topiramate and Brain-Ischemia

Ischemia-reperfusion models are used to evaluate treatment options that may minimize cellular damage after ischemia.. To investigate the effects of amantadine and topiramate on apoptosis and cellular oxidative damage.. This experiment was performed using 30 male Wistar albino rats. The right internal carotid artery was identified and clamped with an aneurysm clip under general anesthesia, except for animals in the control group. After 10 min of occlusion, the aneurysm clip was removed, allowing reperfusion. After reperfusion and a waiting period of 12 h, the test and control groups were intraperitoneally administered the following solutions: the sham group received 10 mg/kg of isotonic solution, the amantadine group received 20 mg/kg of amantadine, the topiramate group received 40 mg/kg of topiramate, and the amantadine-topiramate group received 20 mg/kg of amantadine and 40 mg/kg of topiramate. After 24 h, the rats were euthanized.. Apoptosis was evaluated using the TUNEL method. Total antioxidant status (TAS), total oxidant status (TOS), total thiol, and ischemia-modified albumin (IMA) levels were measured in both brain tissue and serum samples. The rate of apoptosis in the sham and amantadine groups increased significantly compared to the control group and the non-ischemic counter hemisphere. In the amantadine-topiramate group, both serum TAS and tissue thiol levels decreased. Tissue TOS levels were significantly higher in the topiramate group compared to all other test groups. Tissue TAS levels were significantly higher in the amantadine group compared to all other test groups.. This experimental ischemia-reperfusion model revealed that topiramate reduces apoptosis in the early period after ischemia and that its combination with amantadine does not provide additional benefits against cell death. However, topiramate did not have an inhibitory effect on the oxidative stress biomarkers used in our study (TAS, TOS, IMA, and thiol). Studies that reveal the neuroprotective mechanism of action and long-term effects of topiramate are needed to complement this study.

Topics: Amantadine; Animals; Antioxidants; Biomarkers; Brain Ischemia; Male; Oxidative Stress; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Serum Albumin; Topiramate

Topics: Anticonvulsants; Brain; Brain Ischemia; Chorea; Dyskinesias; Female; Fructose; Humans; Middle Aged; Stroke; Topiramate

Migraine with aura is an established stroke risk factor, and excitatory mechanisms such as spreading depression (SD) are implicated in the pathogenesis of both migraine and stroke. Spontaneous SD waves originate within the peri-infarct tissue and exacerbate the metabolic mismatch during focal cerebral ischemia. Genetically enhanced SD susceptibility facilitates anoxic depolarizations and peri-infarct SDs and accelerates infarct growth, suggesting that susceptibility to SD is a critical determinant of vulnerability to ischemic injury. Because chronic treatment with migraine prophylactic drugs suppresses SD susceptibility, we tested whether migraine prophylaxis can also suppress ischemic depolarizations and improve stroke outcome.. We measured the cortical susceptibility to SD and ischemic depolarizations, and determined tissue and neurological outcomes after middle cerebral artery occlusion in wild-type and familial hemiplegic migraine type 1 knock-in mice treated with vehicle, topiramate or lamotrigine daily for 7 weeks or as a single dose shortly before testing.. Chronic treatment with topiramate or lamotrigine reduced the susceptibility to KCl-induced or electric stimulation-induced SDs as well as ischemic depolarizations in both wild-type and familial hemiplegic migraine type 1 mutant mice. Consequently, both tissue and neurological outcomes were improved. Notably, treatment with a single dose of either drug was ineffective.. These data underscore the importance of hyperexcitability as a mechanism for increased stroke risk in migraineurs, and suggest that migraine prophylaxis may not only prevent migraine attacks but also protect migraineurs against ischemic injury.

Topics: Animals; Anticonvulsants; Brain Ischemia; Calcium Channels, N-Type; Chemoprevention; Cortical Spreading Depression; Fructose; Gene Knock-In Techniques; Infarction, Middle Cerebral Artery; Lamotrigine; Mice; Migraine Disorders; Stroke; Topiramate; Triazines

The effect of anticonvulsant drugs on posttraumatic convulsive reactions and the stability of the brain with respect to complete ischemia and hypoxia upon brain injury has been studied in animals with model contact craniocerebral trauma. It is established that lamotrigine, topiramate, and sodium valproate produce a strong effect on convulsive reactions, while magnesium sulfate and gabapentin produce a moderate action. The antiishemic and antihypoxic action of lamotrigine and sodium valproate is stronger than that of topiramate and gabapentin.

Topics: Amines; Animals; Animals, Outbred Strains; Anticonvulsants; Brain; Brain Injuries; Brain Ischemia; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Electric Stimulation; Fructose; Gabapentin; gamma-Aminobutyric Acid; Lamotrigine; Magnesium Sulfate; Mice; Rats; Seizures; Topiramate; Triazines; Valproic Acid

Impaired GABAergic inhibitory synaptic transmission plays an essential role in the pathogenesis of selective neuronal cell death following transient global ischemia. GABA(A) receptor (GABA(A)R), K⁺-Cl⁻ co-transporter 2 (KCC2), Na⁺-K⁺-Cl⁻ co-transporter 1 (NKCC1) and astrocytes are of particular importance to GABAergic transmission. The present study was designed to explore whether the neuroprotective effect of topiramate (TPM) was linked with the alterations of GABAergic signaling and astrocytes. The bilateral carotid arteries were occluded, and TPM (80 mg/kg/day (divided twice daily), i.p.) was injected into gerbils. At day 1, 3 and 7 post-ischemia, neurological deficit was scored and changes in hippocampal neuronal cell death were evaluated by Nissl staining. The apoptosis-related regulatory proteins (procaspase-3, caspase-3, Bax and Bcl-2) and GABAergic signal molecules (GABA(A)R α1, GABA(A)R γ2, KCC2 and NKCC1) were also detected using western blot assay. In addition, the fluorescent intensity and protein level of glial fibrillary acidic protein (GFAP), a major component of astrocyte, were examined by confocal and immunoblot analysis. Our results showed that TPM treatment significantly decreased neurological deficit scores, attenuated the ischemia-induced neuronal loss and remarkably decreased the expression levels of procaspase-3, caspase-3 as well as the ratio of Bax/Bcl-2. Besides, treatment with TPM also resulted in the increased protein expressions of GABA(A)R α1, GABA(A)R γ2 and KCC2 together with the decreased protein level of NKCC1 in gerbils hippocampus. Furthermore, fluorescent intensity and protein level of GFAP were evidently reduced in TPM-treated gerbils. These findings suggest that the therapeutic effect of TPM on global ischemia/reperfusion injury appears to be associated with the enhancement of GABAergic signaling and the inhibition of astrogliosis in gerbils.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Astrocytes; bcl-2-Associated X Protein; Brain Ischemia; Cell Death; Fructose; Gerbillinae; Glial Fibrillary Acidic Protein; Gliosis; Hippocampus; Male; Neurons; Neuroprotective Agents; Proto-Oncogene Proteins c-bcl-2; Receptors, GABA-A; Reperfusion Injury; Topiramate

Acute "silent" seizures after brain injury are associated with a worsening of patient outcome and are often refractory to anti-epileptic drug (AED) therapy. In the present study we evaluated topiramate (TPM, 1-30 mg/kg, i.v.) in a rodent model of spontaneous non-convulsive seizure (NCS) activity induced by focal cerebral ischemia. For seizure detection, electroencephalographic (EEG) activity was continuously recorded for 24h in male Sprague-Dawley rats subjected to permanent middle cerebral artery occlusion (MCAo). Infarct volume, neurological deficit, and NCS were evaluated by an experimenter blinded to the treatment group. All vehicle treated rats (7/7) exhibited NCS following MCAo. TPM treatment, delivered at 20 min post-occlusion and prior to onset of NCS activity, dose-dependently reduced the incidence of NCS (ED(50)=21.1mg/kg). The highest dose of TPM tested (30 mg/kg) exhibited maximal reductions of 76% in the number of NCS/rat (vehicle=22.1+/-5.3, TPM=4.4+/-3.2, P<0.05), 80% in the total time of NCS (vehicle=1259+/-337 s, TPM=253+/-220 s, P<0.05), 20% in core brain infarction (vehicle=45+/-1%, TPM=36+/-4%, percent of ipsilateral volume corrected for swelling, P<0.05), and 38% in neurological deficit score (vehicle=7.4+/-1.2, TPM=4.6+/-1.5, P<0.05). Despite efficacy as a pre-seizure treatment, TPM was not effective when delivered immediately following onset of the first NCS event (36+/-5 min post-MCAo). In conclusion, TPM exhibited significant efficacy for the prophylactic treatment of brain-injury induced NCS and represents a novel class of AED for treatment of this type of silent brain seizure.

Topics: Animals; Anticonvulsants; Brain Ischemia; Electroencephalography; Fructose; Male; Rats; Rats, Sprague-Dawley; Seizures; Topiramate

The possible neuroprotective effects of classic and new antiepileptic drugs on the electrophysiological changes induced by in vitro ischemia on striatal neurons were investigated. In particular, the aim of the study was to correlate the putative neuroprotective effects with the action of these drugs on fast sodium (Na+) and high-voltage-activated (HVA) calcium (Ca2+) currents.. Extracellular field potentials were recorded from rat corticostriatal brain-slice preparations. In vitro ischemia was delivered by switching to an artificial cerebrospinal fluid solution in which glucose and oxygen were omitted. Na+ and HVA Ca2+ currents were analyzed by whole-cell patch-clamp recordings from acutely isolated rat striatal neurons. Excitatory postsynaptic potential was measured following synaptic stimulation in corticostriatal slices by sharp intracellular microelectrodes.. Neuroprotection against in vitro ischemia was observed in slices treated with carbamazepine (CBZ), valproic acid (VPA), and topiramate (TPM), whereas it was not achieved by using levetiracetam (LEV). Fast Na+ conductances were inhibited by CBZ and TPM, whereas VPA and LEV showed no effect. HVA Ca2+ conductances were reduced by CBZ, TPM, and LEV. VPA had no effect on this current. All antiepileptic drugs induced a small reduction of excitatory postsynaptic potential amplitude at concentrations higher than 100 microm without changes of paired-pulse facilitation.. The concomitant inhibition of fast Na+ and HVA Ca2+ conductances is critically important for the neuroprotection, whereas the presynaptic inhibition on glutamate transmission does not seem to play a major role.

Topics: Animals; Anticonvulsants; Brain Ischemia; Calcium Signaling; Carbamazepine; Electrophysiology; Excitatory Postsynaptic Potentials; Fructose; In Vitro Techniques; Ion Transport; Potassium; Rats; Topiramate; Valproic Acid

The mechanisms of action of the anticonvulsant topiramate (TPM) are indicative of a potential benefit during cerebral ischemia. TPM was studied in a transient global forebrain ischemia (TGFI) model in gerbils in which 40 mg/kg was administered before or after TGFI. Control groups were administered 0.9% normal saline similarly. The evaluation consisted of neurochemical, histological, and functional analyses. The data obtained indicates that unlike the focal cerebral ischemia model, TPM is not neuroprotective in TGFI. The difference in effect, which may be due to the difference in species or the type of ischemia, points to the need for caution when extrapolating animal data from this drug to humans.

Topics: Animals; Behavior, Animal; Brain Ischemia; Disease Models, Animal; Fructose; Gerbillinae; Male; Microdialysis; Neuroprotective Agents; Prosencephalon; Topiramate

Potentiators of inhibitory neurotransmission may provide a neuroprotective effect on cerebral tissue exposed to ischemia, without inducing toxic side effects. Topiramate and vigabatrin enhance the action of gamma-aminobutyric acid (GABA), and each has side effect profiles known to be well tolerated through their clinical use as anticonvulsant medications. We assessed the potential benefit through GABA activation by these drugs on infarct size and functional recovery following focal cerebral ischemia in mice.. Silicon-coated suture was advanced through the internal carotid artery of 89 halothane-anesthetized mice to temporarily occlude the right middle cerebral artery for either 45 minutes (topiramate), or 120 minutes (vigabatrin). Animals were treated either at the time of reperfusion with topiramate (100 mg/kg, 40 mg/kg, or saline control), or two hours before arterial occlusion with vigabatrin, (1000 mg/kg, 500 mg/kg, or saline control). Neurological outcome was measured 24 hours after ischemia using a 28-point functional examination score. Infarct volume was estimated by summing area maps of stained slices of infarcted hemispheres.. Functional examination scores at 24 hours were similar between the high dose topiramate group, the low dose topiramate group, and the control group. Similarly, no differences were noted between examination scores of high dose vigabatrin, low dose vigabatrin, and control. Consistent sized right hemisphere infarcts were noted within each group on histological examination. Mean infarct volumes did not differ between groups treated with high dose topiramate, low dose topiramate, or control. Infarct volumes of animals treated with saline control were slightly larger than that of high dose vigabatrin and low dose vigabatrin groups, but the difference did not reach significance.. Treatment with these two potentiators of GABA did not result in significant differences in outcome following focal cerebral ischemia, by either functional or histological measures. These results do not support a substantial neuroprotective role of GABA following ischemia in this mouse suture model.

Topics: Animals; Anticonvulsants; Brain Ischemia; Disease Models, Animal; Fructose; gamma-Aminobutyric Acid; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Stroke; Topiramate; Treatment Failure; Vigabatrin

Thrombolysis is increasingly being used in treating acute ischemic stroke but it is also accompanied with a serious complication of cerebral hemorrhage in a dose-dependent fashion. As a lower dose may result in decreased effectiveness, we tested the efficacy of combining a neuroprotective agent, topiramate (TPM), with lower doses of intra-arterial urokinase in an embolic stroke model. Focal ischemia was produced by introduction of an autogenous thrombus into the right middle cerebral artery. Urokinase was infused via the ipsilateral internal carotid artery and neuroprotective agent, TPM, was administrated intra-peritoneally 2 h following ischemic insult. The animals were assigned to five groups: (1) control group (n=6); (2) urokinase 5000 units/kg (n=8); (3) urokinase at 2500 units/kg (n=8); (4) topiramate at 20 mg/kg (n=8); (5) urokinase at 2500 units/kg and topiramate at 20 mg/kg (n=8). Neurobehavioral outcome and the degree of brain infarct volume were assessed at 24 h. Three animals in the group treated by high dose urokinase developed intracranial hemorrhage but none in other groups. Animals in all medication-groups showed significant improvement in neurobehavioral score. Post-ischemia treatment with urokinase or TPM alone significantly attenuated brain infarct volume (low-dose urokinase, 39.1+/-13.0%, p<0.05; high-dose, 18.4+/-8.5%, p<0.001; TPM, 20. 1+/-11.2%, p<0.001) when compared to the control (54.2+/-9.04%). Addition of TPM to low dose urokinase achieved better neuroprotection (8.2+/-6.0%) than any single-drug-treated groups. Our data suggests that combination of low dose urokinase with a neuroprotective agent may benefit ischemic stroke treatment by improving neurologic recovery, attenuating infarction size, and reducing the risk of cerebral hemorrhage.

Topics: Animals; Brain; Brain Ischemia; Cerebral Hemorrhage; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fructose; Infarction, Middle Cerebral Artery; Injections, Intra-Arterial; Injections, Intraperitoneal; Intracranial Thrombosis; Male; Neuroprotective Agents; Rats; Rats, Wistar; Topiramate; Urokinase-Type Plasminogen Activator

Recent studies have shown that the use of thrombolysis in the setting of acute stroke is associated with an increased risk of cerebral hemorrhage. The time of onset of symptoms to initiation of medication and the dose levels of the thrombolytic agents are important determinants for the risk of cerebral hemorrhage. The authors evaluated the time course of thrombolysis-related hemorrhages in experimental settings and tested whether the addition of neuroprotective medication augments the efficacy of thrombolysis and reduces the incidence of hemorrhages.. Male Wistar rats were subjected to right middle cerebral artery embolization with an autologous thrombus and were then randomly assigned to one of the following groups: Group 1, saline-treated (2 hours after ischemic insult) animals as controls; Groups 2 to 4, high-dose urokinase (5,000 U/kg) at 2, 3, and 6 hours after the insult; Group 5, low-dose urokinase (2,500 U/kg) at 2 hours after the insult; Group 6, 20 mg/kg topiramate (TPM) at 2 hours after the insult; Group 7, a combination of 20 mg/kg TPM at 2 hours and low-dose urokinase (2,500 U/kg) at 6 hours after the insult; and Group 8, 20 mg/kg TPM (20 mg/kg) at 2 hours and high-dose urokinase (5,000 U/kg) at 2 hours after the insult. Neurological behavior and the infarct volume in the brain were assessed following cerebral embolism and the various treatments. All animals in the single therapy and low-dose combination groups survived surgery. Three of eight animals treated with high-dose urokinase alone at 6 hours and three of six animals in the combined high-dose urokinase and TPM group developed fatal intracerebral hemorrhages. There was a significantly better neurological outcome at 24 hours in the animals treated with either medication compared with controls. The volume of the infarct in the saline-treated group was 54.2 +/- 9%. The use of TPM at 2 hours led to a decrease in the infarct to 20.1 +/- 11.2% (p < 0.01). Treatment with urokinase at 6 hours after the occlusion showed a trend toward protection; the infarct volume was 31.9 +/- 14.1% (p < 0.05). The addition of TPM to low- or high-dose urokinase achieved better neuroprotection (8.2 +/- 6% and 11.9 +/- 10.7%, respectively; both p < 0.01).. In this study the authors show that the volume of the infarct can be significantly decreased with 2 to 6-hour delayed intraarterial thrombolysis with urokinase and that the efficacy of thrombolysis may be enhanced by combining neuroprotective agents like TPM. It is also shown that low-dose combination therapy may decrease the likelihood of cerebral hemorrhage.

Topics: Acute Disease; Animals; Brain Ischemia; Cerebral Hemorrhage; Disease Models, Animal; Drug Therapy, Combination; Fructose; Incidence; Infarction, Middle Cerebral Artery; Injections, Intra-Arterial; Intracranial Embolism; Male; Neurologic Examination; Neuroprotective Agents; Placebos; Plasminogen Activators; Random Allocation; Rats; Rats, Wistar; Risk Factors; Stroke; Thrombolytic Therapy; Time Factors; Topiramate; Treatment Outcome; Urokinase-Type Plasminogen Activator

Because topiramate (TPM) suppresses voltage-sensitive Na+ channels and non-N-methyl-D-aspartate (NMDA) receptors and enhances gamma-aminobutyric acid (GABA)-mediated inhibition, we tested whether it would protect against cerebral ischemia. The right middle cerebral artery (MCA) was embolized by an intra-arterial injection of autogenous thrombus. Two hours after thrombus injection, animals received intra-peritoneal injections (i.p.) of normal saline as control (n=6) or alternatively, a low- (20 mg/kg, i.p., n=6) or high-dose (40 mg/kg, i.p., n=6) of TPM. Neurological deficit was scored at 2 h and 24 h following the ischemic insult. The animals were sacrificed 24 h after ischemia and the coronal brain sections were stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC) for determination of the percentage of infarct volume. Administration of TPM significantly improved the 24-h neurological deficit scores (low dose, 1.75+/-0.5; high dose, 1.17+/-0.41; p<0.05 for both doses). A reduction in the percentage of infarct volume (low dose, 22.9+/-8.9%, p=0.002; high dose 7.6+/-3.4%, p<0.001) was seen when compared to the controls (infarct size, 54.2+/-9.0%; neurobehavior score, 2. 67+/-0.52). Treatment with TPM at the higher dose induced more neuroprotection than that at the lower dose (p<0.05). Thus, treatment with TPM resulted in a dose- and use-dependent neuroprotective effect, when used 2 h after MCA embolization in a rat model of focal ischemia.

Topics: Animals; Anticonvulsants; Brain Ischemia; Cerebral Arteries; Fructose; Hemorrhage; Intracranial Embolism and Thrombosis; Male; Rats; Rats, Wistar; Topiramate

Topiramate, a structurally novel anticonvulsant, and phenytoin were evaluated in a rat model of ischemia-induced epilepsy. In this model a transient global cerebral ischemia is induced by cardiac compression. By precisely controlling the experimental conditions the procedure causes reproducible neurological deficits that include audiogenic epileptic seizures. The seizures can be broadly separated into three types reflecting the degree of severity: wild running, clonic seizures, and tonic extension seizures of the forelimbs and hindlimbs. Topiramate and phenytoin blocked all three types of seizures. Calculated ED50 values for topiramate 1 hr after oral administration were 8.2, 13.0 and 36.1 mg/kg for blockade of tonic extension seizures, clonic seizures and wild running, respectively. Corresponding ED50 values for phenytoin were 5.0, 10.8 and 20.7 mg/kg. These results support the concept that the anticonvulsant activity of these drugs is due primarily to an ability to block the spread of seizures.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Brain Ischemia; Epilepsy; Fructose; Male; Phenytoin; Rats; Topiramate