer-Bin Lin, Ming-Chun Hsieh, Cheng-Yuan Lai, Han-Fang Wu, Lih-Chyang Chen, Mei-Ci Chen, Dylan Chou
Summary: Methylone shows significant efficacy in treating depression and social deficits, making it an ideal candidate for anti-depressant medication.
Article
Neurosciences
Aline Freyssin, Allison Carles, Sarra Guehairia, Gilles Rubinstenn, Tangui Maurice
Summary: This study explores the potential of combining FENM and S1R agonists in the treatment of Alzheimer's disease. The results showed that most FENM-based combinations can protect against learning deficits caused by A beta 25-35, with better efficacy in short-term memory.
Article
Neurosciences
J. D. Lorente, J. Cuitavi, L. Rullo, S. Candeletti, P. Romualdi, L. Hipolito
Summary: This study analyzed the effects of pain on negative affect in different sexes and time courses, as well as the involvement of the dynorphinergic and corticotropin releasing factor systems in these pain-related behaviors. The results showed sex and time-dependent anxiety- and anhedonia-like behaviors induced by pain in female rats. The recruitment of KOR/DYN in the NAc was identified as a key neurological substrate mediating pain-induced behavioral alterations.
Article
Neurosciences
Rongjun Liu, Daofan Sun, Xiuzhong Xing, Qingge Chen, Bo Lu, Bo Meng, Hui Yuan, Lan Mo, Liufang Sheng, Jinwei Zheng, Qiusheng Wang, Junping Chen, Xiaowei Chen
Summary: The coexistence of pain and depression is frequently observed in patients with chronic pain and depression. Oxytocin, a neuropeptide, has been reported to relieve chronic pain and depressive symptoms. This study investigated the effect of intranasal oxytocin on neuropathic pain and comorbid depressive symptoms, and found that oxytocin attenuated depression-like behavior but did not alleviate mechanical hyperalgesia. The results suggest that intranasal oxytocin may have the potential to treat depressive symptoms in neuropathic pain patients.
