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[This corrects the article DOI: 10.3389/fneur.2022.1042887.].
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BACKGROUND: Noradrenergic fibers originating from the locus coeruleus densely innervate limbic structures, including the piriform cortex, which is the limbic structure with the lowest seizure threshold. Noradrenaline (NA) modulates limbic seizures while stimulating autophagy through ß2- adrenergic receptors (AR). Since autophagy is related to seizure threshold, this perspective questions whether modulating ß2-AR focally within the anterior piriform cortex affects limbic seizures. OBJECTIVE: In this perspective, we analyzed a potential role for ß2-AR as an anticonvulsant target within the anterior piriform cortex, area tempestas (AT). METHODS: We developed this perspective based on current literature on the role of NA in limbic seizures and autophagy. The perspective is also grounded on preliminary data obtained by microinfusing within AT either a ß2-AR agonist (salbutamol) or a ß2-AR antagonist (butoxamine) 5 minutes before bicuculline. RESULTS: ß2-AR stimulation fully prevents limbic seizures induced by bicuculline micro-infusion in AT. Conversely, antagonism at ß2-AR worsens bicuculline-induced seizure severity and prolongs seizure duration, leading to self-sustaining status epilepticus. These data indicate a specific role for ß2-AR as an anticonvulsant in AT. CONCLUSION: NA counteracts limbic seizures. This relies on various receptors in different brain areas. The anterior piriform cortex plays a key role in patients affected by limbic epilepsy. The anticonvulsant effects of NA through ß2-AR may be related to the stimulation of the autophagy pathway. Recent literature and present data draw a perspective where ß2-AR stimulation while stimulating autophagy mitigates limbic seizures, focally within AT. The mechanism linking ß2-AR to autophagy and seizure modulation should be extensively investigated.
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Anticonvulsivantes , Norepinefrina , Ratos , Animais , Humanos , Norepinefrina/efeitos adversos , Norepinefrina/metabolismo , Bicuculina/efeitos adversos , Ratos Sprague-Dawley , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Receptores AdrenérgicosRESUMO
Temporal lobe epilepsy is the most common form of focal epilepsy and can have various detrimental consequences within many neurologic domains. Recent evidence suggests that the piriform cortex may also be implicated in seizure physiology. The piriform cortex is a primary component of the olfactory network and is located at the junction of the frontal and temporal lobes, wrapping around the entorhinal sulcus. Similar to the hippocampus, it is a tri-layered allocortical structure, with connections to many adjacent regions including the orbitofrontal cortex, amygdala, peri- and entorhinal cortices, and insula. Both animal and human studies have implicated the piriform cortex as a critical node in the temporal lobe epilepsy network. It has additionally been shown that resection of greater than half of the piriform cortex may significantly increase the odds of achieving seizure freedom. Laser interstitial thermal therapy has also been shown to be an effective treatment strategy with recent evidence hinting that ablation of the piriform cortex may be important for seizure control as well. We propose that sampling piriform cortex in intracranial stereoelectroencephalography (sEEG) procedures with the use of a temporal pole or amygdalar electrode would be beneficial for further understanding the role of the piriform cortex in temporal lobe epilepsy.
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BACKGROUND: The piriform cortex, known as area tempestas, has a high propensity to trigger limbic epileptic seizures. Recent studies on human patients indicate that a resection containing the piriform cortex produces a marked improvement in patients suffering from intractable limbic seizures. This calls for looking back at the pharmacological and anatomical data on area tempestas. Within the piriform cortex, status epilepticus can be induced by impairing the desensitization of AMPA receptors. The mechanistic target of rapamycin complex1 (mTORC1) is a promising candidate. OBJECTIVE: The present perspective aims to link the novel role of the piriform cortex with recent evidence on the modulation of AMPA receptors under the influence of mTORC1. This is based on recent evidence and preliminary data, leading to the formulation of interaction between mTORC1 and AMPA receptors to mitigate the onset of long-lasting, self-sustaining, neurotoxic status epilepticus. METHODS: The perspective grounds its method on recent literature along with the actual experimental procedure to elicit status epilepticus from the piriform cortex and the method to administer the mTORC1 inhibitor rapamycin to mitigate seizure expression and brain damage. RESULTS: The available and present perspectives converge to show that rapamycin may disrupt the seizure circuitry initiated in the piriform cortex to mitigate seizure duration, severity, and brain damage. CONCLUSION: The perspective provides a novel scenario to understand refractory epilepsy and selfsustaining status epilepticus. It is expected to provide a beneficial outcome in patients suffering from temporal lobe epilepsy.
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Receptores de AMPA , Estado Epiléptico , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Convulsões/induzido quimicamente , Sirolimo/efeitos adversos , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/metabolismo , Serina-Treonina Quinases TOR/efeitos adversos , Serina-Treonina Quinases TOR/metabolismoRESUMO
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.
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Status epilepticus (SE) of limbic onset might cause degenerative phenomena in different brain structures, and may be associated with chronic cognitive and EEG effects. In the present study SE was evoked focally by microinfusing picomolar doses of cyclothiazide+bicuculline into the anterior extent of the piriform cortex (APC) in rats, the so-called area tempestas, an approach which allows to evaluate selectively the effects of seizure spreading through the natural anatomical circuitries up to secondary generalization. In the brain of rats submitted to SE we analyzed neuronal density, occurrence of degenerative phenomena (by Fluoro-Jade B-FJB- staining) and expression of heat shock protein-70 (HSP-70) in the piriform cortex, the hippocampus and ventromedial thalamus. We further analyzed in detail, the loss of cholinergic neurons, and the presence of FJB- and HSP-70 positive neurons in basal forebrain cholinergic areas, i.e. the medial septal nucleus (MSN, Ch1), the diagonal band of Broca (DBB, Ch2 and Ch3) and the Nucleus basalis of Meynert (NBM, Ch4). In fact, these nuclei are strictly connected with limbic structures, and play a key pivotal role in different cognitive functions and vigilance. Although recent studies begun to investigate these nuclei in experimental epilepsy and in persons with epilepsy, conflicting results were obtained so far. We showed that after severe and long-lasting, focally induced limbic SE there is a significant cell loss within all of the abovementioned cholinergic nuclei ipsi- and contra-laterally to the infusion site. In parallel, these nuclei show also FJB and heat shock protein-70 expression. Those effects vary depending on the single nucleus assessed and on the severity of the SE seizure score. We also showed the occurrence of cell loss and degenerative phenomena in limbic cortex, hippocampus and limbic thalamic areas. These novel findings show direct evidence of SE-induced neuronal damage which is solely due to seizure activity ruling out potential confounding effects produced by systemic pro-convulsant neurotoxins. A damage to basal forebrain cholinergic nuclei, which may underlie cognitive alterations, is documented for the first time in a model of SE triggered focally.
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Prosencéfalo Basal/patologia , Encéfalo/patologia , Neurônios Colinérgicos/patologia , Estado Epiléptico/patologia , Animais , Benzotiadiazinas/administração & dosagem , Bicuculina/administração & dosagem , Encéfalo/metabolismo , Proteínas de Choque Térmico HSP72/metabolismo , Masculino , Córtex Piriforme/metabolismo , Córtex Piriforme/patologia , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamenteRESUMO
Understanding neural network behavior is essential to shed light on epileptogenesis and seizure propagation. The interconnectivity and plasticity of mammalian limbic and neocortical brain regions provide the substrate for the hypersynchrony and hyperexcitability associated with seizure activity. Recurrent unprovoked seizures are the hallmark of epilepsy, and limbic epilepsy is the most common type of medically-intractable focal epilepsy in adolescents and adults that necessitates surgical evaluation. In this review, we describe the role and relationships among the piriform (PIRC), perirhinal (PRC), and entorhinal cortex (ERC) in seizure-generation and epilepsy. The inherent function, anatomy, and histological composition of these cortical regions are discussed. In addition, the neurotransmitters, intrinsic and extrinsic connections, and the interaction of these regions are described. Furthermore, we provide evidence based on clinical research and animal models that suggest that these cortical regions may act as key seizure-trigger zones and, even, epileptogenesis.
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Córtex Entorrinal/fisiopatologia , Córtex Piriforme/fisiopatologia , Convulsões/patologia , Lobo Temporal/fisiopatologia , Animais , Humanos , Rede Nervosa/fisiologiaRESUMO
It is surprising that the piriform cortex, when compared to the hippocampus, has been given relatively little significance in human epilepsy. Like the hippocampus, it has a phylogenetically preserved three-layered cortex that is vulnerable to excitotoxic injury, has broad connections to both limbic and cortical areas, and is highly epileptogenic - being critical to the kindling process. The well-known phenomenon of early olfactory auras in temporal lobe epilepsy highlights its clinical relevance in human beings. Perhaps because it is anatomically indistinct and difficult to approach surgically, as it clasps the middle cerebral artery, it has, until now, been understandably neglected. In this review, we emphasize how its unique anatomical and functional properties, as primary olfactory cortex, predispose it to involvement in focal epilepsy. From recent convergent findings in human neuroimaging, clinical epileptology, and experimental animal models, we make the case that the piriform cortex is likely to play a facilitating and amplifying role in human focal epileptogenesis, and may influence progression to epileptic intractability.
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Late seizure relapses following temporal lobectomy for drug-resistant temporal lobe epilepsy occur in 18-30% of operated-on cases, and recent evidence suggests that a significant proportion of them are due to maturation and activation of proepileptic tissue having defied initial resection and located at the vicinity of or at a short distance from its borders, usually over the posterior medial, basal temporal-occipital, and lateral temporal regions. Experimental studies in animals and functional imaging studies in humans suggest that the area tempestas, a particular region of the basal-frontal piriform cortex, is critical for kindling and initiation and propagation of seizure activity arising from different cortical foci, especially limbic ones. This case report of a patient with late seizure relapse, three years following an initially successful right temporal lobectomy for ipsilateral medial temporal sclerosis, is the first one in the literature to demonstrate interictal EEG-fMRI evidence of significant BOLD signal changes over the inferior, basal and lateral temporal and temporooccipital cortices posterior to the resection margin, plus a significant BOLD signal change over the ipsilateral basal frontal region, closely corresponding to the piriform cortex/area tempestas. Our case study provides further functional imaging evidence in support of maturation/activation of proepileptic tissue located at the vicinity of the initial temporal lobe resection in cases of late seizure relapses and suggests, in addition, a possible role for the piriform cortex/area tempestas in the relapsing process.
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The anterior piriform cortex (APC) may house the sensor for essential amino acid homeostasis in the brain. Several lines of evidence suggest that the APC is activated shortly after ingestion of an amino acid deficient diet. We examined the averaged evoked potentials elicited in the APC by stimulation of the lateral olfactory tract, in awake, behaving rats before and after feeding basal (BAS), threonine devoid (DEV), or corrected (COR) diets to determine directly whether the APC is activated after eating a DEV diet. When fed the DEV diet, the absolute values for the amplitude of the first negative wave differed by 36.8 ± 5.8% (P≤ 0.005) from that seen after eating the BAS diet. The latency to the second negative wave was altered by 17.2 ± 3.7% (P ≤ 0.02) compared with BAS. These results were seen by 3 h after introduction of the diet, and show that the APC is indeed activated after ingestion of a DEV diet. Also, the responses to COR returned to BAS levels by 3 h. This supports the hypothesis that the APC is important both for rejection of the DEV diet and for the recognition of the replenishment of the limiting amino acid by the COR diet.