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Neurotoxicity Research Feb 2018The goal of the present study was to examine the effects of N-methyl-aspartate (NMDA) receptor antagonists-memantine and ketamine and the drugs modifying the NO:cGMP...
The goal of the present study was to examine the effects of N-methyl-aspartate (NMDA) receptor antagonists-memantine and ketamine and the drugs modifying the NO:cGMP pathway-NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), the endogenous precursor of NO-L-arginine, and the guanylyl cyclase inhibitor-methylene blue (MB) on the development of sensitization to withdrawal signs precipitated after chronic, interrupted treatment with diazepam, a benzodiazepine receptor agonist, in mice. To develop the sensitization, the mice were divided into groups: continuously and sporadically (with two diazepam-free periods) treated with diazepam (15 mg/kg, sc). To precipitate the withdrawal syndrome (clonic and tonic seizures, and death), pentylenetetrazole (55 mg/kg, sc) with the benzodiazepine receptor antagonist, flumazenil (5.0 mg/kg, ip), were administered after the last injection of diazepam or saline. Memantine (2.5, 5.0 mg/kg), and ketamine (2.5, 5.0 mg/kg), L-NAME (100, 200 mg/kg) and 7-NI (20 and 40 mg/kg), L-arginine (250, 500 mg/kg) and MB (5 and 10 mg/kg) were administered ip in sporadically diazepam-treated mice during the diazepam-free periods. Our results indicated that both NMDA receptor antagonists and drugs that inhibit the NO:cGMP pathway, except L-arginine (the endogenous donor of NO), attenuated the diazepam-induced sensitization to withdrawal signs in mice. Thus, NMDA receptors and the NO:cGMP pathway are involved in the mechanisms of sensitization to benzodiazepine withdrawal.
Topics: Animals; Benzodiazepines; Cyclic GMP; Diazepam; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Substance Withdrawal Syndrome
PubMed: 28936791
DOI: 10.1007/s12640-017-9810-1 -
European Review For Medical and... Jul 2016Sambucus (S) spp. is reported to possess a variety of activities and has been used in traditional medicine for many years. In spite of CNS activity of this genus,...
OBJECTIVE
Sambucus (S) spp. is reported to possess a variety of activities and has been used in traditional medicine for many years. In spite of CNS activity of this genus, nothing is known about the anticonvulsant activity of S. nigra.
MATERIALS AND METHODS
Anticonvulsant activities of methanolic extracts of bark, fruit and leaf of S. nigra at doses of 250, 500 and 1000 mg kg-1 were determined by pentylenetetrazole (PTZ) induced and maximal electroshock (MES) induced convulsions in mice.
RESULTS
Normal saline treated mice showed tonic hind limb extension for a duration of 6.58 ± 1.24 s in MES model. Administration of extracts significantly and dose-dependently increased the delay of the onset of seizures and decreased significantly the duration of tonic hind limb extension. Bark extract at 500 and leaf extract at 1000 mg kg-1 gave 100% protection against seizures. They inhibited induction of convulsion and gave 100% protections against mortality. PTZ (100 mg kg-1) induced tonic seizures in all of the control mice. Pretreatment with leaf extract at 500 and 1000 mg kg-1 significantly decreased duration of tonic hind limb extension (p < 0.05 and p < 0.001).
CONCLUSIONS
GABA receptors were involved in epilepsy. Reduction of mortality and increase the onset of convulsion in MES model was comparable with that of diazepam. Extracts might possibly be producing an antiepileptic action by increasing the level of GABA.
Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Mice; Pentylenetetrazole; Plant Extracts; Sambucus nigra; Seizures
PubMed: 27460744
DOI: No ID Found -
Zhongguo Ying Yong Sheng Li Xue Za Zhi... Sep 2022In the present study, we determined whether the glycogen phosphorylase(GP)inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) ameliorates pentylenetetrazole (PTZ)-induced...
OBJECTIVE
In the present study, we determined whether the glycogen phosphorylase(GP)inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) ameliorates pentylenetetrazole (PTZ)-induced acute seizure, neuroinflammation and memory impairment in rats.
METHODS
In experiment 1, rats were randomly divided into the Vehicle (=5) and PTZ (=5) groups, and received intraperitoneal injection of saline or PTZ (70 mg/kg), respectively. Hippocampal tissues were collected 30 min after drug injection. Western blot was used to examine the levels of GP expression. Colorimetric assay was used to determine the levels of lactate. In experiment 2, rats were randomly divided into the Vehicle+Vehicle (=18), DAB+Vehicle (=18), Vehicle+PTZ (=19) and DAB+PTZ (=18) groups. Rats received intracerebroventricular injection of PBS or DAB (50 μg/2 μl) 15 min before receiving intraperitoneal injection of saline or PTZ (70 mg/kg). Behavioural assays and the Racine scale were used to evaluate seizure severity. Western blot was used to examine the levels of targeted protein of hippocampal tissues. Novel object recognition test was used to assess memory performance.
RESULTS
① Compared with the Vehicle group, the levels of GP and lactate in the hippocampal tissues of the PTZ group were increased significantly (both <0.01). ② Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of myoclonic body jerk latency, forelimb clonus latency and tonic-clonic seizure latency were increased significantly (all <0.01), while the duration of seizure and seizure scores were decreased significantly (both <0.01). ③ Compared with the Vehicle+Vehicle group, in the Vehicle +PTZ group, the levels of IL-1β, IL-6, TNF-α, IBA-1 and GFAP in the hippocampal tissues were increased significantly (all <0.01), and the discrimination index in the novel object recognition test was decreased significantly (<0.01). Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of IL-1β, TNF-α, IBA-1 and GFAP in the hippocampal tissues were decreased significantly (all, <0.01), while the discrimination index in the novel object recognition test was increased significantly (<0.01).
CONCLUSION
DAB ameliorates PTZ-induced seizure, neuroinflammation and memory impairment in rats, suggesting that DAB may serve as a novel agent for potential clinical treatment of epilepsy.
Topics: Animals; Rats; Anticonvulsants; Glycogen Phosphorylase; Lactates; Neuroinflammatory Diseases; Pentylenetetrazole; Seizures; Tumor Necrosis Factor-alpha
PubMed: 37088742
DOI: 10.12047/j.cjap.6283.2022.076 -
Brain Stimulation 2020Epilepsy is a neurological disorder characterized by abnormal neuron discharge, and one-third of epilepsy patients suffer from drug-resistant epilepsy (DRE). The current...
BACKGROUND
Epilepsy is a neurological disorder characterized by abnormal neuron discharge, and one-third of epilepsy patients suffer from drug-resistant epilepsy (DRE). The current management for DRE includes epileptogenic lesion resection, disconnection, and neuromodulation. Neuromodulation is achieved through invasive electrical stimulus including deep brain stimulation, vagus nerve stimulation, or responsive neurostimulation (RNS). As an alternative therapy, transcranial focused ultrasound (FUS) can transcranially and non-invasively modulate neuron activity.
OBJECTIVE
This study seeks to verify the use of FUS pulsations to suppress spikes in an acute epileptic small-animal model, and to investigate possible biological mechanisms by which FUS pulsations interfere with epileptic neuronal activity.
METHODS
The study used a total of 76 Sprague-Dawley rats. For the epilepsy model, rats were administered pentylenetetrazol (PTZ) to induce acute epileptic-like abnormal neuron discharges, followed by FUS exposure. Various ultrasound parameters were set to test the epilepsy-suppressing effect, while concurrently monitoring and analyzing electroencephalogram (EEG) signals. Animal behavior was monitored and histological examinations were conducted to evaluate the hazard posed by ultrasound exposure and the expression of neuronal activity markers. Western blotting was used to evaluate the correlation between FUS-induced epileptic suppression and the PI3K-mTOR signaling pathway.
RESULTS
We observed that FUS pulsations effectively suppressed epileptic activity and observed EEG spectrum oscillations; the spike-suppressing effect depended on the selection of ultrasound parameters and highly correlated with FUS exposure level. Expression level changes of c-Fos and GAD65 were confirmed in the cortex and hippocampus, indicating that FUS pulsations deactivated excitatory cells and activated GABAergic terminals. No tissue damage, inflammatory response, or behavioral abnormalities were observed in rats treated with FUS under these exposure parameters. We also found that the FUS pulsations down-regulated the S6 phosphorylation and decreased pAKT expression.
CONCLUSION
Our results suggest that pulsed FUS exposure effectively suppresses epileptic spikes in an acute epilepsy animal model, and finds that ultrasound pulsation interferes with neuronal activity and affects the PTZ-induced PI3K-Akt-mTOR pathway, which might help explain the mechanism underlying ultrasound-related epileptic spike control.
Topics: Animals; Cerebral Cortex; Electroencephalography; Epilepsy; Heart Rate; Hippocampus; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Ultrasonic Therapy
PubMed: 31575487
DOI: 10.1016/j.brs.2019.09.011 -
Neuropharmacology May 2020Since 1993, over 20 new anti-seizure drugs (ASDs) have been identified in well-established animal seizure and epilepsy models and subsequently demonstrated to be... (Review)
Review
Since 1993, over 20 new anti-seizure drugs (ASDs) have been identified in well-established animal seizure and epilepsy models and subsequently demonstrated to be clinically effective in double-blinded, placebo-controlled clinical trials in patients with focal onset seizures. All clinically-available ASDs on the market today are effective in at least one of only three preclinical seizure and epilepsy models: the acute maximal electroshock (MES), the acute subcutaneous pentylenetetrazol (scPTZ) test, or the kindled rodent with chronic evoked seizures. Thus, it reasons that preclinical ASD discovery does not need significant revision to successfully identify ASDs for the symptomatic treatment of epilepsy. Unfortunately, a significant need still persists for more efficacious and better tolerated ASDs. This is particularly true for those patients whose seizures remain drug resistant. This review will focus on the continued utility of the acute MES and scPTZ tests, as well as the kindled rodent for current and future ASD discovery. These are the only "clinically validated" rodent models to date and been heavily used in the search for novel and more efficacious ASDs. This is to say that promising ASDs have been brought to the clinic on the basis of efficacy in these particular seizure and epilepsy models alone. This review also discusses some of the inherent advantages and limitations of these models relative to existing and emerging preclinical models. It then offers insight into future efforts to develop a preclinical model that will advance a truly transformative therapy for the symptomatic treatment of difficult to treat focal onset epilepsy. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Epilepsy; Humans; Kindling, Neurologic; Pentylenetetrazole; Reproducibility of Results; Seizures
PubMed: 31469995
DOI: 10.1016/j.neuropharm.2019.107750 -
Brazilian Journal of Biology = Revista... 2021Regarding the proven anticonvulsant effect of Zhumeria majdae essential oil (ZMEO) in previous studies we were prompted to investigate the ZMEO effects on the tolerance...
Chemical composition of Zhumeria majdae essential oil and its effects on the expression of morphine withdrawal syndrome and tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice.
Regarding the proven anticonvulsant effect of Zhumeria majdae essential oil (ZMEO) in previous studies we were prompted to investigate the ZMEO effects on the tolerance to the anticonvulsant effects of morphine and the morphine withdrawal syndrome. Tolerance to the morphine anticonvulsant effect was induced in mice by subcutaneous injection of 2.5 mg/kg of morphine for 4 days. Subsequent doses of ZMEO (20 mg/kg) were used to study the expression and development of morphine tolerance. Clonidine was used as the standard drug to inhibit the morphine withdrawal syndrome symptoms. To study the ZMEO effect on withdrawal syndrome, mice received appropriate morphine values for 4 days and on the fifth day, 60 min before administration of naloxone. The effective dose of ZMEO was determined and the number of jumps, stands and changes in the dry stool weight, as symptoms of withdrawal syndrome were evaluated. The dose of 20 mg/kg of ZMEO decreased the tolerance in development and expression groups significantly. Counting the number of jumping, standing and defecation were assessed 30 min after morphine and 1 h after the vehicle and clonidine. The dose of 40 mg/kg ZMEO decreased all the signs of withdrawal syndrome significantly. ZMEO was analyzed by GC/MS and linalool (53.1%) and camphor (23.8%) were characterized as the main components. The results suggest that ZMEO possesses constituent(s) that have activity against tolerance to the anticonvulsant effects of morphine and the morphine withdrawal symptoms.
Topics: Animals; Anticonvulsants; Mice; Morphine; Oils, Volatile; Pentylenetetrazole; Seizures; Substance Withdrawal Syndrome
PubMed: 33053122
DOI: 10.1590/1519-6984.228825 -
Neuroscience Letters Jan 2021Epilepsy is a chronic neurological condition that affects 1%-2% of the world population. Although research about the disease is advancing and a wide variety of drugs is...
Epilepsy is a chronic neurological condition that affects 1%-2% of the world population. Although research about the disease is advancing and a wide variety of drugs is available, about 30 % of patients have refractory epilepsy which cannot be controlled with the most common drugs. This highlights the need for a better understanding of the disorder and new types of treatment for it. Against this backdrop, a growing body of evidence has reported that inflammation may play a role both in the origin and in the progression of seizures. It has shown a tendency to be both the root and the result of epilepsy. This investigation aimed to assess the impact of prednisolone, a steroidal anti-inflammatory drug, in an animal model of pentylenetetrazole (PTZ)-induced seizures, at 1 mg/kg and 5 mg/kg doses. We also examined the degree of seizure severity and the modulation of pro-inflammatory cytokines in the treated animals. Four treatment groups were used (saline, diazepam, prednisolone 1 mg/kg, and prednisolone 5 mg/kg) and, in addition to their own daily treatments, subconvulsant doses of pentylenetetrazole (25 mg/kg) were administered every other day during a test protocol that lasted 14 days. After treatment, the cytokines interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) were measured in the animals' sera, hippocampi, and prefrontal cortices. Animals treated with prednisolone presented less severe seizures than the animals in the saline group, and there was a decrease in pro-inflammatory cytokine levels in central structures, but not peripheral ones. In short, an animal model of chemically-induced epileptic seizures was used, in which the animals were treated with doses of prednisolone, and these animals presented less severe seizures than the negative control group (saline), in addition to showing decreased levels of pro-inflammatory cytokines IL-6, IL-1β and TNF-α, in the hippocampi and prefrontal cortices, but not the sera.
Topics: Animals; Anti-Inflammatory Agents; Brain; Inflammation Mediators; Locomotion; Male; Pentylenetetrazole; Prednisolone; Rats; Rats, Wistar; Seizures; Treatment Outcome
PubMed: 33359047
DOI: 10.1016/j.neulet.2020.135560 -
Epilepsia Apr 2022As a key member of the transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability....
OBJECTIVE
As a key member of the transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability. Ablation of TRPC3 lessens pilocarpine-induced seizures in mice, suggesting that TRPC3 inhibition might represent a novel antiseizure strategy. Among current TRPC3 inhibitors, pyrazole 3 (Pyr3) is most selective and potent. However, Pyr3 only provides limited benefits in pilocarpine-treated mice, likely due to its low metabolic stability and potential toxicity. We recently reported a modified pyrazole compound 20 (or JW-65) that has improved stability and safety. The objective of this study was to explore the effects of TRPC3 inhibition by our current lead compound JW-65 on seizure susceptibility.
METHODS
We first examined the pharmacokinetic properties including plasma half-life and brain to plasma ratio of JW-65 after systemic administration in mice. We then investigated the effects of TRPC3 inhibition by JW-65 on behavioral and electrographic seizures in mice treated with pilocarpine. To ensure our findings are not model specific, we assessed the susceptibility of JW-65-treated mice to pentylenetetrazole (PTZ)-induced seizures with phenytoin as a comparator.
RESULTS
JW-65 showed adequate half-life and brain penetration in mice, justifying its use for central nervous system conditions. Systemic treatment with JW-65 before pilocarpine injection in mice markedly impaired the initiation of behavioral seizures. This antiseizure action was recapitulated when JW-65 was administered after pilocarpine-induced behavioral seizures were well established and was confirmed by time-locked electroencephalographic monitoring and synchronized video. Moreover, JW-65-treated mice showed substantially decreased susceptibility to PTZ-induced seizures in a dose-dependent manner.
SIGNIFICANCE
These results suggest that pharmacological inhibition of the TRPC3 channels by our novel compound JW-65 might represent a new antiseizure strategy engaging a previously undrugged mechanism of action. Hence, this proof-of-concept study establishes TRPC3 as a novel feasible therapeutic target for the treatment of some forms of epilepsy.
Topics: Animals; Disease Models, Animal; Mice; Pentylenetetrazole; Pilocarpine; Pyrazoles; Seizures
PubMed: 35179226
DOI: 10.1111/epi.17190 -
Molecules (Basel, Switzerland) Oct 2015Stereoisomers of the monoterpene epoxycarvone (EC), namely (+)-cis-EC, (-)-cis-EC, (+)-trans-EC, and (-)-trans-EC, were comparatively evaluated for anticonvulsant...
Stereoisomers of the monoterpene epoxycarvone (EC), namely (+)-cis-EC, (-)-cis-EC, (+)-trans-EC, and (-)-trans-EC, were comparatively evaluated for anticonvulsant activity in specific methodologies. In the pentylenetetrazole (PTZ)-induced anticonvulsant test, all of the stereoisomers (at 300 mg/kg) increased the latency to seizure onset, and afforded 100% protection against the death of the animals. In the maximal electroshock-induced seizures (MES) test, prevention of tonic seizures was also verified for all of the isomers tested. However, the isomeric forms (+) and (-)-trans-EC showed 25% and 12.5% inhibition of convulsions, respectively. In the pilocarpine-induced seizures test, all stereoisomers demonstrated an anticonvulsant profile, yet the stereoisomers (+) and (-)-trans-EC (at 300 mg/kg) showed a more pronounced effect. A strychnine-induced anticonvulsant test was performed, and none of the stereoisomers significantly increased the latency to onset of convulsions; the stereoisomers probably do not act in this pathway. However, the stereoisomers (+)-cis-EC and (+)-trans-EC greatly increased the latency to death of the animals, thus presenting some protection. The four EC stereoisomers show promise for anticonvulsant activity, an effect emphasized in the isomers (+)-cis-EC, (+)-trans-EC, and (-)-trans-EC for certain parameters of the tested methodologies. These results serve as support for further research and development of antiepileptic drugs from monoterpenes.
Topics: Animals; Anticonvulsants; Cyclohexane Monoterpenes; Electroshock; Male; Mice; Molecular Structure; Monoterpenes; Pentylenetetrazole; Seizures; Stereoisomerism; Strychnine
PubMed: 26528962
DOI: 10.3390/molecules201119649 -
Molecules (Basel, Switzerland) Mar 2020The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy....
The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1-10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.
Topics: Animals; Diterpenes, Clerodane; Drug Evaluation, Preclinical; Electroshock; Injections, Intravenous; Male; Mice; Muscle, Skeletal; Pentylenetetrazole; Seizures
PubMed: 32155979
DOI: 10.3390/molecules25051204