Therapeutic role of targeting mTOR signaling and neuroinflammation in epilepsy

Hodges, Samantha L.; Lugo, Joaquín N.

doi:10.1016/j.eplepsyres.2020.106282

Cited by 57 publications

(38 citation statements)

References 188 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While this increase could be a result of loss of neuronal homeostasis due to mitochondrial dysfunction [69], increased protein synthesis may be driven by altered mTOR signaling, which was a prominent finding in our results. mTOR signaling pathways are implicated in a number of epileptogenic processes [70]. Our results suggest increased ribosome biogenesis and protein production in chronic epilepsy.…”

Section: Discussionmentioning

confidence: 58%

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pires

Leitner

Drummond

et al. 2020

Preprint

View full text Add to dashboard Cite

Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., Sudden Unexpected Death in Epilepsy [SUDEP], accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with epilepsy, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry (MS) was performed on the hippocampal CA1-3 region, frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n=14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1-3 region, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein Subunit Beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signaling and G-protein–coupled receptors (GPCRs) in epilepsy. Our results provide insights into the molecular mechanisms underlying epilepsy, which may allow for novel targeted therapeutic strategies.

show abstract

Section: Discussionmentioning

confidence: 58%

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pires

Leitner

Drummond

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Much of the available information regarding mTOR signaling in the brain focuses on mTORC1 as a crucial regulator of neuronal excitability since its involvement in the modulation of several processes such as: (1) cerebral cortical development [65,66]; (2) protein synthesis [67,68]; (3) cell differentiation, proliferation, growth, and survival [69][70][71][72]; (4) axonal sprouting, regeneration, and myelination [73,74]; (5) glial functions [75]; (6) dendritic morphogenesis [76]; (7) ionic and receptor channel modulation [68,77,78]; and (8) some forms of neuronal plasticity such as long-term potentiation, long-term depression, learning and memory [79][80][81]. However, changes in mTORC1 activity are known to result in increases in translation, transcription, autophagy, cell signaling, metabolism and altered cytoskeleton dynamics [82,83] that have been correlated with the pathophysiological development/progression of some psychiatric diseases and neurological disorders such as depression [84,85], schizophrenia [86,87], autism [88,89], Parkinson's disease [90,91], Alzheimer's disease [92] and epilepsy [93,94], among others.…”

Section: The Mammalian Target Of Rapamycin (Mtor) Signaling Pathwaymentioning

confidence: 99%

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Zavala-Tecuapetla

Cuéllar-Herrera

Luna-Munguía

2020

IJMS

View full text Add to dashboard Cite

Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy. For this reason, it is a high priority objective in preclinical research to find novel therapeutic targets and to develop effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression. Among these potential therapeutic targets, we highlight currently available information involving signaling pathways (Wnt/β-catenin, Mammalian Target of Rapamycin (mTOR) signaling and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel) and receptors (galanin and melatonin receptors). All of them have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity and in modifying the progression of epilepsy. Although some research with these specific targets has been done in relation with epilepsy, they have not been fully explored as potential therapeutic targets that could help address the unsolved issue of drug-resistant epilepsy and develop new antiseizure therapies for the treatment of epilepsy.

show abstract

“…As noted above, some inflammatory mediators (such as IL-1β and ROS) can function through the mTOR pathway in epileptogenesis, and IL-1β has been found to participate in epilepsy by activating mTOR upstream regulators [35,42]. The mTOR pathway is critical for biological processes of the CNS, including cortical development, axonal and dendritic morphology, immune responses, neurotransmitter expression, ion channel expression, synaptic plasticity, cognition, and behavior [113,114]. Disturbance of the mTOR pathway and the subsequent abnormal state of the above biological processes can contribute to the development of epilepsy.…”

Section: Rosmentioning

confidence: 98%

The role of inflammation in epileptogenesis

Meng

Yao

2020

Acta Epileptologica

View full text Add to dashboard Cite

Epilepsy is a chronic neurological disorder that has an extensive impact on a patient’s life. Accumulating evidence has suggested that inflammation participates in the progression of spontaneous and recurrent seizures. Pro-convulsant incidences can stimulate immune cells, augment the release of pro-inflammatory cytokines, elicit neuronal excitation as well as blood-brain barrier (BBB) dysfunction, and finally trigger the generation or recurrence of seizures. Understanding the pathogenic roles of inflammatory mediators, including inflammatory cytokines, cells, and BBB, in epileptogenesis will be beneficial for the treatment of epilepsy. In this systematic review, we performed a literature search on the PubMed database using the following keywords: “epilepsy” or “seizures” or “epileptogenesis”, and “immunity” or “inflammation” or “neuroinflammation” or “damage-associated molecular patterns” or “cytokines” or “chemokines” or “adhesion molecules” or “microglia” or “astrocyte” or “blood-brain barrier”. We summarized the classic inflammatory mediators and their pathogenic effects in the pathogenesis of epilepsy, based on the most recent findings from both human and animal model studies.

show abstract

Therapeutic role of targeting mTOR signaling and neuroinflammation in epilepsy

Cited by 57 publications

References 188 publications

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

The role of inflammation in epileptogenesis

Contact Info

Product

Resources

About