topiramate and Hypoxia-Ischemia--Brain

Hypoxic ischemic encephalopathy (HIE) is brain injury caused by different reasons and the most common diagnosed is neonatal HIE. Most of the existing treatments have their own shortcomings or there are still some unexplained mechanisms in it. Topiramate (TPM) is a new drug for the treatment for seizures in neonates with HIE, but is currently used off-label. Our protocol aims to access the efficiency and safety of TPM for HIE.. Eight databases will be searched by 2 independent researchers for the article on the topic of using TPM as treatment for HIE, including PubMed, the Cochrane Central Register of Controlled Trials (Cochrane Library), Embase, and Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wang Fang Database and Chinese Science and Technology Periodical database (VIP). The included papers are those published from the established date of the databases to 2019. The therapeutic effects based on the grade of neonatal behavioral neurological assessment will be regarded as the primary outcomes. RevMan V5.3 will be used to compute the data synthesis and carry out meta-analysis. The risk of bias will be appraised by the Cochrane risk of bias tool. Rare ratio for dichotomous outcomes and mean different for continuous data will be expressed with 95% confidence intervals (CI) for analysis. A random effects model or a fixed effects model will be employed, when heterogeneity is found or not. Subgroup analysis and sensitivity analysis will be applied if the heterogeneity is obvious.. This study will provide the recent evidence of TPM for HIE from reducing seizure acticity.. The conclusion of this study will provide proof to evaluate if TPM is effective and safe in the treatment of HIE.PROSPERO registration number: PROSPERO CRD42018117981.

Topics: Anticonvulsants; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Oxidative Stress; Randomized Controlled Trials as Topic; Research Design; Seizures; Severity of Illness Index; Topiramate

Neonatal brain injury (NBI) remains a major contributor to neonatal mortality and long-term neurodevelopmental morbidity. Although therapeutic hypothermia is the only proven treatment to minimize brain injury caused by neonatal encephalopathy in term neonates, it provides incomplete neuroprotection. There are no specific drugs yet proven to prevent NBI in preterm neonates. This review discusses the scientific and emerging clinical trial data for several neuroprotective drugs in development, examining potential efficacy and safety concerns. Drugs with the highest likelihood of success and closest to clinical application include erythropoietin for term and preterm neonates and antenatal magnesium for preterm neonates.

Topics: Adrenal Cortex Hormones; Allopurinol; Anesthetics, Inhalation; Anticonvulsants; Antioxidants; Cerebral Intraventricular Hemorrhage; Cyclooxygenase Inhibitors; Darbepoetin alfa; Erythropoietin; Free Radical Scavengers; Hematinics; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Indomethacin; Infant, Newborn; Leukomalacia, Periventricular; Magnesium; Melatonin; Neuroprotection; Prenatal Care; Topiramate; Xenon

This article explains the mechanisms underlying choices of pharmacotherapy for hypoxic-ischemic insults of both preterm and term babies. Some preclinical data are strong enough that clinical trials are now underway. Challenges remain in deciding the best combination therapies for each age and insult.

Topics: Acetylcysteine; Allopurinol; Antioxidants; Ascorbic Acid; Biopterins; Erythropoietin; Excitatory Amino Acid Antagonists; Free Radical Scavengers; Fructose; Humans; Hypoxia-Ischemia, Brain; Infant, Extremely Premature; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Melatonin; Memantine; Neuroprotective Agents; Nitric Oxide Synthase Type III; Resveratrol; Stilbenes; Topiramate; Vitamin E; Xenon

Neuroprotection is a major health care priority, given the enormous burden of human suffering and financial cost caused by perinatal brain damage. With the advent of hypothermia as therapy for term hypoxic-ischemic encephalopathy, there is hope for repair and protection of the brain after a profound neonatal insult. However, it is clear from the published clinical trials and animal studies that hypothermia alone will not provide complete protection or stimulate the repair that is necessary for normal neurodevelopmental outcome. This review critically discusses drugs used to treat seizures after hypoxia-ischemia in the neonate with attention to evidence of possible synergies for therapy. In addition, other agents such as xenon, N-acetylcysteine, erythropoietin, melatonin and cannabinoids are discussed as future potential therapeutic agents that might augment protection from hypothermia. Finally, compounds that might damage the developing brain or counteract the neuroprotective effects of hypothermia are discussed.

Topics: Acetylcysteine; Anticonvulsants; Body Temperature; Cannabinoids; Combined Modality Therapy; Erythropoietin; Fructose; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Levetiracetam; Melatonin; Neuroprotective Agents; Piracetam; Topiramate; Xenon

Topics: Animals; Brain; Cell Death; Cerebral Infarction; Fructose; Humans; Hypoxia-Ischemia, Brain; Nerve Degeneration; Neuroprotective Agents; Neurotoxins; Receptors, Glutamate; Topiramate

Therapeutic interventions to improve the efficacy of whole-body cooling for hypoxic-ischemic encephalopathy (HIE) are desirable. Topiramate has been effective in reducing brain damage in experimental studies. However, in the clinical setting information is limited to a small number of feasibility trials. We launched a randomized controlled double-blinded topiramate/placebo multicenter trial with the primary objective being to reduce the antiepileptic activity in cooled neonates with HIE and assess if brain damage would be reduced as a consequence.. Neonates were randomly assigned to topiramate or placebo at the initiation of hypothermia. Topiramate was administered via a nasogastric tube. Brain electric activity was continuously monitored. Topiramate pharmacokinetics, energy-related and Krebs' cycle intermediates, and lipid peroxidation biomarkers were determined using liquid chromatography-mass spectrometry and MRI for assessing brain damage.. Out of 180 eligible patients 110 were randomized, 57 (51.8%) to topiramate and 53 (48.2%) to placebo. No differences in the perinatal or postnatal variables were found. The topiramate group exhibited less seizure burden in the first 24 h of hypothermia (topiramate, n = 14 [25.9%] vs. placebo, n = 22 [42%]); needed less additional medication, and had lower mortality (topiramate, n = 5 [9.2%] vs. placebo, n = 10 [19.2%]); however, these results did not achieve statistical significance. Topiramate achieved a therapeutic range in 37.5 and 75.5% of the patients at 24 and 48 h, respectively. A significant association between serum topiramate levels and seizure activity (p < 0.016) was established. No differences for oxidative stress, energy-related metabolites, or MRI were found.. Topiramate reduced seizures in patients achieving therapeutic levels in the first hours after treatment initiation; however, they represented only a part of the study population. Our results warrant further studies with higher loading and maintenance dosing of topiramate.

Topics: Combined Modality Therapy; Double-Blind Method; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Logistic Models; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Topiramate

To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE).. Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes.. Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM.. Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.

Topics: Feasibility Studies; Female; Fructose; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Magnetic Resonance Imaging; Male; Neuroimaging; Neuroprotective Agents; Topiramate; Treatment Outcome

The objective of this study was to compare the effects of two neuroprotective agents; melatonin, a free radical scavenger and topiramate, AMPA/kainate receptor antagonist, administered alone or in combination in neonatal hypoxic-ischemic model.. After being anesthetized, 7-day-old pups underwent ischemia followed by exposure to hypoxia. The pups were divided into 4 groups in order to receive the vehicle, melatonin, topiramate and combination of topiramate and melatonin. These were administered intraperitoneally for three times; the first before ischemia, the second after hypoxia and the third 24 hours after the second dose. After sacrification, infarct volume and apoptosis were evaluated.. Percent infarcted brain volume was significantly reduced in rats which received drugs compared with those which received the vehicle. The number of TUNEL positive cells per unit area in hippocampus and cortex were markedly reduced in drug treated groups compared with control group. No significant differences were found regarding percent infarcted brain volume and number of TUNEL positive cells among drug-treated groups.. Melatonin and topiramate, administered either alone or in combination significantly reduced the percent infarcted brain volume and number of TUNEL positive cells suggesting that these agents may confer benefit in treatment of infants with hypoxic-ischemic encephalopathy.

Topics: Analysis of Variance; Animals; Animals, Newborn; Brain; Brain Infarction; Caspase 3; Cell Count; Cell Death; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fructose; Hypoxia-Ischemia, Brain; In Situ Nick-End Labeling; Male; Melatonin; Neuroprotective Agents; Rats; Topiramate

Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2-3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment.. Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests.. This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.

Topics: Combined Modality Therapy; Fructose; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Neuroprotective Agents; Topiramate

Topics: Cold Temperature; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant; Seizures; Topiramate

The adequate dosing of topiramate in neonates undergoing therapeutic hypothermia has not been established. The aim of this study was to design a dosing schedule capable of providing topiramate serum concentrations within the accepted therapeutic range.. Neonates (n = 52) with hypoxic ischaemic encephalopathy and subjected to therapeutic hypothermia were dosed with topiramate, 5 mg/kg on day one and 3 mg/kg on days two to five, to decrease seizure events. A total of 451 topiramate serum concentrations obtained in the patients were used to develop a population pharmacokinetic model using a non-linear mixed-effects modelling approach.. A one-compartment model with first-order absorption and two different clearance terms, one for the cooling period and another for the post-warming period, were used to describe the concentration-time topiramate data. The probability of no-seizure events could not be related to topiramate concentrations, which was attributed to excessively low topiramate concentrations. A modified dosage schedule was designed with the aim of obtaining more than 90% of patients with topiramate concentrations within the therapeutic range after the first dose.. The dosage schedule of topiramate in these patients should be modified with the aim of decreasing the frequency of seizure events.

Topics: Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Seizures; Topiramate

Hypoxic-ischemic encephalopathy (HIE) is a major cause of perinatal mortality and subsequent severe neurological sequelae. Mild hypothermia is a standard therapy for HIE, but is used only in selected Reference Centers and in neonates >1800 g. Since neuronal death following HIE occurs by a cascade of events triggered by activation of glutamate receptors, we used in vitro and in vivo models of HIE to examine whether the AMPA/kainate receptor antagonist topiramate and the NMDA receptor antagonist memantine could exert neuroprotective effects, alone or in combination with hypothermia. For the in vitro experiments, rat organotypic hippocampal slices were exposed to a 30 min duration of oxygen-glucose deprivation (OGD): treatment with topiramate (1 μM) and memantine (10-30 μM) or hypothermia (35 °C or 32 °C) significantly attenuated CA1 damage after 24 h. The combination of hypothermia with topiramate and memantine enhanced their protective effect. For the in vivo experiments, we used 7 day-old rat pups subjected to permanent left common carotid artery occlusion followed by 120 min of hypoxia. Administration of topiramate or memantine (i.p., 20 mg/kg) immediately and 2 h after hypoxia or exposure to hypothermia (32 °C for 4 h beginning 1 h after hypoxia) significantly reduced the extent of the resulting infarct. The combination of topiramate or memantine with hypothermia elicited a reduction of the infarct that was greater than that produced by drugs or hypothermia alone. Notably, memantine displayed a higher degree of neuroprotection as compared to topiramate both in vitro and in vivo and, when used alone at 20 mg/kg in vivo, produced a greater reduction in brain damage than observed using topiramate in combination with hypothermia. These results suggest that memantine may be more advantageous than topiramate as a therapeutic agent in neonates with HIE treated with hypothermia.

Topics: Animals; Animals, Newborn; Combined Modality Therapy; Disease Models, Animal; Fructose; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Memantine; Neuroprotective Agents; Rats; Rats, Wistar; Topiramate

To explore protective effect of topiramate (TPM) on hypoxic-ischemic brain injury.. A total of 360 neonatal rats were selected then randomly divided into sham operation group, ischemia and hypoxia group, conventional treatment group and degradation therapy group (n=90). After surgical treatment, sham and ischemic hypoxia group were treat with normal saline; conventional treatment group was received TPM solution 100 mg/kg, 2 times/d; degradation therapy group received TPM solution 150 mg/kg, 2 times/d, per 3 d treatment each dosage was reduced 50 mg/kg, the lowest reduced to 50 mg/kg. Four groups received continuous treatment for 10 d. After treatment for 1 d, 4 d, 7 d, 10 d the cerebral edema, neuron-specific enolase (NSE) and γ-aminobutyric acid (GABA) levels and cognitive abilities of four groups were observed.. After 1 d, 4 d of treatment, the brain water content and NSE levels in ischemia and hypoxia group, the conventional treatment group and the degradation therapy group were significantly higher than that in sham group (P<0.05), the brain water content and NSE levels of the conventional treatment group and the degradation therapy group were significantly lower than that in the ischemic hypoxia group (P<0.05). GABA levels and learning ability of the ischemia and hypoxia group, the conventional treatment group and degradation therapy group were significantly lower than the sham group (P<0.05), the GABA levels and learning ability of the conventional treatment group and degradation therapy group were significantly higher than the ischemia and hypoxia group (P<0.05). After 7 d, 10 d of treatment, the brain water content and NSE levels in the sham operation group, the conventional treatment group and degradation therapy group were significantly lower than the ischemia and hypoxia group (P<0.05), while the GABA levels and learning ability of these three groups were significantly higher than that in the ischemia and hypoxia group (P<0.05), the GABA levels in the conventional treatment group were significantly higher than degradation therapy group (P<0.05); After 10 d of treatment, the GABA levels of the conventional treatment group were significantly higher than the sham group, the learning ability of the degradation therapy group and sham operation group were significantly higher than the conventional treatment group (P<0.05).. The correct amount of short-term TPM has protective effect on hypoxic-ischemic brain injury, but long-term or excessive use may cause new damage to the brain and reduce the cognitive ability.

Topics: Animals; Animals, Newborn; Body Water; Brain Chemistry; Fructose; gamma-Aminobutyric Acid; Hypoxia-Ischemia, Brain; Maze Learning; Phosphopyruvate Hydratase; Protective Agents; Rats; Topiramate

Whole-body deep hypothermia (DH) could be a new therapeutic strategy for asphyxiated newborn. Aim of this study was to describe how DH (core temperature 30-33°C) modifies the respiratory function if compared with mild hypothermia (MH; core temperature 33-34°C). This is an observational study. Results were obtained from a pilot study of safety of DH and topiramate in neonatal hypoxic-ischaemic encephalopathy. Fifty-seven newborns were enrolled: 29 patients in DH and 28 in MH. Recruitment criteria were moderate-severe hypoxic-ischaemic encephalopathy and gestational age ≥36 weeks. Mechanical ventilation was set to maintain SaO(2) between 92% and 95%. Nineteen patients in DH and 18 in MH required mechanical ventilation. Of these patients, 10 and 12, respectively, did not required oxygen. No significant differences were observed in hours of oxygen and ventilation support, respiratory rate and PaCO(2). Maximum FiO(2), peak inspiratory pressure, positive end-expiratory pressure, minute ventilation and tidal volume during hypothermia were similar. Pulmonary function with different levels of hypothermia was similar.

Topics: Body Temperature; Carbon Dioxide; Combined Modality Therapy; Female; Fructose; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Lung; Male; Neuroprotective Agents; Oxygen; Oxygen Inhalation Therapy; Partial Pressure; Pilot Projects; Respiration, Artificial; Respiratory Rate; Retrospective Studies; Topiramate

To investigate whether topiramate associated with mild or deep hypothermia in asphyxiated term infants is safe in relation to the short-term outcome.. We report on 27 consecutive asphyxiated newborns who were treated with whole body hypothermia and 27 additional consecutive newborns with hypothermia who were co-treated with oral topiramate, once a day for 3 consecutive days, at 2 different doses.. Newborns were divided in 6 groups according to the depth of hypothermia and the association with higher or lower topiramate dosage. A statistical comparison of the groups identified some differences in biochemical and hemodynamic variables, but no adverse effects attributable to topiramate were detected. There were no statistically significant differences in the groups in short-term outcomes, survival rate at discharge, or incidence of pathologic brain magnetic resonance imaging.. Although the number of newborns in this study was limited, the short-term outcome and the safety data appear to support the evaluation of topiramate in clinical trials to explore its possible additive neuroprotective action.

Topics: Administration, Oral; Combined Modality Therapy; Female; Fructose; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Neuroprotective Agents; Retrospective Studies; Topiramate

Glutamate receptor-mediated neurotoxicity is a major mechanism contributing to hypoxic-ischemic brain injury (HIBI). Memantine is a safe non-competitive NMDA receptor blocker characterized by its low affinity and fast unblocking kinetics. Topiramate is an AMPA/KA receptor blocker and use-dependent sodium channel blocker with several other neuroprotective actions and little neurotoxicity. We hypothesized that the coadministration of memantine and topiramate would be highly effective to attenuate HIBI in neonatal rats. Seven-day-old Sprague-Dawley rat pups were subjected to right common carotid artery ligation and hypoxia for 2 h, and then were randomly and blindly assigned to one of four groups: vehicle, memantine, topiramate and combination group. Brain injury was evaluated by gross damage and weight deficit of the right hemisphere at 22d after hypoxic-ischemia (HI) and by neurofunctional assessment (foot-fault test) at 21d post-HI. Acute neuronal injury was also evaluated by microscopic damage grading at 72 h post-HI. Results showed the combination of memantine and topiramate improved both pathological outcome and performance significantly. The drug-induced apoptotic neurodegeneration was assessed by TUNEL staining at 48 h post-HI and the result showed no elevated apoptosis in all observed areas. The result of the experiment indicates the combination therapy is safe and highly effective to reduce brain damage after HIBI.

Topics: Animals; Animals, Newborn; Anticonvulsants; Apoptosis; Brain; Brain Infarction; Disease Models, Animal; Excitatory Amino Acid Antagonists; Female; Fructose; Glutamic Acid; Hypoxia-Ischemia, Brain; In Situ Nick-End Labeling; Male; Memantine; Nerve Degeneration; Neurons; Neuroprotective Agents; Neurotoxins; Rats; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Topiramate; Treatment Outcome

Therapeutic hypothermia reduces mortality and neurologic impairment in neonates with hypoxic-ischemic encephalopathy. Topiramate exerts a neuroprotective effect in asphyxiated neonatal animal models. However, no studies have investigated the association of hypothermia and topiramate, because topiramate pharmacokinetics during hypothermia and the optimal administration schedule are unknown. The influence of hypothermia on topiramate pharmacokinetics was evaluated in asphyxiated neonates treated with prolonged whole-body hypothermia and topiramate.. Thirteen term newborns were treated with mild or deep whole body hypothermia for 72 h; all received oral topiramate, 5 mg/kg once a day for the first 3 days of life, and seven had concomitant phenobarbital treatment. Topiramate concentrations were measured on serial dried blood spots.. Topiramate concentrations were within the reference range in 11 of 13 newborns, whereas concentrations exceeded the upper limit in 2 of 13, both newborns on deep hypothermia. Topiramate concentrations reached a virtual steady state in nine newborns, for whom pharmacokinetic parameters were calculated. Values of topiramate maximal and minimal concentration, half-life, average concentration, and area under the time-concentration curve resulted in considerably higher values than those reported in normothermic infants. With respect to normothermic infants, time of maximal concentration was mildly delayed and apparent total body clearance was lower, suggesting slower absorption and elimination. Pharmacokinetic parameters did not differ significantly between infants on deep versus mild hypothermia and in those on topiramate monotherapy versus add-on phenobarbital.. Most neonates on prolonged hypothermia treated with topiramate 5 mg/kg once a day exhibited drug concentrations within the reference range for the entire treatment duration.

Topics: Asphyxia Neonatorum; Combined Modality Therapy; Drug Therapy, Combination; Female; Fructose; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Neuroprotective Agents; Phenobarbital; Topiramate; Treatment Outcome

Refractory status epilepticus is a catastrophic illness of the central nervous system, with a mortality rate that reaches 50%. We report three patients admitted with refractory status epilepticus: a 24 year-old male that discontinued antiepileptic medications, a 46 year-old male with a focal epilepsy secondary to an encephalitis that discontinued medications due to gastrointestinal problems and a 59 year-old male with an ischemic encephalopathy AH were treated with topiramate, delivered through a nasogastric tube with a good response.

Topics: Administration, Oral; Anticonvulsants; Fructose; Humans; Hypoxia-Ischemia, Brain; Male; Middle Aged; Patient Dropouts; Status Epilepticus; Topiramate; Young Adult

Perinatal hypoxia-ischemia is one of the most common risk factors for neonatal mortality and permanent neurodevelopmental disability. Topiramate [2,3:4,5-bis-o-(1-methylethylidene) beta-D-fructo-pyranose sulfamate; TPM] is widely used as an antiepileptic agent with multiple targets. In the present study, we found that treatment with TPM reduced the neuronal damage induced by oxygen-glucose deprivation in vitro with strong inhibition of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor. Because perinatal hypoxia is mediated, at least in part, by aberrant glutamatergic excitation, we tested whether treatment with TPM was effective against perinatal brain hypoxia-ischemia. Intraperitoneal or oral pretreatment with TPM was found to reduce the brain damage and subsequent cognitive impairments induced by transient hypoxia-ischemia in perinatal rats. A potent neuroprotective effect of TPM was also observed in a post-treatment regime although post-treatment window appears to be relatively narrow (<2 h). These results suggest that TPM treatment may be beneficial for perinatal hypoxia-ischemia and related damage.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Administration, Oral; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Animals, Newborn; Behavior, Animal; Cell Hypoxia; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Fructose; Hypoxia-Ischemia, Brain; Injections, Intraperitoneal; Maze Learning; N-Methylaspartate; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Topiramate

Perinatal hypoxia-ischemia (HI) is associated with delayed cerebral damage, which involves receptor-mediated excitotoxicity. Until now, successful interventions to reduce excitotoxicity early after HI in experimental settings failed to transform into clinical applications owing to negative side effects. A promising new approach using the anticonvulsant Topiramate (TPM) has shown to be effective to reduce brain damage after early HI in a rodent model of combined TPM-hypothermia. Here, we used TPM solely administered 1 h after HI in a neonatal piglet model in order to verify possible neuroprotection.. Newborn piglets were subjected to HI by transient occlusion of carotid arteries and hypotension (62-65% of baseline). Fifteen minutes later, an additional reduction of the inspired oxygen fraction to 0.06 was performed for 13 min. One cohort (VEHICLE, n = 8) received saline solution i.v. 1 h after HI and then twice a day. Two further cohorts were treated at same times with TPM (HI-TPM10, n = 8, loading dose 20 mg/kg; maintenance dose 10 mg/kg/day; HI-TPM20, n = 8, loading dose 50 mg/kg; maintenance dose 20 mg/kg/day). Untreated animals (CONTROL, n = 8) received all experimental procedures except HI. Animals were monitored 3 days after HI concerning occurrence of seizures as well as neurological and behavioral functions. After 72 h, the brains were perfused and processed to assess neuronal loss and DNA-fragments (TUNEL staining).. There was a significant reduction of neuronal cell loss in HI-TPM20 animals. However, apoptosis was increased in the frontal white matter of HI-TPM20 animals.. Exclusive TPM treatment shows neuroprotection in newborn piglets after HI.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Brain; Brain Infarction; Disease Models, Animal; DNA Fragmentation; Fructose; Humans; Hypoxia-Ischemia, Brain; In Situ Nick-End Labeling; Infant, Newborn; Nerve Degeneration; Neuroprotective Agents; Sus scrofa; Topiramate; Treatment Outcome

Periventricular leukomalacia is a form of hypoxic-ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic-ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA-kainate-type glutamate receptor blockade in a rodent model of periventricular leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic-ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23-32 weeks gestation, the period of highest risk for periventricular leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo, is protective against selective hypoxic-ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA-kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA-kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, protective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro. Taken together, these results suggest that AMPA-kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter.

Topics: Animals; Calcium; Cell Death; Cell Differentiation; Cell Division; Disease Models, Animal; Dose-Response Relationship, Drug; Erythroid Precursor Cells; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Fructose; Gestational Age; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Kainic Acid; Leukomalacia, Periventricular; Movement Disorders; Neuroprotective Agents; Oligodendroglia; Quinoxalines; Rats; Receptors, AMPA; Receptors, Glutamate; Topiramate; Treatment Outcome

Pre-clinical studies suggest that the anticonvulsant topiramate confers neurologic protection against ischemia. An intravenous formulation of topiramate has been developed for administration during conditions such as hypoxia-ischemia when enteral absorption may be unpredictable. The plasma pharmacokinetics, cerebrospinal fluid (CSF) penetration and pharmacodynamics of intravenous topiramate were studied in an established piglet model of hypoxia-ischemia.. The plasma pharmacokinetics of topiramate were studied in a group of chronically instrumented conscious piglets (n = 8), and in a group of piglets following an episode of hypoxia-ischemia (n = 8). These groups were divided into equal dose cohorts in which two doses of intravenously administered topiramate, 5 and 40 mg/kg, were studied. The animals' heart rate, arterial pressure and EEG were monitored. Plasma for topiramate concentration was sampled for up to 26 h. A single CSF topiramate concentration was determined 1 h following drug administration. Topiramate was quantified using a specific LC/MS assay.. The animals tolerated intravenous topiramate well, with no significant changes in physiologic and neurologic parameters. Plasma topiramate concentrations following an intravenous dose were best described by a bi-exponential equation, with a mean clearance of 39+/-18 ml/h/kg, and a terminal half-life of 14.3 (range 7.5-48.1) h. A dose of 5 mg/kg was sufficient to maintain plasma drug concentrations greater than 10 micro M for 24 h. CSF topiramate concentration at 1 h was 12+/-1 micro M and 109+/-26 micro M at the 5 and 40 mg/kg doses, respectively.. Topiramate administered intravenously was well tolerated. Slow clearance of the drug allowed for maintenance of potential neuroprotective concentrations following a single dose of drug for 24 h. High drug penetration into the CSF is an ideal pharmacologic characteristic of any potential neuroprotective agent. The pharmacokinetic profile of intravenously administered topiramate, including its penetration into the CSF, appears to achieve this goal.

Topics: Animals; Animals, Newborn; Anticonvulsants; Blood Pressure; Chromatography, Liquid; Electrocardiography; Female; Fructose; Half-Life; Heart Rate; Hypoxia-Ischemia, Brain; Injections, Intravenous; Male; Mass Spectrometry; Neuroprotective Agents; Swine; Time Factors; Topiramate