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Cellular and Molecular Life Sciences :... Apr 2023The pharmacological activation of the GPR39 receptor has been proposed as a novel strategy for treating seizures; however, this hypothesis has not been verified...
TC-G 1008 facilitates epileptogenesis by acting selectively at the GPR39 receptor but non-selectively activates CREB in the hippocampus of pentylenetetrazole-kindled mice.
The pharmacological activation of the GPR39 receptor has been proposed as a novel strategy for treating seizures; however, this hypothesis has not been verified experimentally. TC-G 1008 is a small molecule agonist increasingly used to study GPR39 receptor function but has not been validated using gene knockout. Our aim was to assess whether TC-G 1008 produces anti-seizure/anti-epileptogenic effects in vivo and whether the effects are mediated by GPR39. To obtain this goal we utilized various animal models of seizures/epileptogenesis and GPR39 knockout mice model. Generally, TC-G 1008 exacerbated behavioral seizures. Furthermore, it increased the mean duration of local field potential recordings in response to pentylenetetrazole (PTZ) in zebrafish larvae. It facilitated the development of epileptogenesis in the PTZ-induced kindling model of epilepsy in mice. We demonstrated that TC-G 1008 aggravated PTZ-epileptogenesis by selectively acting at GPR39. However, a concomitant analysis of the downstream effects on the cyclic-AMP-response element binding protein in the hippocampus of GPR39 knockout mice suggested that the molecule also acts via other targets. Our data argue against GPR39 activation being a viable therapeutic strategy for treating epilepsy and suggest investigating whether TC-G 1008 is a selective agonist of the GPR39 receptor.
Topics: Animals; Mice; Brain-Derived Neurotrophic Factor; Epilepsy; Hippocampus; Mice, Knockout; Pentylenetetrazole; Receptors, G-Protein-Coupled; Zebrafish
PubMed: 37185787
DOI: 10.1007/s00018-023-04766-z -
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 -
Molecules (Basel, Switzerland) May 2022Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to...
Evaluation of Neurotropic Activity and Molecular Docking Study of New Derivatives of pyrano[4″,3″:4',5']pyrido[3',2':4,5]thieno[3,2-]pyrimidines on the Basis of pyrano[3,4-]pyridines.
BACKGROUND
Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem.
METHODS
Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used.
RESULTS
As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the "open field" and "elevated plus maze" (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3-]pyridines and tetracyclic pyridothieno[3,2-]pyrimidin-8-ones, especially pronounced in compounds - and . The studied compounds increase the latent time of first immobilization on the "forced swimming" (FS) model and exhibit antidepressant effects; compounds and especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds and bound tightly in the active site of γ-aminobutyric acid type A (GABA) receptors with a value of the scoring function that estimates free energy of binding (∆G) at -10.0 ± 5 kcal/mol. Compound showed the best affinity ((∆G) at -11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds - and practically bound with the groove of T4L of 5HT_1A and blocked it completely, while the best affinity observed was in compound ((∆G) at -9.3 ± 0.46 kcal/mol).
CONCLUSIONS
The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects.
Topics: Anti-Anxiety Agents; Anticonvulsants; Antidepressive Agents; Molecular Docking Simulation; Pentylenetetrazole; Pyridines; Pyrimidines; Receptors, GABA-A; Structure-Activity Relationship
PubMed: 35684318
DOI: 10.3390/molecules27113380 -
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 -
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 -
Neuroscience and Biobehavioral Reviews Oct 2014Excess inhibition in the brain of individuals carrying an extra copy of chromosome 21 could be responsible for cognitive deficits observed throughout their lives. A... (Review)
Review
Excess inhibition in the brain of individuals carrying an extra copy of chromosome 21 could be responsible for cognitive deficits observed throughout their lives. A change in the excitatory/inhibitory balance in adulthood would alter synaptic plasticity, potentially triggering learning and memory deficits. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system and binds to GABAA receptors, opens a chloride channel, and reduces neuronal excitability. In this review we discuss methods to alleviate neuronal inhibition in a mouse model of Down syndrome, the Ts65Dn mouse, using either an antagonist (pentylenetetrazol) or two different inverse agonists selective for the α5-subunit containing receptor. Both inverse agonists, which reduce inhibitory GABAergic transmission, could rescue learning and memory deficits in Ts65Dn mice. We also discuss safety issues since modulation of the excitatory-inhibitory balance to improve cognition without inducing seizures remains particularly difficult when using GABA antagonists.
Topics: Animals; Benzodiazepines; Down Syndrome; Drug Inverse Agonism; GABA-A Receptor Antagonists; Humans; Imidazoles; Neural Inhibition; Nootropic Agents; Pentylenetetrazole; Receptors, GABA-A
PubMed: 24412222
DOI: 10.1016/j.neubiorev.2013.12.008 -
Brain : a Journal of Neurology Mar 2022The risk of seizures is 10-fold higher in patients with Alzheimer's disease than the general population, yet the mechanisms underlying this susceptibility and the...
The risk of seizures is 10-fold higher in patients with Alzheimer's disease than the general population, yet the mechanisms underlying this susceptibility and the effects of these seizures are poorly understood. To elucidate the proposed bidirectional relationship between Alzheimer's disease and seizures, we studied human brain samples (n = 34) from patients with Alzheimer's disease and found that those with a history of seizures (n = 14) had increased amyloid-β and tau pathology, with upregulation of the mechanistic target of rapamycin (mTOR) pathway, compared with patients without a known history of seizures (n = 20). To establish whether seizures accelerate the progression of Alzheimer's disease, we induced chronic hyperexcitability in the five times familial Alzheimer's disease mouse model by kindling with the chemoconvulsant pentylenetetrazol and observed that the mouse model exhibited more severe seizures than the wild-type. Furthermore, kindled seizures exacerbated later cognitive impairment, Alzheimer's disease neuropathology and mTOR complex 1 activation. Finally, we demonstrated that the administration of the mTOR inhibitor rapamycin following kindled seizures rescued enhanced remote and long-term memory deficits associated with earlier kindling and prevented seizure-induced increases in Alzheimer's disease neuropathology. These data demonstrated an important link between chronic hyperexcitability and progressive Alzheimer's disease pathology and suggest a mechanism whereby rapamycin may serve as an adjunct therapy to attenuate progression of the disease.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Humans; Mechanistic Target of Rapamycin Complex 1; Mice; Pentylenetetrazole; Seizures
PubMed: 34264340
DOI: 10.1093/brain/awab268 -
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 -
Environmental Science and Pollution... Jul 2022Epilepsy is one of the most common serious brain disorders, affecting about 1% of the population all over the world. Ginkgo biloba extract (GbE) and L-carnitine (LC)...
Epilepsy is one of the most common serious brain disorders, affecting about 1% of the population all over the world. Ginkgo biloba extract (GbE) and L-carnitine (LC) reportedly possess the antioxidative activity and neuroprotective potential. In this report, we investigated the possible protective and therapeutic effects of GbE and LC against pentylenetetrazol (PTZ)-induced epileptic seizures in rat hippocampus and hypothalamus. Adult male albino rats were equally divided into eight groups: control, GbE (100 mg/kg), LC (300 mg/kg), PTZ (40 mg/kg), protective groups (GbE + PTZ and LC + PTZ), and therapeutic groups (PTZ + GbE and PTZ + LC). The oxidative stress, antioxidant, and neurochemical parameters, viz., malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), acetylcholine esterase (AchE), dopamine (DA), norepinephrine (NE), and serotonin (5-HT), in the hippocampal and hypothalamic regions have been evaluated. PTZ injection leads to an increase in the seizure score, the levels of MDA and NO, and to a decrease in the activity of GSH, SOD, CAT, and GPx. Besides, monoamine neurotransmitters, DA, NE, and 5-HT, were depleted in PTZ-kindled rats. Furthermore, PTZ administration caused a significant elevation in the activity of AchE. Hippocampal and hypothalamic sections from PTZ-treated animals were characterized by severe histopathological alterations and, intensely, increased the ezrin immunolabeled astrocytes. Pre- and post-treatment of PTZ rats with GbE and LC suppressed the kindling acquisition process and remarkably alleviated all the aforementioned PTZ-induced effects. GbE and LC have potent protective and therapeutic effects against PTZ-induced kindling seizures via the amelioration of oxidative/antioxidative imbalance, neuromodulatory, and antiepileptic actions.
Topics: Animals; Male; Antioxidants; Carnitine; Epilepsy; Ginkgo biloba; Glutathione Peroxidase; Oxidative Stress; Pentylenetetrazole; Plant Extracts; Serotonin; Superoxide Dismutase; Rats
PubMed: 35194715
DOI: 10.1007/s11356-022-19251-6 -
The Journal of Toxicological Sciences Aug 1982At the onset of pentylenetetrazole induced convulsions, the adenylate cyclase activity and phosphodiesterase activity were increased. The former was markedly stimulated...
At the onset of pentylenetetrazole induced convulsions, the adenylate cyclase activity and phosphodiesterase activity were increased. The former was markedly stimulated in the brain stem of rats. In the cerebral cortex and brain stem, the glucose level was significantly decreased, and the concentration of glucose-6-phosphate was increased. However, the definite changes in energy reserve system of the brain could not be observed at the onset of penetylentetrazole induced seizures. The present study revealed some correlation between pentylenetetrazole convulsions and the adenylate cyclase activity and glycometabolism.
Topics: Adenylyl Cyclases; Animals; Brain; Energy Metabolism; Glucose; Male; Pentylenetetrazole; Phosphoric Diester Hydrolases; Rats; Rats, Inbred Strains; Seizures
PubMed: 6296419
DOI: 10.2131/jts.7.229