Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Zavala-Tecuapetla, Cecilia; Cuéllar-Herrera, Manola; Luna-Munguía, Hiram

doi:10.3390/ijms21228573

Cited by 35 publications

(25 citation statements)

References 597 publications

(708 reference statements)

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“…Dysregulation of the classical (C1inh, C4), alternative (FH, properdin, C3) and terminal (TC) pathways also contributes to the pathogenesis of epilepsy [31]. Overexpression of various complement proteins has been demonstrated in surgically removed tissue of patients with epilepsy, as well as in rodent models [32,33].…”

Section: Epilepsy the Characteristics Of The Pathogenesis The Relationship With Inflammatory Processes Drug-resistant Epilepsymentioning

confidence: 99%

“…C3, C4, Properdin, FH, C1Inh and Clu Known as markers of epilepsy [32,33]. Components including C9, C8, C4-B are activated in patients.…”

Section: Complement Systemmentioning

confidence: 99%

“…Consequently, the complement cascade is involved in the chronic epileptic phase in animals and humans. Complement activation can promote a sustained inflammatory response and destabilize neural networks involved in the pathological process [32]. In epilepsy, both classical (C1inh, C4) and alternative (FH, properdin, C3) pathways are damaged.…”

Section: Complement Systemmentioning

confidence: 99%

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Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review

2021

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Epilepsy is a chronic neurological disorder characterized by recurring spontaneous seizures. Drug resistance appears in 30% of patients and it can lead to premature death, brain damage or a reduced quality of life. The purpose of the study was to analyze the drug resistance mechanisms, especially neuroinflammation, in the epileptogenesis. The information bases of biomedical literature Scopus, PubMed, Google Scholar and SciVerse were used. To obtain full-text documents, electronic resources of PubMed Central and Research Gate were used. The article examines the recent research of the mechanisms of drug resistance in epilepsy and discusses the hypotheses of drug resistance development (genetic, epigenetic, target hypothesis, etc.). Drug-resistant epilepsy is associated with neuroinflammatory, autoimmune and neurodegenerative processes. Neuroinflammation causes immune, pathophysiological, biochemical and psychological consequences. Focal or systemic unregulated inflammatory processes lead to the formation of aberrant neural connections and hyperexcitable neural networks. Inflammatory mediators affect the endothelium of cerebral vessels, destroy contacts between endothelial cells and induce abnormal angiogenesis (the formation of “leaky” vessels), thereby affecting the blood–brain barrier permeability. Thus, the analysis of pro-inflammatory and other components of epileptogenesis can contribute to the further development of the therapeutic treatment of drug-resistant epilepsy.

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Section: Epilepsy the Characteristics Of The Pathogenesis The Relationship With Inflammatory Processes Drug-resistant Epilepsymentioning

confidence: 99%

“…C3, C4, Properdin, FH, C1Inh and Clu Known as markers of epilepsy [32,33]. Components including C9, C8, C4-B are activated in patients.…”

Section: Complement Systemmentioning

confidence: 99%

Section: Complement Systemmentioning

confidence: 99%

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Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review

2021

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“…Emerging evidence suggests Trpv1 mediates the anticonvulsant effects of the phytocannabinoid CBD (Vilela et al, 2014;Gray et al, 2020). Moreover, Trpv1 has been characterized as a novel anticonvulsant drug target in conventional animal seizure models (Zavala-Tecuapetla et al, 2020). However, whether this channel is a viable target in animal models of drug-resistant epilepsy is unknown.…”

Section: Discussionmentioning

confidence: 99%

The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome

Janve¹,

Anderson²,

Bahceci³

et al. 2021

Front. Pharmacol.

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Cannabidiol has been approved for the treatment of drug-resistant childhood epilepsies including Dravet syndrome (DS). Although the mechanism of anticonvulsant action of cannabidiol is unknown, emerging data suggests involvement of the transient receptor potential cation channel subfamily V member 1 (Trpv1). Pharmacological and genetic studies in conventional seizure models suggest Trpv1 is a novel anticonvulsant target. However, whether targeting Trpv1 is anticonvulsant in animal models of drug-resistant epilepsies is not known. Thus, we examined whether Trpv1 affects the epilepsy phenotype of the F1.Scn1a+/− mouse model of DS. We found that cortical Trpv1 mRNA expression was increased in seizure susceptible F1.Scn1a+/− mice with a hybrid genetic background compared to seizure resistant 129.Scn1a+/− mice isogenic on 129S6/SvEvTac background, suggesting Trpv1 could be a genetic modifier. Previous studies show functional loss of Trpv1 is anticonvulsant. However, Trpv1 selective antagonist SB-705498 did not affect hyperthermia-induced seizure threshold, frequency of spontaneous seizures or survival of F1.Scn1a+/− mice. Surprisingly, Trpv1 deletion had both pro- and anti-seizure effects. Trpv1 deletion did not affect hyperthermia-induced seizure temperature thresholds of F1.Scn1a+/−; Trpv1+/− at P14-16 but was proconvulsant at P18 as it reduced seizure temperature thresholds. Conversely, Trpv1 deletion did not alter the frequency of spontaneous seizures but reduced their severity. These results suggest that Trpv1 is a modest genetic modifier of spontaneous seizure severity in the F1.Scn1a+/− model of DS. However, the opposing pro- and anti-seizure effects of Trpv1 deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS.

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“…In addition to HSP, the anti-apoptotic protein kinase B (AKT) is upregulated in resected TLE tissue, and AKT is a crucial survival factor following brain injury [24]. Activation of AKT by mammalian target of rapamycin (mTOR) signaling pathway (mTORC2) can prevent cell death caused by seizures [25,26].…”

Section: Introductionmentioning

confidence: 99%

Adenosine A1 Receptor Agonist (R-PIA) before Pilocarpine Modulates Pro- and Anti-Apoptotic Factors in an Animal Model of Epilepsy

2021

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We aimed to characterize the mechanisms involved in neuroprotection by R-PIA administered before pilocarpine-induced seizures. Caspase-1 and caspase-3 activities were assayed using fluorimetry, and cathepsin D, HSP-70, and AKT expression levels were assayed using Western Blot of hippocampal samples. R-PIA was injected before pilocarpine (PILO), and four groups were studied at 1 h 30 min and 7 days following initiation of status epilepticus (SE): PILO, R-PIA+PILO, SALINE, and R-PIA+SALINE. At 1 h 30 min, significantly higher activities of caspase-1 and -3 were observed in the PILO group than in the SALINE group. Caspase-1 and -3 activities were higher in the R-PIA+PILO group than in the PILO group. At 7 days following SE, caspase-1 and -3 activities were higher than in the initial post-seizure phase compared to the SALINE group. The pretreatment of rats receiving PILO significantly reduced caspase activities compared to the PILO group. Expression of HSP-70, AKT, and cathepsin D was significantly higher in the PILO group than in the SALINE. In the R-PIA+PILO group, the expression of AKT and HSP-70 was greater than in rats receiving only PILO, while cathepsin D presented decreased expression. Pretreatment with R-PIA in PILO-injected rats strongly inhibited caspase-1 and caspase-3 activities and cathepsin D expression. It also increased expression levels of the neuroprotective proteins HSP-70 and AKT, suggesting an important role in modulating the cellular survival cascade.

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Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Cited by 35 publications

References 597 publications

Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review

Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review

The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome

Adenosine A1 Receptor Agonist (R-PIA) before Pilocarpine Modulates Pro- and Anti-Apoptotic Factors in an Animal Model of Epilepsy

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