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Baseline activity and KA-induced seizure event in the medial septum (MS), hippocampus (Hip), entorhinal cortex (Ent) and amygdala (BA). (A, B) Local field potentials and (C-F) respective spectrograms showing the short-time Fourier transform of the activity before (A, C, E) and 20 min after the KA injection (B, D, F).
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Status epilepticus (SE) is a medical emergency associated with a high rate of mortality if not treated promptly. Exogenous and endogenous cannabinoids have been shown to possess anticonvulsant properties both in vivo and in vitro. Here we study the influence of endocannabinoid metabolism on the development of kainic acid-induced SE in guinea pigs....
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... baseline values (Fig. 1A, Table S1). Changes in the LFPs were accompanied by slight anxiety in the behavior of the animals. In our previous studies we have seen that administration of saline also induced short-time decrease in the LFP power (Sinelnikova, 2012). Overall, these observations demonstrate that changes of LFPs observed after the i.c.v. (Fig. 2B, Video 3). Baseline activity never manifested electrographic or behavioral seizures ( Fig. 2A). High-frequency oscillations were most prominent in the hippocampus and entorhinal cortex, whereas the medial septum and amygdala exhibited low-amplitude, low-frequency paroxysmal bursts (Fig. 2D and F). A wider frequency range compared with the other ...
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... the behavior of the animals. In our previous studies we have seen that administration of saline also induced short-time decrease in the LFP power (Sinelnikova, 2012). Overall, these observations demonstrate that changes of LFPs observed after the i.c.v. (Fig. 2B, Video 3). Baseline activity never manifested electrographic or behavioral seizures ( Fig. 2A). High-frequency oscillations were most prominent in the hippocampus and entorhinal cortex, whereas the medial septum and amygdala exhibited low-amplitude, low-frequency paroxysmal bursts (Fig. 2D and F). A wider frequency range compared with the other recorded brain structures was characteristic for both hippocampal baseline and ...
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... that changes of LFPs observed after the i.c.v. (Fig. 2B, Video 3). Baseline activity never manifested electrographic or behavioral seizures ( Fig. 2A). High-frequency oscillations were most prominent in the hippocampus and entorhinal cortex, whereas the medial septum and amygdala exhibited low-amplitude, low-frequency paroxysmal bursts (Fig. 2D and F). A wider frequency range compared with the other recorded brain structures was characteristic for both hippocampal baseline and seizure activity (Fig. 2C-F, Video 3). Generally, secondarily generated seizure discharges were seen predominantly in the entorhinal cortex 2-3 s after the seizure events (Fig. S1). Electrographic seizures ...
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... High-frequency oscillations were most prominent in the hippocampus and entorhinal cortex, whereas the medial septum and amygdala exhibited low-amplitude, low-frequency paroxysmal bursts (Fig. 2D and F). A wider frequency range compared with the other recorded brain structures was characteristic for both hippocampal baseline and seizure activity (Fig. 2C-F, Video 3). Generally, secondarily generated seizure discharges were seen predominantly in the entorhinal cortex 2-3 s after the seizure events (Fig. S1). Electrographic seizures were rarely accompanied by behavioral manifestations stronger than freezing, chewing, isolated twitches or unilateral forelimb clonus (stages 1-3). Usually, motor ...
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... A special study showed that THC in 100% of cases provided a reduction in the intensity of seizures, while phenobarbital and diphenylhydantoin did not [143]. Facts were obtained that demonstrated the neuroprotective influence of cannabinoid drugs and their anticonvulsant effect in the development of acute seizure activity (143,147,(149)(150)(151)(152)(153)(154). ...
... The blockers of eCB inactivation (AM404 and URB597) significantly weakened status epilepticus, reducing its behavioral manifestations and the duration of seizures [153]. In addition, the use of these modulators led to a weakening of brain pathological manifestations in the chronic kainic acid model of TLE: a decrease or complete elimination of disturbances of electrical activity, damage to and/or death of cells, and the reorganization of hippocampal neural networks [153,158,159]. ...
... The blockers of eCB inactivation (AM404 and URB597) significantly weakened status epilepticus, reducing its behavioral manifestations and the duration of seizures [153]. In addition, the use of these modulators led to a weakening of brain pathological manifestations in the chronic kainic acid model of TLE: a decrease or complete elimination of disturbances of electrical activity, damage to and/or death of cells, and the reorganization of hippocampal neural networks [153,158,159]. As mentioned above, the enhancement of eCB signaling can stop the onset of seizures. ...
Cognitive functions are based on neuronal plasticity, which is provided by various mechanisms involving numerous bioactive molecules, the most important of which are endocannabinoids (eCBs). Over the past three decades, a lot of data have been accumulated on the involvement of eCBs in the mechanisms of memory and other cognitive functions. These functions are impaired in neurodegenerative diseases such as Alzheimer's disease (AD) and temporal lobe epilepsy (TLE). The main pathological feature of neurons in AD and TLE is increased excitability; therefore, an activation of the endocannabinoid system, which controls cellular excitation, may be a promising approach in their therapy. The available information about the effect of (endo)cannabinoids on cognitive functions is contradictory, which may depend on the drugs used, their dose, and the experimental conditions. There is an extensive literature indicating a protective effect of cannabinoids in the treatment of neurodegenerative diseases in humans and in animal models of cognitive deficits. This review, focusing on the recent researches, is devoted to the analysis of the effects of endocannabinoid system activation on cognitive functions in norm and in the brain with neurodegeneration that occurs in AD and TLE diseases. Possible reasons for inconsistencies in the available data are discussed.
... For example, both the patients with epilepsy and experimental animals treated by ketogenic diet showed a decrease of serum AA concentrations and reduce in seizure severity (Dahlin et al. 2007;Porta et al. 2009a, b;Zibell et al. 2009). Inhibition of endocannabinoid metabolism attenuated kainic acid-induced SE (Shubina et al. 2015), and inhibition of COX-2, a major inflammatory mediator, plays a role in the control of seizure activities by ameliorating deleterious consequences of neurological injury resulting from epileptic seizures (Rojas et al. 2019;Zibell et al. 2009), and thus the COX-2 enzyme is believed to be a potential therapeutic target for epilepsy (Rojas et al. 2014). However, some conflicting data suggest that COX-2 inhibition did not play protective effects on epileptic seizures (Holtman et al. 2009), and even led to an increased number of seizures ). ...
Arachidonic acid (AA), a polyunsaturated fatty acid, is involved in the modulation of neuronal excitability in the brain. Arachidonate lipoxygenase 3 (ALOXE3), a critical enzyme in the AA metabolic pathway, catalyzes the derivate of AA into hepoxilins. However, the expression pattern of ALOXE3 and its role in the brain has not been described until now. Here we showed that the levels of Aloxe3 mRNA and protein kept increasing since birth and reached the highest level at postnatal day 30 in the mouse hippocampus and temporal cortex. Histomorphological analyses indicated that ALOXE3 was enriched in adult hippocampus, somatosensory cortex and striatum. The distribution was restricted to the neurites of function-specific subregions, such as mossy fibre connecting hilus and CA3 neurons, termini of Schaffer collateral projections, and the layers III and IV of somatosensory cortex. The spatiotemporal expression pattern of ALOXE3 suggests its potential role in the modulation of neural excitability and seizure susceptibility. In fact, decreased expression of ALOXE3 and elevated concentration of AA in the hippocampus was found after status epilepticus (SE) induced by pilocarpine. Local overexpression of ALOXE3 via adeno-associated virus gene transfer restored the elevated AA level induced by SE, alleviated seizure severities by increasing the latencies to myclonic switch, clonic convulsions and tonic hindlimb extensions, and decreased the mortality rate in the pilocarpine-induced SE model. These results suggest that the expression of ALOXE3 is a crucial regulator of AA metabolism in brain, and potentially acts as a regulator of neural excitability, thereby controlling brain development and seizure susceptibility.
... Animal experiments yielded facts demonstrating the anticonvulsant and neuroprotective actions of cannabinoid formulations in the development of acute convulsive activity [Wallace et al., 2003;Shubina and Kichigina, 2011;Shubina, 2015;Shubina et al., 2015;Malkova et al., 2018) and the development of chronic impairments in models of temporal epilepsy [Suleymanova et al., 2016]. Recent studies have shown that subchronic systemic administration of PEA, an endogenous analog of AEA, signifi cantly decreased convulsion intensity, had neuroprotective effects, and induced modulation of EC in plasma and the hippocampus in a kainate model of TE in mice [Post et al., 2018]. ...
Cannabinoids are natural compounds found in the hemp (Cannabis sativa). Scientific interest in cannabinoids arose after the discovery of the major psychoactive component in hemp, Δ9-tetrahydrocannabinol. Subsequent studies detected receptors in the brain subject to the actions of this compound, along with ligands for these receptors, i.e., endogenous cannabinoids (EC), which make up, along with the enzymes synthesizing, transporting, and degrading them, the endocannabinoid system (ECS). Interest in EC has consistently increased in recent years, especially after their important role in cognitive functions was discovered. They are regulators of synaptic transmission in the brain, mediate numerous forms of plasticity, and control neuron energy metabolism. EC exert influences using a series of mechanisms and interactions with neuromediators, neurotrophic factors, and neuropeptides. The main functions of EC in the brain are retrograde synaptic signaling and neuromodulation, which maintain cellular homeostasis. Information on the influences of cannabinoid drugs on cognitive functions is very contradictory. The cause of this may be that there are still inadequate strictly scientific data from clinical and sociological studies, while in animal experiments different authors use different methods and approaches for actions on the ECS. Thus, effects can differ depending on the substances used, their doses, and routes of administration, and the tasks and experimental conditions selected for testing. There is an extensive literature on the protective effect of ECS activation in neurodegenerative diseases in humans and models of cognitive deficit in animals. This review addresses data providing evidence of the influences of cannabinoid drugs and activation of the EC system on cognitive functions in the normal brain and in neurodegenerative diseases, Alzheimer’s disease, and temporal epilepsy. The possible causes of contradictions in existing data are also discussed.
... During the electrical recording, behavior of the animals was controlled visually and monitored with a video system. To identify KA-induced SE, the modified Racine Scale (Racine, 1972) adapted for guinea pigs (Shubina et al., 2015) was used. Stages 4-5 (tonic-clonic seizures, anticlockwise exploration with postural loss and falling) were identified as developed SE. ...
... Microinjection of KA (0.4 lg, i.c.v.) induced prominent convulsive SE lasting several hours (Shubina et al., 2015). Two to three minutes after the KA injection, animals showed freezing, chewing, facial movements accompanied by lowamplitude high-frequency activity in the hippocampus and/ or the entorhinal cortex. ...
Background/Introduction: Despite the fact that brain rhythms are widely studied and officially classified, there is no consensus on their relationship, which can shed light on the genesis of rhythmic activity, its synchronization, functional role, and the formation of pathological reactions. Using the experimental status epilepticus (SE) as a model of brain in a hypersynchronized state with well-defined rhythms, we aimed to study the relationship between the rhythmic components of the brain electrical activity.
Methods:
Local field potentials (LFP) were recorded simultaneously from the hippocampus, entorhinal cortex, medial septum and amygdala during normal conditions and after kainic acid administration in waking guinea pigs. The dynamical spectral LFP properties were analysed with the aid of Fast Fourier transform.
Results:
Kainic acid induces prominent SE with periodic combination of epileptiform discharge complexes and relatively quiet interdischarge intervals in the electrical activity of the brain. We have shown that new components appeared in the LFP spectra during the development of SE, representing a sequential doubling of the frequency, which had initially been dominating in the background records.
Discussion:
The phenomenon of frequency doubling can be interpreted as the octave principle of the LFP spectrum rhythmic carcass structure. The spectra of discharge complexes represent an alternation of harmonic spectra, where fundamental frequency coincides with one of the doubled frequencies dominating in the interdischarge activity. Using a nonlinear recurrent operation of rhythm multiplication and the obtained data we propose an operational model of the generation of rhythms and pathological discharges in the brain based on the octave principle.
... Anandamide and 2-AG are released after neuronal hyperexcitability to counteract glutamate excitotoxicity during seizures [100]. FAAH inhibitors protected against seizures induced by pentylenetetrazole or kainic acid [101,102]. CBD had anti-convulsant effects in the pilocarpine model of temporal lobe epilepsy via GPR55 antagonism and TRPV1 desensitization [5,[103][104]. It also rescued morphological anomalies in interneurons induced by epilepsy [105]. ...
Medical benefi ts of cannabis and related compounds is widely known. Discovery of
psychotropic plant cannabinoid Δ9-tetrahydrocannabinol have urged researchers to study more
about the cannabinoid system and related therapeutics in the fi eld of neurology and medicine.
Where activation of cannabinoid receptor type 1 (CB1R) yielded in unwanted and serious side
eff ects, discovery of cannabinoid receptor type 2 (CB2R) and its ligands gave a new hope. Till
now there is limited success in this fi eld because of complex expanded endocannabinoid system
comprising of receptors, ligands and enzymes. In this review we will update about the role of
endocannabinoidome relevant to neurological disorders.
... The presence of CB1 receptors in the rat MS indicates that the septohippocampal cholinergic transmission system is finely regulated by endocannabinoid signaling [11]. The modulatory role of endocannabinoids in the MS region has been reported on kainic acid induced status epilepticus [12]. Evidence shows that endocannabinoids in the septal nucleus modulate excitatory transmission in the hippocampus and aids in the gating of sensory information [13,14]. ...
The role of medial septum in the genesis of slow-wave sleep and the inhibition of rapid eye movement sleep has been established using neurotoxic lesion and chemical stimulation of the medial septum. Intracerebroventricular injection of endocannabinoids (anandamide) decreases wake and increases slow-wave and rapid eye movement sleep in rats. Central cannabinoid (CB1) receptors are localized in the rat medial septum; however, the role of cannabinoid receptors at the medial septum on the regulation of sleep-wakefulness in rats lacks evidence. In this study, we have examined the changes in sleep architecture of 21 male Wistar rats, divided into three groups. Initially, 6 rats were used for dose standardization. Subsequently, one group (n=6) was microinjected with CB1 receptor agonist, R-(+)-WIN 55,212-2 mesylate salt, the second group (n=6) received microinjection of CB1 receptor antagonist LY 320135, and the third group (n=5) was microinjected with the vehicle, DMSO at the medial septum using stereotaxy. The sleep-wake cycle was recorded using electroencephalogram, electro-oculogram, and electromyogram. Microinjection of CB1 receptor agonist at the medial septum decreased slow-wave sleep and increased total sleep time. The increase in total sleep time was due to an increased percentage of rapid eye movement sleep. After the third and fourth hour of CB1 receptor antagonist microinjection at the medial septum, slow-wave sleep decreased when compared to vehicle injection, while rapid eye movement sleep decreased compared to baseline. We conclude that the endocannabinoid system at the septal nucleus acts through CB1 receptors to increase rapid eye movement sleep in rats.
... 57,58 Additionally, blockade of the FAAH alleviated behavioral but not electrographic SE induced by kainic acid. 59,60 Here, we tested whether different doses of 2a (2, 5, and 10 mg/kg, i.p.) were able to affect pilocarpine-induced SE ( Figure 12). ...
Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocanna-binoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor 2a. When tested in two rodent models of epilepsy, 2a reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, 2a did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors (3a− m). Biological studies highlighted 3h and 3m as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, 3h and 3m could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for 3h (Langendorff perfused rat heart). Finally, the new analogue 3h reduced the severity of the pilocarpine-induced status epilepticus as observed for 2a.
... In a study of the effects of N-acyl dopamines on cerebral microcirculation, it was shown that they are able to increase the local blood flow in the brain tissues of rats, and exert antiaggregant effects. Neuroprotective effects of EC against glutamate excitotoxicity that J o u r n a l P r e -p r o o f occurs during the development of a number of neurodegenerative diseases, as well as in acute brain injury were also demonstrated (Bobrov et al., 2008;Shubina et al., 2015;Soltesz et al., 2015). EC affect both neurons and non-neuronal brain cells including astrocytes and oligodendrocytes (de Almeida and Martins-de-Souza, 2018;Ilyasov et al., 2018;Ruiz-Calvo et al., 2019;Saliba et al., 2018). ...
The prominent protective effects in diverse neuron injury paradigms exerted by cannabinoids and in particular their endogenously produced species render the endocannabinoid system a promising molecular target in the treatment of neurodegenerative diseases.
However, the effects of individual endocannabinoids in human cells remain poorly investigated.
Neural derivatives of human induced pluripotent stem cells (iPSC) offer unique opportunities for studying the neuroprotective compounds and development of patient-specific treatment. For the first time the cytotoxic and neuroprotective effects endocannabinoids N-arachidonoyl dopamine (N-ADA) and N-docosahexaenoyl dopamine (N-DDA) were assessed in human neural progenitors and dopamine neurons derived from iPSCs of healthy donors and patients with Parkinson’s disease. While the short-term treatment with the investigated compounds in 0.1–10 μM concentration range exerted no toxicity in these cell types, the long-term exposure to 0.1–5 μM N-ADA or N-DDA reduced the survival of human neural progenitors. At the same time, both N-ADA and N-DDA protected neural progenitors and terminally differentiated neurons both from healthy donors and patients with Parkinson’s disease against oxidative stress induced by hydrogen peroxide. The observed dramatic difference in the mode of action of N-acyl dopamines points on the possible existence of novel pathogenic mechanism of neurodegeneration induced by prolonged uncompensated production of these substances within neuronal tissue and should also be considered as a precaution in the future development of N-acyl dopamine-based therapeutic drugs.
... The endocannabinoid system has shown promise as a target for seizure control, but there are conflicting reports about the efficacy of cannabinoid (CB) receptor targeting compounds in suppressing seizures (Rosenberg et al., 2017). One of the most promising candidates are CB1 receptor agonists, which exert anticonvulsant effects against generalized tonic seizures in the maximal electroshock test (Luszczki et al., 2006;Florek-Luszczki et al., 2014b;Tutka et al., 2018), but produce mixed effects against generalized seizures evoked by pentylenetetrazole (Bahremand et al., 2008a;Andres-Mach et al., 2012;Vilela et al., 2013;Aghaei et al., 2015;Huizenga et al., 2017) and limbic seizures in the kainic acid model (Bojnik et al., 2012;Shubina et al., 2015). These models are characterized by different types of seizures: the former by tonic seizures that critically rely on brainstem networks (Merrill et al., 2003(Merrill et al., , 2005, and the later by limbic seizures that critically rely on forebrain networks (Browning et al., 1993). ...
Cannabinoid (CB) receptor agonists are of growing interest as targets for anti-seizure therapies. Here we examined the effect of systemic administration of the CB receptor agonist WIN 55,212-2 (WIN) against audiogenic seizures (AGSs) in the Genetically Epilepsy Prone Rat (GEPR)-3 strain, and against seizures evoked focally from the Area Tempestas (AT). We compared these results to the effect of focal administration of the CB1/2 receptor agonist CP 55940 into the deep layers of the superior colliculus (DLSC), a brain site expressing CB1 receptors. While systemic administration of WIN dose-dependently decreased AGS in GEPR-3s, it was without effect in the AT model. By contrast, intra-DLSC infusion of CP 55940 decreased seizures in both models. To determine if the effects of systemic WIN were dependent upon activation of CB1 receptors in the DSLC, we next microinjected the CB1 receptor antagonist SR141716, before WIN systemic treatment, and tested animals for AGS susceptibility. The pretreatment of the DLSC with SR141716 was without effect on its own and did not alter the anti-convulsant action of WIN systemic administration. Thus, while CB receptors in the DLSC are a potential site of anticonvulsant action, they are not necessary for the effects of systemically administered CB agonists.
... Evidence from multiple animal models of epilepsy has shown that the ECS is dynamically altered following acute and chronic seizures [183]. In both kainate and pilocarpine models of induced-SE, the endogenous levels of AEA and 2-AG are increased [184][185][186][187], suggesting that an on-demand release of eCBs may trigger a neuroprotective action against seizure-induced neurotoxicity. ...
... eCBs can be increased by inhibiting degrading enzymes. In fact, inhibition of FAAH by the synthetic blocker URB597, which promotes an increase in the endogenous levels of AEA, can result in reduced seizure severity, duration, and amplitude in animal models of epilepsy, as well as protecting hippocampal neurons against damage [184,[256][257][258]. However, these effects have been shown to be AEA-dose dependent. ...
Epilepsy is one of the most common brain diseases worldwide, having a huge burden in society. The main hallmark of epilepsy is the occurrence of spontaneous recurrent seizures, having a tremendous impact on the lives of the patients and of their relatives. Currently, the therapeutic strategies are mostly based on the use of antiepileptic drugs, and because several types of epilepsies are of unknown origin, a high percentage of patients are resistant to the available pharmacotherapy, continuing to experience seizures overtime. Therefore, the search for new drugs and therapeutic targets is highly important. One key aspect to be targeted is the aberrant adult hippocampal neurogenesis (AHN) derived from Neural Stem Cells (NSCs). Indeed, targeting seizure-induced AHN may reduce recurrent seizures and shed some light on the mechanisms of disease. The endocannabinoid system is a known modulator of AHN, and due to the known endogenous antiepileptic properties, it is an interesting candidate for the generation of new antiepileptic drugs. However, further studies and clinical trials are required to investigate the putative mechanisms by which cannabinoids can be used to treat epilepsy. In this manuscript, we will review how cannabinoid-induced modulation of NSCs may promote neural plasticity and whether these drugs can be used as putative antiepileptic treatment.
