scholarly journals Chronic convection-enhanced muscimol delivery into the subthalamic nucleus produces transient anticonvulsant effects in an acute rat seizure model.

2020 ◽  
Author(s):  
Malte Feja ◽  
Lillian S. Deking ◽  
Manuela Gernert
Keyword(s):  
Adverse Effects ◽  
Subthalamic Nucleus ◽  
Seizure Threshold ◽  
Epileptic Focus ◽  
Anticonvulsant Effect ◽  
Continuous Administration ◽  
Gaba A ◽  
Seizure Model ◽  
Epilepsy Models ◽  
Anticonvulsant Effects

Aims : Intracerebral drug delivery is an emerging strategy for the treatment of refractory epilepsies. Recently, the GABA A receptor agonist muscimol was infused into the epileptic focus in drug-resistant epilepsy patients (Heiss et al. 2019 Neurosurgery). In seizure and epilepsy models in rats, muscimol has shown anticonvulsant potential when injected acutely into the subthalamic nucleus (STN). However, continuous administration would be required for the clinical setting. Thus, we hypothesized that chronic convection-enhanced muscimol delivery into the STN produces anticonvulsant effects in an acute rat seizure model. Methods : We examined the effects of intra-STN muscimol following a single microinjection (30 and 60 ng/250 nl) and during continuous administration via a microinfusion pump (60 and 600 ng/day over 3 weeks) on the seizure threshold of female Wistar Unilever rats. Timed intravenous pentylenetetrazole (PTZ) infusion was used as an acute seizure test particularly sensitive to GABA-potentiating manipulations. Results : Acute STN muscimol infusion significantly increased PTZ seizure thresholds compared to vehicle-injected animals. The anticonvulsant effect persisted in the first week during chronic STN inhibition and diminished in the second week, indicating tolerance. Low doses of muscimol were well tolerated and not associated with behavioral adverse effects (e.g., sedation, circling) observed after infusion of higher doses. Evaluation of the spatial distribution of BODIPY-labeled muscimol revealed behavioral adverse effects may be attributable to drug spread into adjacent regions of the STN. Conclusions : These results substantiate the STN as a key region in seizure control and indicate the potential of chronic targeted muscimol delivery for prolonged anticonvulsant effects.

Possible Involvement of Endogenous Opioids and Nitric Oxide in the Anticonvulsant Effect of Acute Chloroquine Treatment in Mice

2017 ◽  
Vol 41 (S1) ◽  
pp. S630-S630
Author(s):  
A. Abkhoo
Keyword(s):  
Nitric Oxide ◽  
Effective Dose ◽  
Clonic Seizure ◽  
Endogenous Opioids ◽  
Seizure Threshold ◽  
Anticonvulsant Effect ◽  
Nitric Oxide Signaling ◽  
Nos Inhibitor ◽  
Neuronal Nos ◽  
Anticonvulsant Effects

IntroductionChloroquine, a 4-aminoquinoline derivative, has long been used for the treatment of malaria and rheumatological disorders, including rheumatoid arthritis and systemic lupus erythematosus. Accumulating evidence now suggests potential use of chloroquine as a neuroprotectant. Studies have shown that nitric oxide (NO) pathway is involved in the chloroquine actions. Considering the fact that nitrergic neurotransmission plays a crucial role in the central nervous system functioning, in the present study we evaluated whether nitrergic system is involved in the anticonvulsant effects of chloroquine in a model of clonicseizure in mice.MethodsClonic seizure threshold was determined by infusion of pentylenetetrazole (PTZ, 0.5%) at a constant rate of 1 mL/min into the tail vein of male Swiss mice (23–29 g). Minimal dose of PTZ (mg/kg of mice weight) needed to induce clonicseizure was considered as an index of seizure threshold.ResultsChloroquine (5 mg/kg, acutely 30 min before test, intraperitoneally), i.p significantly increased the seizure threshold. Acute co-administration of a non-effective dose of the non-selective NO synthase (NOS) inhibitor, L-NAME (L-NG-Nitro-L-arginine methyl ester hydrochloride,5 mg/kg, i.p.) or the selective inhibitor of neuronal NOS, 7-NI (7-nitroindazole, 40 mg/kg, i.p.) with an effective dose of chloroquine (5 mg/kg) inhibited its anticonvulsant effects. Co-administration of a non-effective dose the selective inducible NOS inhibitor, aminoguanidine (100 mg/kg, i.p.) with chloroquine 5 mg/kg did not alter its anticonvulsant effects.ConclusionChloroquine increases the PTZ-induced clonic seizure threshold in mice. We demonstrated for the first time that nitric oxide signaling probably through neuronal NOS could be involved in the anticonvulsant effects of chloroquine in this model of seizure in mice.Disclosure of interestThe author has not supplied his/her declaration of competing interest.

scholarly journals Anticonvulsant Effects by Bilateral and Unilateral Transplantation of GABA-Producing Cells into the Subthalamic Nucleus in an Acute Seizure Model

2014 ◽  
Vol 23 (1) ◽  
pp. 111-132 ◽  
Author(s):  
Annelie Handreck ◽  
Bianca Backofen-Wehrhahn ◽  
Sonja Bröer ◽  
Wolfgang Löscher ◽  
Manuela Gernert
Keyword(s):  
Subthalamic Nucleus ◽  
Acute Seizure ◽  
Seizure Model ◽  
Anticonvulsant Effects

Verapamil enhances the anticonvulsant effect of oxcarbazepine in the maximal electroshock-induced seizure model in mice

2009 ◽  
Vol 22 (2) ◽  
pp. 115-124
Author(s):  
Anna Zadrożniak ◽  
MichaŁ K. Trojnar ◽  
Marcin P. Trojnar ◽  
Żaneta Kimber-Trojnar ◽  
Monika Dudra-Jastrzębska ◽  
...  
Keyword(s):  
Anticonvulsant Effect ◽  
Maximal Electroshock ◽  
Seizure Model

scholarly journals Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

2021 ◽  
Author(s):  
Dorota Zolkowska ◽  
Chun-Yi Wu ◽  
Michael A. Rogawski
Keyword(s):  
Adverse Effects ◽  
Screen Test ◽  
Brain Regions ◽  
Seizure Threshold ◽  
Brain Delivery ◽  
Intranasal Delivery ◽  
Behavioral Impairment ◽  
Loss Of Righting Reflex ◽  
Ptz Test ◽  
Central Nervous System Activity

AbstractAllopregnanolone, a positive modulator of GABAA receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED50, 5.6 mg/kg), picrotoxin (ED50, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a Tmax of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (Cmax, 16,000 ng/mg) whereas much lower levels (Cmax, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.

Comparison of Subthalamic Nucleus and Globus Pallidus Deep Brain Stimulation in Parkinson’s Disease: A Systematic Review

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Azari H ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Adverse Effects ◽  
Globus Pallidus ◽  
Subthalamic Nucleus ◽  
Brain Stimulation ◽  
Stn Dbs ◽  
Deep Brain

Background: Deep Brain Stimulation (DBS) is regarded as a viable therapeutic choice for Parkinson’s Disease (PD). The two most common sites for DBS are the Subthalamic Nucleus (STN) and Globus Pallidus (GPi). In this study, the clinical effectiveness of these two targets was compared. Methods: A systematic literature search in electronic databases were restricted to English language publications 2010 to 2021. Specified MeSH terms were searched in all databases. Studies that evaluated the Unified Parkinson’s Disease Rating Scale (UPDRS) III were selected by meeting the following criteria: (1) had at least three months follow-up period; (2) compared both GPi and STN DBS; (3) at least five participants in each group; (4) conducted after 2010. Study quality assessment was performed using the Modified Jadad Scale. Results: 3577 potentially relevant articles were identified 3569 were excluded based on title and abstract, duplicate and unsuitable article removal. Eight articles satisfied the inclusion criteria and were scrutinized (458 PD patients). Majority of studies reported no statistically significant between-group difference for improvements in UPDRS III scores. Conclusions: Although there were some results in terms of action tremor, rigidity, and urinary symptoms, which indicated that STN DBS might be a better choice or regarding the adverse effects, GPi seemed better; but it cannot be concluded that one target is superior. Other larger randomized clinical trials with longer follow-up periods and control groups are needed to decide which target is more efficient for stimulation and imposes fewer adverse effects on the patients.

DIPHENYLHYDANTOIN (DILANTIN®) AFTER 20 YEARS

PEDIATRICS ◽  
1959 ◽  
Vol 23 (1) ◽  
pp. 151-161
Author(s):  
Patrick F. Bray
Keyword(s):  
Good Control ◽  
Side Reaction ◽  
Seizure Threshold ◽  
Anticonvulsant Effect ◽  
Gingival Hyperplasia ◽  
Neurologic Diseases ◽  
Anticonvulsant Medication ◽  
Number Of Patients ◽  
Adequate Dosage ◽  
The Brain

Twenty years ago diphenylhydantoin was introduced for the treatment of epilepsy. It quickly became the most useful anticonvulsant medication because it was effective in preventing seizures and its sedative effect was minimal. The treatment of 84 epileptics has been included in this report with three goals in mind: 1) to show that the drug is generally useful by itself; 2) to point out that diphenylhydantoin is superior to other anticonvulsants in some patients; and 3) to emphasize the need for adequate dosage. Progressive neurologic diseases and fixed structural lesions of the brain are present in a significant number of patients in whom good control of seizure cannot be achieved. Uncommonly one sees sensitivity reactions which are similar to the allergic responses to other medications. Toxic reactions occur frequently if one exceeds the patient's tolerance to the drug but these are readily reversible. The cause of gingival hyperplasia, which is an annoying and common side reaction, was discussed in detail. It seems most likely that this reaction is due primarily to a local toxic effect of diphenylhydantoin as it is secreted in the saliva. The mechanism of action of diphenylhydantoin was discussed in the light of recent and relevant research. The effect of the drug in animals on seizure patterns, seizure threshold and concentration of electrolytes in the brain was reviewed. The basic clue to its primary anticonvulsant effect may be its ability to produce a shift of sodium from inside the cells of the brain to the extracellular space. Other metabolic and humoral effects of diphenylhydantoin were cited and these include its relationship to the pituitary-adrenal system, its ability to lower the permeability of the blood-brain barrier, and its property of increasing the concentration of serotonin in brain tissue. The important anticonvulsants which have been introduced since the advent of diphenylhydantoin were reviewed and emphasis was placed upon the usefulness and limitations in comparison to diphenylhydantoin.

Anticonvulsant effect of minocycline on pentylenetetrazole-induced seizure in mice: involvement of nitric oxide and N-methyl-d-aspartate receptor

2018 ◽  
Vol 96 (8) ◽  
pp. 742-750 ◽  
Author(s):  
Hossein Amini-Khoei ◽  
Nastaran Kordjazy ◽  
Arvin Haj-Mirzaian ◽  
Shayan Amiri ◽  
Arya Haj-Mirzaian ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nmda Receptor ◽  
Seizure Threshold ◽  
Anticonvulsant Effect ◽  
Acute Administration ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Nitrite Level ◽  
Nos Inhibitor ◽  
Neuronal Nos

Anticonvulsant effects of minocycline have been explored recently. This study was designed to examine the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole-induced seizures in mouse considering the possible role of the nitric oxide/N-methyl-d-aspartate (NMDA) pathway. We induced seizure using intravenous administration of pentylenetetrazole. Our results showed that acute administration of minocycline increased the seizure threshold. Furthermore, co-administration of subeffective doses of the nonselective nitric oxide synthase (NOS) inhibitor NG-l-arginine methyl ester (10 mg/kg) and the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg) enhanced the anticonvulsant effect of subeffective doses of minocycline (40 mg/kg). We found that inducible NOS inhibitor aminoguanidine (100 mg/kg) had no effect on the antiseizure effect of minocycline. Moreover, l-arginine (60 mg/kg), as a NOS substrate, reduced the anticonvulsant effect of minocycline. We also demonstrated that pretreatment with the NMDA receptor antagonists ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg) increased the anticonvulsant effect of subeffective doses of minocycline. Results showed that minocycline significantly decreased the hippocampal nitrite level. Furthermore, co-administration of a neuronal NOS inhibitor like NMDA receptor antagonists augmented the effect of minocycline on the hippocampal nitrite level. In conclusion, we revealed that anticonvulsant effect of minocycline might be, at least in part, due to a decline in constitutive hippocampal nitric oxide activity as well as inhibition of NMDA receptors.

Anticonvulsant effect of A1 but not A2A adenosine receptors of piriform cortex in amygdala-kindled rats

2007 ◽  
Vol 85 (6) ◽  
pp. 606-612 ◽  
Author(s):  
Mohammad Ebrahim Rezvani ◽  
Javad Mirnajafi-Zadeh ◽  
Yaghoub Fathollahi ◽  
Mohammad Reza Palizvan
Keyword(s):  
Electrical Stimulation ◽  
Adenosine Receptors ◽  
Piriform Cortex ◽  
Anticonvulsant Effect ◽  
Seizure Duration ◽  
A2a Adenosine Receptors ◽  
Stage 4 ◽  
Kindled Seizures ◽  
Anticonvulsant Effects ◽  
Stimulation Of

In this study, the effect of A1 and A2A adenosine receptor activity of the piriform cortex (PC) on amygdala-kindled seizures was investigated in rats. Animals were kindled by daily electrical stimulation of the amygdala. In fully kindled rats, N6-cyclohexyladenosine (CHA, a selective A1 agonist), 8-cyclopentyl-1,3-dimethylxanthine (CPT, a selective A1 antagonist), CGS21680 hydrochloride (CGS, a selective A2A agonist), and ZM241385 (ZM, a selective A2A antagonist) were microinjected bilaterally into the PC. Rats were stimulated 5 min post-drug microinjection and seizure parameters were measured. Results showed that intra-PC CHA (10 and 100 μmol/L) decreased the duration of both afterdischarge and stage 5 seizure and significantly increased the latency to stage 4 seizure. Intra-PC CPT increased afterdischarge and stage 5 seizure duration at the dose of 20 μmol/L. The anticonvulsant effect of CHA (100 μmol/L) was eliminated by CPT (10 μmol/L) pretreatment. On the other hand, neither intra-PC CGS nor ZM had a significant effect on kindled seizures. These results suggest that activity of A1, but not A2A, receptors of the PC have anticonvulsant effects on kindled seizures elicited from electrical stimulation of the amygdala.

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