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Abend NS, Wusthoff CJ, Jensen FE, Inder TE, Volpe JJ. Neonatal Seizures. VOLPE'S NEUROLOGY OF THE NEWBORN 2025:381-448.e17. [DOI: 10.1016/b978-0-443-10513-5.00015-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Hajipour S, Khombi Shooshtari M, Farbood Y, Ali Mard S, Sarkaki A, Moradi Chameh H, Sistani Karampour N, Ghafouri S. Fingolimod administration following hypoxia induced neonatal seizure can restore impaired long-term potentiation and memory performance in adult rats. Neuroscience 2023; 519:107-119. [PMID: 36990271 DOI: 10.1016/j.neuroscience.2023.03.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/18/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023]
Abstract
Neonatal seizures commonly caused by hypoxia can lead to long-term neurological outcomes. Early inflammation plays an important role in the pathology of these outcomes. Therefore, in the current study, we explored the long-term effects of Fingolimod (FTY720), an analog of sphingosine and potentsphingosine 1-phosphate(S1P) receptors modulator, as an anti-inflammatory and neuroprotective agent in attenuating anxiety, memory impairment, and possible alterations in gene expression of hippocampal inhibitory and excitatory receptors following hypoxia-induced neonatal seizure (HINS). Seizure was induced in 24 male and female pups (6 in each experimental group) at postnatal day 10 (P10) by premixed gas (5% oxygen/ 95% nitrogen) in a hypoxic chamber for 15 minutes. Sixty minutes after the onset of hypoxia, FTY720 (0.3 mg/kg) or saline (100 µl) was administered for 12 days (from P10 up to P21). Anxiety-like behavior and hippocampal memory function were assessed at P90 by elevated plus maze (EPM) and novel object recognition (NOR), respectively. Long-term potentiation (LTP) was recorded from hippocampal dentate gyrus region (DG) following stimulation of perforant pathway (PP). In addition, the hippocampal concentration of superoxide dismutase activity (SOD), malondialdehyde (MDA), and thiol as indices of oxidative stress were evaluated. Finally, the gene expression of NR2A subunit of N-Methyl-D-aspartic acid (NMDA) receptor, GluR2 subunit of (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AMPA receptor and γ2 subunit of γ-Aminobutyric acid (GABAA) receptor were assessed at P90 by the quantitative real-time PCR. FTY720 significantly reduced later-life anxiety-like behavior, ameliorated object recognition memory and increased the amplitude and slope of the field excitatory postsynaptic potential (fEPSP) in the rats following HINS. These effects were associated with restoration of the hippocampal thiol content to the normal values and the regulatory role of FTY720 in the expression of hippocampal GABA and glutamate receptors subunits. In conclusion, FTY720 could restore the dysregulated gene expression of excitatory and inhibitory receptors. It also increased the reduced hippocampal thiol content, which was accompanied with attenuation of HINS-induced anxiety, reduced the impaired hippocampal related memory, and prevented hippocampal LTP deficits in later life following HINS.
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Guidotti I, Lugli L, Ori L, Roversi MF, Casa Muttini ED, Bedetti L, Pugliese M, Cavalleri F, Stefanelli F, Ferrari F, Berardi A. Neonatal seizures treatment based on conventional multichannel EEG monitoring: an overview of therapeutic options. Expert Rev Neurother 2022; 22:623-638. [PMID: 35876114 DOI: 10.1080/14737175.2022.2105698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/21/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Seizures are the main neurological emergency during the neonatal period and are mostly acute and focal. The prognosis mainly depends on the underlying etiology. Conventional multichannel video-electroencephalographic (cEEG) monitoring is the gold standard for diagnosis, but treatment remains a challenge. AREAS COVERED This review, based on PubMed search over the last 4 decades, focuses on the current treatment options for neonatal seizures based on cEEG monitoring. There is still no consensus on seizure therapy, owing to poor scientific evidence. Traditionally, the first-line treatments are phenobarbital and phenytoin, followed by midazolam and lidocaine, but their efficacy is limited. Therefore, current evidence strongly suggests the use of alternative antiseizure medications. Randomized controlled trials of new drugs are ongoing. EXPERT OPINION Therapy for neonatal seizures should be prompt and tailored, based on semeiology, mirror of the underlying cause, and cEEG features. Further research should focus on antiseizure medications that directly act on the etiopathogenetic mechanism responsible for seizures and are therefore more effective in seizure control.
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Affiliation(s)
- Isotta Guidotti
- Division of Neonatology and Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, Modena, Italy
| | - Licia Lugli
- Division of Neonatology and Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, Modena, Italy
| | - Luca Ori
- Division of Neonatology and Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, Modena, Italy
| | - Maria Federica Roversi
- Division of Neonatology and Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, Modena, Italy
| | - Elisa Della Casa Muttini
- Division of Neonatology and Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, Modena, Italy
| | - Luca Bedetti
- Division of Neonatology and Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, Modena, Italy
| | - Marisa Pugliese
- Division of Neonatology and Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, Modena, Italy
| | - Francesca Cavalleri
- Division of Neuroradiology, Department of Neuroscience, Nuovo Ospedale Civile S. Agostino-Estense, Modena, Italy
| | - Francesca Stefanelli
- Department of Medical and Surgical Sciences of the Mothers, Children and Adults, Post Graduate School of Pediatrics, University of Modena and Reggio Emilia, Modena, Italy
| | - Fabrizio Ferrari
- Division of Neonatology and Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, Modena, Italy
| | - Alberto Berardi
- Division of Neonatology and Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital, Modena, Italy
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Sun X, Xue F, Wen J, Gao L, Li Y, Jiang Q, Yang L, Cui H. Seizure Characteristics and Background Amplitude-Integrated Electroencephalography Activity in Neonatal Rats Subjected to Hypoxia-Ischemia. Front Pediatr 2022; 10:837909. [PMID: 35463911 PMCID: PMC9021695 DOI: 10.3389/fped.2022.837909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/14/2022] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of epilepsy and chronic neurologic morbidity in premature infants. This study aimed to investigate the characteristics of acute seizures and the pattern of background activity on amplitude-integrated electroencephalography (aEEG) in neonatal rats with HIE. METHODS Hypoxia-ischemia (HI) was induced in postnatal day (P) 3 neonatal rats (n = 12) by ligation of the left carotid artery and exposure to airtight hypoxia for 2 h. Data regarding seizure type, frequency, and duration and those related to neurobehavioral development were collected, and the integrated power of background EEG was analyzed to evaluate the effect of HI. RESULTS All neonatal rats in the HI group experienced frequent seizures during hypoxia, and 83.3% of rats (10/12) experienced seizures immediately after hypoxia. Seizure frequency and duration gradually decreased with increasing age. The mortality rate of the HI group was 8.33% (1/12); 120 h after HI induction, only 27.3% (3/11) of pups had low-frequency and short-duration electrographic seizures, respectively. HI rats, which presented seizure activities 96 h after HI insult, exhibited an increase in righting reflex time and a decrease in forelimb grip reflex time. Background EEG was significantly inhibited during HI induction and immediately after hypoxia and gradually recovered 72 h after hypoxia. CONCLUSION Seizures caused by HI brain damage in premature infants can be simulated in the P3 neonatal rat model.
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Affiliation(s)
- Xiaowei Sun
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Fenqin Xue
- Core Facility Center, Capital Medical University, Beijing, China
| | - Jialin Wen
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Limin Gao
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yang Li
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Qianqian Jiang
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lijun Yang
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hong Cui
- Department of Pediatrics, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Ziobro JM, Eschbach K, Shellhaas RA. Novel Therapeutics for Neonatal Seizures. Neurotherapeutics 2021; 18:1564-1581. [PMID: 34386906 PMCID: PMC8608938 DOI: 10.1007/s13311-021-01085-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2021] [Indexed: 02/04/2023] Open
Abstract
Neonatal seizures are a common neurologic emergency for which therapies have not significantly changed in decades. Improvements in diagnosis and pathophysiologic understanding of the distinct features of acute symptomatic seizures and neonatal-onset epilepsies present exceptional opportunities for development of precision therapies with potential to improve outcomes. Herein, we discuss the pathophysiology of neonatal seizures and review the evidence for currently available treatment. We present emerging therapies in clinical and preclinical development for the treatment of acute symptomatic neonatal seizures. Lastly, we discuss the role of precision therapies for genetic neonatal-onset epilepsies and address barriers and goals for developing new therapies for clinical care.
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Affiliation(s)
- Julie M Ziobro
- Department of Pediatrics, Michigan Medicine, C.S. Mott Children's Hospital, University of Michigan, 1540 E. Hospital Dr, Ann Arbor, MI, USA.
| | - Krista Eschbach
- Department of Pediatrics, Section of Neurology, Denver Anschutz School of Medicine, Children's Hospital Colorado, University of Colorado, Aurora, CO, 80045, USA
| | - Renée A Shellhaas
- Department of Pediatrics, Michigan Medicine, C.S. Mott Children's Hospital, University of Michigan, 1540 E. Hospital Dr, Ann Arbor, MI, USA
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Pospelov AS, Ala-Kurikka T, Kurki S, Voipio J, Kaila K. Carbonic anhydrase inhibitors suppress seizures in a rat model of birth asphyxia. Epilepsia 2021; 62:1971-1984. [PMID: 34180051 DOI: 10.1111/epi.16963] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/21/2021] [Accepted: 05/28/2021] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Seizures are common in neonates recovering from birth asphyxia but there is general consensus that current pharmacotherapy is suboptimal and that novel antiseizure drugs are needed. We recently showed in a rat model of birth asphyxia that seizures are triggered by the post-asphyxia recovery of brain pH. Here our aim was to investigate whether carbonic anhydrase inhibitors (CAIs), which induce systemic acidosis, block the post-asphyxia seizures. METHODS The CAIs acetazolamide (AZA), benzolamide (BZA), and ethoxzolamide (EZA) were administered intraperitoneally or intravenously to 11-day-old rats exposed to intermittent asphyxia (30 min; three 7+3 min cycles of 9% and 5% O2 at 20% CO2 ). Electrode measurements of intracortical pH, Po2 , and local field potentials (LFPs) were made under urethane anesthesia. Convulsive seizures and blood acid-base parameters were examined in freely behaving animals. RESULTS The three CAIs decreased brain pH by 0.14-0.17 pH units and suppressed electrographic post-asphyxia seizures. AZA, BZA, and EZA differ greatly in their lipid solubility (EZA > AZA > BZA) and pharmacokinetics. However, there were only minor differences in the delay (range 0.8-3.7 min) from intraperitoneal application to their action on brain pH. The CAIs induced a modest post-asphyxia elevation of brain Po2 that had no effect on LFP activity. AZA was tested in freely behaving rats, in which it induced a respiratory acidosis and decreased the incidence of convulsive seizures from 9 of 20 to 2 of 17 animals. SIGNIFICANCE AZA, BZA, and EZA effectively block post-asphyxia seizures. Despite the differences in their pharmacokinetics, they had similar effects on brain pH, which indicates that their antiseizure mode of action was based on respiratory (hypercapnic) acidosis resulting from inhibition of blood-borne and extracellular vascular carbonic anhydrases. AZA has been used for several indications in neonates, suggesting that it can be safely repurposed for the treatment of neonatal seizures as an add-on to the current treatment regimen.
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Affiliation(s)
- Alexey S Pospelov
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland.,Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Tommi Ala-Kurikka
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland.,Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Samu Kurki
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland.,Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Juha Voipio
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland
| | - Kai Kaila
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland.,Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland
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Löscher W, Sills GJ, White HS. The ups and downs of alkyl-carbamates in epilepsy therapy: How does cenobamate differ? Epilepsia 2021; 62:596-614. [PMID: 33580520 DOI: 10.1111/epi.16832] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/11/2021] [Accepted: 01/13/2021] [Indexed: 12/13/2022]
Abstract
Since 1955, several alkyl-carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, and cenobamate. They have each enjoyed varying levels of success as antiseizure drugs; however, they have all been plagued by the emergence of serious and sometimes life-threatening adverse events. In this review, we compare and contrast their predominant molecular mechanisms of action, their antiseizure profile, and where possible, their clinical efficacy. The preclinical, clinical, and mechanistic profile of the prototypical γ-aminobutyric acidergic (GABAergic) modulator phenobarbital is included for comparison. Like phenobarbital, all of the clinically approved alkyl-carbamates share an ability to enhance inhibitory neurotransmission through modulation of the GABAA receptor, although the specific mechanism of interaction differs among the different drugs discussed. In addition, several alkyl-carbamates have been shown to interact with voltage-gated ion channels. Flupirtine and retigabine share an ability to activate K+ currents mediated by KCNQ (Kv7) K+ channels, and felbamate, carisbamate, and cenobamate have been shown to block Na+ channels. In contrast to other alkyl-carbamates, cenobamate seems to be unique in its ability to preferentially attenuate the persistent rather than transient Na+ current. Results from recent randomized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl-carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993. Given that ceno-bamate's mechanistic profile is unique among the alkyl-carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABAA receptor and on persistent Na+ currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate.
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Affiliation(s)
- Wolfgang Löscher
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.,Center for Systems Neuroscience Hannover, Hannover, Germany
| | - Graeme J Sills
- School of Life Sciences, University of Glasgow, Glasgow, UK
| | - H Steve White
- Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, USA
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Perinatal Brain Injury and Inflammation: Lessons from Experimental Murine Models. Cells 2020; 9:cells9122640. [PMID: 33302543 PMCID: PMC7764185 DOI: 10.3390/cells9122640] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/19/2020] [Accepted: 12/02/2020] [Indexed: 02/07/2023] Open
Abstract
Perinatal brain injury or neonatal encephalopathy (NE) is a state of disturbed neurological function in neonates, caused by a number of different aetiologies. The most prominent cause of NE is hypoxic ischaemic encephalopathy, which can often induce seizures. NE and neonatal seizures are both associated with poor neurological outcomes, resulting in conditions such as cerebral palsy, epilepsy, autism, schizophrenia and intellectual disability. The current treatment strategies for NE and neonatal seizures have suboptimal success in effectively treating neonates. Therapeutic hypothermia is currently used to treat NE and has been shown to reduce morbidity and has neuroprotective effects. However, its success varies between developed and developing countries, most likely as a result of lack of sufficient resources. The first-line pharmacological treatment for NE is phenobarbital, followed by phenytoin, fosphenytoin and lidocaine as second-line treatments. While these drugs are mostly effective at halting seizure activity, they are associated with long-lasting adverse neurological effects on development. Over the last years, inflammation has been recognized as a trigger of NE and seizures, and evidence has indicated that this inflammation plays a role in the long-term neuronal damage experienced by survivors. Researchers are therefore investigating the possible neuroprotective effects that could be achieved by using anti-inflammatory drugs in the treatment of NE. In this review we will highlight the current knowledge of the inflammatory response after perinatal brain injury and what we can learn from animal models.
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Pisani F, Fusco C, Nagarajan L, Spagnoli C. Acute symptomatic neonatal seizures, brain injury, and long-term outcome: The role of neuroprotective strategies. Expert Rev Neurother 2020; 21:189-203. [PMID: 33176104 DOI: 10.1080/14737175.2021.1848547] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Neonatal seizures are frequent but underdiagnosed manifestations of acute brain dysfunction and an important contributor to unfavorable outcomes. Etiology and severity of brain injury are the single strongest outcome determinants. AREAS COVERED The authors will discuss the prognostic role of acute symptomatic seizures versus brain injury and the main neuroprotective and neurorestorative strategies for full-term and preterm infants. EXPERT OPINION Prolonged acute symptomatic seizures likely contribute to long-term outcomes by independently adding further brain injury to initial insults. Correct timing and dosing of therapeutic interventions, depending on etiology and gestational ages, need careful evaluation. Although promising strategies are under study, the only standard of care is whole-body therapeutic hypothermia in full-term newborns with hypoxic-ischemic encephalopathy.
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Affiliation(s)
- Francesco Pisani
- Child Neuropsychiatric Unit, Medicine and Surgery Department, University of Parma , Parma, Italy
| | - Carlo Fusco
- Child Neurology Unit, Department of Paediatrics, Azienda USL-IRCCS Di Reggio Emilia , Reggio Emilia, Italy
| | - Lakshmi Nagarajan
- Department of Neurology, Perth Children's Hospital, University of Western Australia , Perth, Australia
| | - Carlotta Spagnoli
- Child Neurology Unit, Department of Paediatrics, Azienda USL-IRCCS Di Reggio Emilia , Reggio Emilia, Italy
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Abstract
The highly structurally similar drugs flupirtine and retigabine have been regarded as safe and effective for many years but lately they turned out to exert intolerable side effects. While the twin molecules share the mode of action, both stabilize the open state of voltage-gated potassium channels, the form and severity of adverse effects is different. The analgesic flupirtine caused drug-induced liver injury in rare but fatal cases, whereas prolonged use of the antiepileptic retigabine led to blue tissue discoloration. Because the adverse effects seem unrelated to the mode of action, it is likely, that both drugs that occupied important therapeutic niches, could be replaced. Reasons for the clinically relevant toxicity will be clarified and future substitutes for these drugs presented in this review.
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Lawson K. Pharmacology and clinical applications of flupirtine: Current and future options. World J Pharmacol 2019; 8:1-13. [DOI: 10.5497/wjp.v8.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/17/2018] [Accepted: 01/05/2019] [Indexed: 02/06/2023] Open
Abstract
Flupirtine is the first representative in a class of triaminopyridines that exhibits pharmacological properties leading to the suppression of over-excitability of neuronal and non-neuronal cells. Consequently, this drug has been used as a centrally acting analgesic in patients with a range of acute and persistent pain conditions without the adverse effects characteristic of opioids and non-steroidal anti-inflammatory drug and is well tolerated. The pharmacological profile exhibited involves actions on several cellular targets, including Kv7 channels, G-protein-regulated inwardly rectifying K channels and γ-aminobutyric acid type A receptors, but also there is evidence of additional as yet unidentified mechanisms of action involved in the effects of flupirtine. Flupirtine has exhibited effects in a range of cells and tissues related to the locations of these targets. In additional to analgesia, flupirtine has demonstrated pharmacological properties consistent with use as an anticonvulsant, a neuroprotectant, skeletal and smooth muscle relaxant, in treatment of auditory and visual disorders, and treatment of memory and cognitive impairment. Flupirtine is providing important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving hyper-excitability of cells. Identification of molecules exhibiting specificity for the pharmacological targets (e.g., Kv7 isoforms) involved in the actions of flupirtine will provide further insight into clinical applications. Whether the broad-spectrum pharmacology of flupirtine or target-specific actions is preferential to gain benefit, especially in complex clinical conditions, requires further investigation. This review will consider recent advancement in understanding of the pharmacological profile and related clinical applications of flupirtine.
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Affiliation(s)
- Kim Lawson
- Department of Biosciences and Chemistry, Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, United Kingdom
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Toro-Urrego N, Vesga-Jiménez DJ, Herrera MI, Luaces JP, Capani F. Neuroprotective Role of Hypothermia in Hypoxic-ischemic Brain Injury: Combined Therapies using Estrogen. Curr Neuropharmacol 2019; 17:874-890. [PMID: 30520375 PMCID: PMC7052835 DOI: 10.2174/1570159x17666181206101314] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/26/2018] [Accepted: 11/28/2018] [Indexed: 12/15/2022] Open
Abstract
Hypoxic-ischemic brain injury is a complex network of factors, which is mainly characterized by a decrease in levels of oxygen concentration and blood flow, which lead to an inefficient supply of nutrients to the brain. Hypoxic-ischemic brain injury can be found in perinatal asphyxia and ischemic-stroke, which represent one of the main causes of mortality and morbidity in children and adults worldwide. Therefore, knowledge of underlying mechanisms triggering these insults may help establish neuroprotective treatments. Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators exert several neuroprotective effects, including a decrease of reactive oxygen species, maintenance of cell viability, mitochondrial survival, among others. However, these strategies represent a traditional approach of targeting a single factor of pathology without satisfactory results. Hence, combined therapies, such as the administration of therapeutic hypothermia with a complementary neuroprotective agent, constitute a promising alternative. In this sense, the present review summarizes the underlying mechanisms of hypoxic-ischemic brain injury and compiles several neuroprotective strategies, including Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators, which represent putative agents for combined therapies with therapeutic hypothermia.
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Affiliation(s)
- Nicolás Toro-Urrego
- Address correspondence to this author at the Laboratorio de Citoarquitectura y Plasticidad Neuronal, Instituto de Investigaciones Cardiológicas, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; E-mail:
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Patil MA, Matter BA, Raol YH, Bourne DWA, Kelley RA, Kompella UB. Brain Distribution and Metabolism of Flupirtine, a Nonopioid Analgesic Drug with Antiseizure Effects, in Neonatal Rats. Pharmaceutics 2018; 10:E281. [PMID: 30558371 PMCID: PMC6320943 DOI: 10.3390/pharmaceutics10040281] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 12/13/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023] Open
Abstract
Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in various tissues such as brain in neonate animals. On postnatal day 7, rat pups received 25 mg/kg of flupirtine intraperitoneally. Liver; heart; kidney; lung; spleen; retina; serum; and brain regions hippocampus, cortex, and the remaining brain (devoid of cerebellum) were harvested up to 24-h postdosing. An LC-MS/MS assay was developed to quantify flupirtine and D-13223. Flupirtine was delivered to all tissues assessed, with the highest area under the concentration vs. time curve (AUC0⁻24h) in liver (488 µg·h/g tissue) and the lowest in spleen (82 µg·h/g tissue). Flupirtine reached the brain, including the hippocampus and cortex, within 1 h of dosing and persisted at 24 h. Flupirtine AUC in various brain regions was approximately 195 µg·h/g tissue. The half-life of flupirtine in various tissues ranged from 3.1 to 5.2 h. D-13223 was formed in vivo and detected in all tissues assessed, with the concentrations being the highest in the liver. Incubation of isolated neonatal rat liver, heart, kidney, lung, spleen, whole eye, serum, or whole brain with flupirtine for 3 h at 37 °C formed D-13223 in all tissues, except serum. D-13223 formation was the highest in isolated liver tissue. Tissue partition coefficients based on isolated tissue uptake correlated well with in vivo tissue:serum drug exposure ratios. Thus, flupirtine reaches the target brain tissues from the systemic route in neonatal rats, and brain tissue forms the active metabolite D-13223.
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Affiliation(s)
- Madhoosudan A Patil
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Brock A Matter
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Yogendra H Raol
- Department of Pediatrics, Division of Neurology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - David W A Bourne
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Ryan A Kelley
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Uday B Kompella
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
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Hefter D, Marti HH, Gass P, Inta D. Perinatal Hypoxia and Ischemia in Animal Models of Schizophrenia. Front Psychiatry 2018; 9:106. [PMID: 29651259 PMCID: PMC5884869 DOI: 10.3389/fpsyt.2018.00106] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 03/16/2018] [Indexed: 12/12/2022] Open
Abstract
Intrauterine or perinatal complications constitute a major risk for psychiatric diseases. Infants who suffered from hypoxia-ischemia (HI) are at twofold risk to develop schizophrenia in later life. Several animal models attempt to reproduce these complications to study the yet unknown steps between an insult in early life and outbreak of the disease decades later. However, it is very challenging to find the right type and severity of insult leading to a disease-like phenotype in the animal, but not causing necrosis and focal neurological deficits. By contrast, too mild, repetitive insults may even be protective via conditioning effects. Thus, it is not surprising that animal models of hypoxia lead to mixed results. To achieve clinically translatable findings, better protocols are urgently needed. Therefore, we compare widely used models of hypoxia and HI and propose future directions for the field.
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Affiliation(s)
- Dimitri Hefter
- RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Heidelberg, Germany.,RG Neuro- and Sensory Physiology, Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany
| | - Hugo H Marti
- RG Neurovascular Research, Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany
| | - Peter Gass
- RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Heidelberg, Germany
| | - Dragos Inta
- RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Heidelberg, Germany.,Department of Psychiatry, University of Basel, Basel, Switzerland
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Abend NS, Jensen FE, Inder TE, Volpe JJ. Neonatal Seizures. VOLPE'S NEUROLOGY OF THE NEWBORN 2018:275-321.e14. [DOI: 10.1016/b978-0-323-42876-7.00012-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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16
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Zhang T, Todorovic MS, Williamson J, Kapur J. Flupirtine and diazepam combination terminates established status epilepticus: results in three rodent models. Ann Clin Transl Neurol 2017; 4:888-896. [PMID: 29296617 PMCID: PMC5740237 DOI: 10.1002/acn3.497] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 09/30/2017] [Accepted: 10/09/2017] [Indexed: 12/17/2022] Open
Abstract
Objective Status epilepticus (SE) is a neurological emergency requiring rapid termination of seizures. New treatment choices are needed for benzodiazepine-refractory SE or established SE (ESE). Previous studies have demonstrated that the potassium-channel opener flupirtine terminates seizures in neonatal animals. However, its effectiveness in adult ESE has not been tested. We tested whether flupirtine alone or in combination with the benzodiazepine diazepam would terminate ESE in three animal models. Methods SE was induced by administration of lithium followed by pilocarpine, by electrical stimulation of the hippocampus or by diisopropylfluorophosphate (DFP) administration. Seizures were assessed by EEG recorded from the hippocampus and cortex. Results Flupirtine alone did not terminate ESE within 60 min of administration in any of the three models of ESE. A combination of flupirtine and diazepam terminated ESE within 60 min in all the three models. The drug combination shortened the duration of ESE in all three models. Drug responsiveness was distinct between each model. Conclusion A combination of the potassium channel opener flupirtine and diazepam is a potential therapy for ESE.
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Affiliation(s)
- Terry Zhang
- Department of Neurology University of Virginia Health Sciences Center Charlottesville Virginia 22908
| | - Marko S Todorovic
- Department of Neurology University of Virginia Health Sciences Center Charlottesville Virginia 22908
| | - John Williamson
- Department of Neurology University of Virginia Health Sciences Center Charlottesville Virginia 22908
| | - Jaideep Kapur
- Department of Neurology University of Virginia Health Sciences Center Charlottesville Virginia 22908.,Department of Neuroscience University of Virginia Health Sciences Center Charlottesville Virginia 22908
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Sampath D, Valdez R, White AM, Raol YH. Anticonvulsant effect of flupirtine in an animal model of neonatal hypoxic-ischemic encephalopathy. Neuropharmacology 2017; 123:126-135. [PMID: 28587899 DOI: 10.1016/j.neuropharm.2017.06.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 05/07/2017] [Accepted: 06/02/2017] [Indexed: 12/20/2022]
Abstract
Research studies suggest that neonatal seizures, which are most commonly associated with hypoxic-ischemic injury, may contribute to brain injury and adverse neurologic outcome. Unfortunately, neonatal seizures are often resistant to treatment with current anticonvulsants. In the present study, we evaluated the efficacy of flupirtine, administered at clinically relevant time-points, for the treatment of neonatal seizures in an animal model of hypoxic-ischemic injury that closely replicates features of the human syndrome. We also compared the efficacy of flupirtine to that of phenobarbital, the current first-line drug for neonatal seizures. Flupirtine is a KCNQ potassium channel opener. KCNQ channels play an important role in controlling brain excitability during early development. In this study, hypoxic-ischemic injury was induced in neonatal rats, and synchronized video-EEG records were acquired at various time-points during the experiment to identify seizures. The results revealed that flupirtine, administered either 5 min after the first electroclinical seizure, or following completion of 2 h of hypoxia, i.e., during the immediate reperfusion period, reduced the number of rats with electroclinical seizures, and also the frequency and total duration of electroclinical seizures. Further, daily dosing of flupirtine decreased the seizure burden over 3 days following HI-induction, and modified the natural evolution of acute seizures. Moreover, compared to a therapeutic dose of phenobarbital, which was modestly effective against electroclinical seizures, flupirtine showed greater efficacy. Our results indicate that flupirtine is an extremely effective treatment for neonatal seizures in rats and provide evidence for a trial of this medication in newborn humans.
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Affiliation(s)
- Dayalan Sampath
- Department of Pediatrics, Division of Neurology, School of Medicine, Translational Epilepsy Research Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Robert Valdez
- Department of Pediatrics, Division of Neurology, School of Medicine, Translational Epilepsy Research Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Andrew M White
- Department of Pediatrics, Division of Neurology, School of Medicine, Translational Epilepsy Research Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Yogendra H Raol
- Department of Pediatrics, Division of Neurology, School of Medicine, Translational Epilepsy Research Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
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Millar LJ, Shi L, Hoerder-Suabedissen A, Molnár Z. Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges. Front Cell Neurosci 2017; 11:78. [PMID: 28533743 PMCID: PMC5420571 DOI: 10.3389/fncel.2017.00078] [Citation(s) in RCA: 231] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 03/07/2017] [Indexed: 12/11/2022] Open
Abstract
Neonatal hypoxia-ischaemia (HI) is the most common cause of death and disability in human neonates, and is often associated with persistent motor, sensory, and cognitive impairment. Improved intensive care technology has increased survival without preventing neurological disorder, increasing morbidity throughout the adult population. Early preventative or neuroprotective interventions have the potential to rescue brain development in neonates, yet only one therapeutic intervention is currently licensed for use in developed countries. Recent investigations of the transient cortical layer known as subplate, especially regarding subplate's secretory role, opens up a novel set of potential molecular modulators of neonatal HI injury. This review examines the biological mechanisms of human neonatal HI, discusses evidence for the relevance of subplate-secreted molecules to this condition, and evaluates available animal models. Neuroserpin, a neuronally released neuroprotective factor, is discussed as a case study for developing new potential pharmacological interventions for use post-ischaemic injury.
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Affiliation(s)
- Lancelot J. Millar
- Molnár Group, Department of Physiology, Anatomy and Genetics, University of OxfordOxford, UK
| | - Lei Shi
- Molnár Group, Department of Physiology, Anatomy and Genetics, University of OxfordOxford, UK
- JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan UniversityGuangzhou, China
| | | | - Zoltán Molnár
- Molnár Group, Department of Physiology, Anatomy and Genetics, University of OxfordOxford, UK
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Yadav G, Jain G, Singh M. Role of flupirtine in reducing preoperative anxiety of patients undergoing craniotomy procedure. Saudi J Anaesth 2017; 11:158-162. [PMID: 28442953 PMCID: PMC5389233 DOI: 10.4103/1658-354x.203028] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background: Kv7 neuronal channels are recognized as a potential drug target for anxiolytic effects. We hypothesize that flupirtine as a potassium channel opener would effectively reduce the preoperative anxiety of patients undergoing craniotomy procedure. Methods: In prospective-double-blinded fashion, 124 counseled patients were randomized to receive 5 sequential doses of capsule flupirtine 100 mg (F Group) or physically similar starch capsules (C Group), at 12 h intervals during preoperative hospitalization. Primary outcome included various aspects of patient anxiety measured by visual analog scale (VAS) just before preoperative counseling and 2 h after the completion of drug regimen under trial. Statistical tool included Mann–Whitney U-test and Wilcoxon signed rank test. Results: Baseline VAS scores were higher for fear of surgical harm, being at the mercy of medical staff, and not awakening after surgery. A significant decline in VAS scores was observed after the completion of drug regime, but to a higher extent in flupirtine-treated patients; it achieved statistical significance in comparison to Group C. No side effects were observed in any patient. Conclusion: Flupirtine is a useful premedication in conjunction with behavioral therapy to alleviate patient anxiety during the preoperative period.
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Affiliation(s)
- Ghanshyam Yadav
- Department of Anaesthesiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Gaurav Jain
- Department of Anaesthesiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Malkhan Singh
- Department of Anaesthesiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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Kang SK, Kadam SD. Neonatal Seizures: Impact on Neurodevelopmental Outcomes. Front Pediatr 2015; 3:101. [PMID: 26636052 PMCID: PMC4655485 DOI: 10.3389/fped.2015.00101] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 11/05/2015] [Indexed: 11/24/2022] Open
Abstract
Neonatal period is the most vulnerable time for the occurrence of seizures, and neonatal seizures often pose a clinical challenge both for their acute management and frequency of associated long-term co-morbidities. Etiologies of neonatal seizures are known to play a primary role in the anti-epileptic drug responsiveness and the long-term sequelae. Recent studies have suggested that burden of acute recurrent seizures in neonates may also impact chronic outcomes independent of the etiology. However, not many studies, either clinical or pre-clinical, have addressed the long-term outcomes of neonatal seizures in an etiology-specific manner. In this review, we briefly review the available clinical and pre-clinical research for long-term outcomes following neonatal seizures. As the most frequent cause of acquired neonatal seizures, we focus on the studies evaluating long-term effects of HIE-seizures with the goal to evaluate (1) what parameters evaluated during acute stages of neonatal seizures can reliably be used to predict long-term outcomes? and (2) what available clinical and pre-clinical data are available help determine importance of etiology vs. seizure burdens in long-term sequelae.
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Affiliation(s)
- Seok Kyu Kang
- Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger , Baltimore, MD , USA
| | - Shilpa D Kadam
- Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger , Baltimore, MD , USA ; Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MD , USA
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