An insight into crosstalk among multiple signaling pathways contributing to epileptogenesis

Gautam, Vipasha; Rawat, Kajal; Sandhu, Arushi; Kumari, Puja; Singh, Neha; Saha, Lekha

doi:10.1016/j.ejphar.2021.174469

Cited by 17 publications

(10 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar ndings were formerly reported (Abdel-Rahman et al 2013, Odenwald &Turner 2017, Wang et al 2018). GSH plays pivotal roles in the antioxidant defense system and the maintaining the redox homeostasis in neurons (Gautam et al 2021). It can suppress the production or directly reacting of free radicals by promoting the action of GPx.…”

Section: Discussionmentioning

confidence: 99%

Monosodium glutamate induces cortical oxidative, apoptotic, and inflammatory challenges in rats: the potential neuroprotective role of apigenin

Albrakati

2022

Environ Sci Pollut Res

View full text Add to dashboard Cite

Monosodium glutamate (MSG) is used as a avor, and a taste enhancer was reported to evoke marked neuronal impairments. This study investigated the neuroprotective ability of avonoid apigenin against neural damage in MSG-administered rats. Adult male rats were allocated into four groups; control, apigenin (20 mg/kg, orally), MSG (4 g/kg, orally), and apigenin + MSG at the aforementioned doses for 30 days. Regarding the levels of neurotransmitters, our results revealed that apigenin augmented the activity of acetylcholinesterase (AChE) markedly, and levels of brain monoamines (dopamine, norepinephrine, and serotonin) accompanied by lessening the activity of monoamine oxidase (MAO) as compared to MSG treatment. Moreover, apigenin counteracted the MSG-mediated oxidative stress by decreasing the malondialdehyde (MDA) levels together with elevating the glutathione (GSH) levels. In addition, pretreatment with apigenin induced notable increases in the activities of cortical superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). Further, apigenin attenuated the cortical in ammatory stress as indicated by lower levels of pro-in ammatory mediators as interleukin-1 b (IL-1b), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) as well as downregulated inducible nitric oxide synthase (iNOS) expression levels. Histopathological screening validated the abovementioned results and revealed that apigenin restored the distorted cytoarchitecture of the brain cortex. Thus, the present ndings collectively suggest that apigenin exerted signi cant protection against MSG-induced neurotoxicity by enhancing the cellular antioxidant response and attenuating in ammatory machineries in the rat brain cortex.

show abstract

Section: Discussionmentioning

confidence: 99%

Monosodium glutamate induces cortical oxidative, apoptotic, and inflammatory challenges in rats: the potential neuroprotective role of apigenin

Albrakati

2022

Environ Sci Pollut Res

View full text Add to dashboard Cite

show abstract

“…Yet, we found that indirect inhibition of ERK did not attenuate SNC80-induced seizures in wild-type mice and actually prolonged seizures in β-arrestin 1 knockout mice. It is possible that ERK is modulating mTOR signaling ( Roux et al, 2007 ; Gautam et al, 2021 ). In that respect, AKT can also be activated through β-arrestin 2 and induce mTOR activation ( Kendall et al, 2014 ) is part of the larger P13K/AKT/mTOR pathway, a vastly influential, multifaceted signaling pathway crucial for cell growth and survival ( Porta et al, 2014 ), although by our knowledge this pathway has not been established at the δOR.…”

Section: Discussionmentioning

confidence: 99%

Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions

et al. 2022

View full text Add to dashboard Cite

The δ-opioid receptor (δOR) has been considered as a therapeutic target in multiple neurological and neuropsychiatric disorders particularly as δOR agonists are deemed safer alternatives relative to the more abuse-liable µ-opioid receptor drugs. Clinical development of δOR agonists, however, has been challenging in part due to the seizure-inducing effects of certain δOR agonists. Especially agonists that resemble the δOR-selective agonist SNC80 have well-established convulsive activity. Close inspection suggests that many of those seizurogenic δOR agonists efficaciously recruit β-arrestin, yet surprisingly, SNC80 displays enhanced seizure activity in β-arrestin 1 knockout mice. This finding led us to hypothesize that perhaps β-arrestin 1 is protective against, whereas β-arrestin 2 is detrimental for δOR-agonist-induced seizures. To investigate our hypothesis, we characterized three different δOR agonists (SNC80, ADL5859, ARM390) in cellular assays and in vivo in wild-type and β-arrestin 1 and β-arrestin 2 knockout mice for seizure activity. We also investigated downstream kinases associated with β-arrestin-dependent signal transduction. We discovered that δOR agonist-induced seizure activity strongly and positively correlates with β-arrestin 2 efficacy for the agonist, but that indirect inhibition of ERK activation using the MEK inhibitor SL327 did not inhibit seizure potency and duration. Inhibition of the PI3K/AKT/mTOR signaling with honokiol but not PQR530, attenuated SNC80 seizure duration in β-arrestin 1 knockout, but honokiol did not reduce SNC80-induced seizures in wild-type mice. Ultimately, our results indicate that β-arrestin 2 is correlated with δOR agonist-induced seizure intensity, but that global β-arrestin 1 knockout mice are a poor model system to investigate their mechanism of action.

show abstract

“…MAPK pathways are composed of several different families with different signaling motifs and crosstalk between pathways which can activate or deactivate each other in a context dependent manner ( Shen et al, 2003 ; Aksamitiene et al, 2012 ; Fey et al, 2012 ). All of our 13 pathways have previously been linked to various models of epilepsy, and the potential crosstalk between them has been discussed elsewhere ( Gautam et al, 2021 ). Though the role of interaction and crosstalk between pathways still are not well understood, studies suggest that under non-pathological conditions one way of gaining signal specificity and maintaining robustness in signaling transduction systems is through molecular species acting to mutually inhibit one another ( Natarajan et al, 2006 ; McClean et al, 2007 ), and that most potential interactions between molecules are not realized, limiting cellular responses to discrete subsets of ligands and pathways to enhance specific cellular functions ( Hsueh et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

“…While these MAPKs respond to a variety of stimuli and there is a considerable amount of crosstalk between them (Shen et al, 2003;Fey et al, 2012), they initiate exquisitely specific cellular responses and have traditionally been split between the classical (the first discovered) MAPK ERK and the stress activated protein kinases (SAPKs), p38 and JNK. With regard to epileptogenesis, ERK has been associated with synaptic remodeling and plasticity while p38 and JNK tend to be associated with immune and inflammatory responses (Gautam et al, 2021). It should be noted that these delineations are oversimplifications and cellular responses may often involve concerted action across interacting pathways (Liu, 2011; Frontiers in Cell and Developmental Biology frontiersin.org Kyriakis and Avruch, 2012;Gautam et al, 2021).…”

Section: Single-pathway Associated Genesmentioning

confidence: 99%

“…With regard to epileptogenesis, ERK has been associated with synaptic remodeling and plasticity while p38 and JNK tend to be associated with immune and inflammatory responses (Gautam et al, 2021). It should be noted that these delineations are oversimplifications and cellular responses may often involve concerted action across interacting pathways (Liu, 2011; Frontiers in Cell and Developmental Biology frontiersin.org Kyriakis and Avruch, 2012;Gautam et al, 2021). Stress related pathways had a different distribution in P15: there were no TNFα annotated genes and almost no single-pathway annotated genes for p38, JNK, and Rho/Cdc42/Rac (Table 4).…”

Section: Single-pathway Associated Genesmentioning

confidence: 99%

See 1 more Smart Citation

Time and age dependent regulation of neuroinflammation in a rat model of mesial temporal lobe epilepsy: Correlation with human data

Erisken

Nune

Chung

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Acute brain insults trigger diverse cellular and signaling responses and often precipitate epilepsy. The cellular, molecular and signaling events relevant to the emergence of the epileptic brain, however, remain poorly understood. These multiplex structural and functional alterations tend also to be opposing - some homeostatic and reparative while others disruptive; some associated with growth and proliferation while others, with cell death. To differentiate pathological from protective consequences, we compared seizure-induced changes in gene expression hours and days following kainic acid (KA)-induced status epilepticus (SE) in postnatal day (P) 30 and P15 rats by capitalizing on age-dependent differential physiologic responses to KA-SE; only mature rats, not immature rats, have been shown to develop spontaneous recurrent seizures after KA-SE. To correlate gene expression profiles in epileptic rats with epilepsy patients and demonstrate the clinical relevance of our findings, we performed gene analysis on four patient samples obtained from temporal lobectomy and compared to four control brains from NICHD Brain Bank. Pro-inflammatory gene expressions were at higher magnitudes and more sustained in P30. The inflammatory response was driven by the cytokines IL-1β, IL-6, and IL-18 in the acute period up to 72 h and by IL-18 in the subacute period through the 10-day time point. In addition, a panoply of other immune system genes was upregulated, including chemokines, glia markers and adhesion molecules. Genes associated with the mitogen activated protein kinase (MAPK) pathways comprised the largest functional group identified. Through the integration of multiple ontological databases, we analyzed genes belonging to 13 separate pathways linked to Classical MAPK ERK, as well as stress activated protein kinases (SAPKs) p38 and JNK. Interestingly, genes belonging to the Classical MAPK pathways were mostly transiently activated within the first 24 h, while genes in the SAPK pathways had divergent time courses of expression, showing sustained activation only in P30. Genes in P30 also had different regulatory functions than in P15: P30 animals showed marked increases in positive regulators of transcription, of signaling pathways as well as of MAPKKK cascades. Many of the same inflammation-related genes as in epileptic rats were significantly upregulated in human hippocampus, higher than in lateral temporal neocortex. They included glia-associated genes, cytokines, chemokines and adhesion molecules and MAPK pathway genes. Uniquely expressed in human hippocampus were adaptive immune system genes including immune receptors CDs and MHC II HLAs. In the brain, many immune molecules have additional roles in synaptic plasticity and the promotion of neurite outgrowth. We propose that persistent changes in inflammatory gene expression after SE leads not only to structural damage but also to aberrant synaptogenesis that may lead to epileptogenesis. Furthermore, the sustained pattern of inflammatory genes upregulated in the epileptic mature brain was distinct from that of the immature brain that show transient changes and are resistant to cell death and neuropathologic changes. Our data suggest that the epileptogenic process may be a result of failed cellular signaling mechanisms, where insults overwhelm the system beyond a homeostatic threshold.

show abstract

An insight into crosstalk among multiple signaling pathways contributing to epileptogenesis

Cited by 17 publications

References 131 publications

Monosodium glutamate induces cortical oxidative, apoptotic, and inflammatory challenges in rats: the potential neuroprotective role of apigenin

Monosodium glutamate induces cortical oxidative, apoptotic, and inflammatory challenges in rats: the potential neuroprotective role of apigenin

Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions

Time and age dependent regulation of neuroinflammation in a rat model of mesial temporal lobe epilepsy: Correlation with human data

Contact Info

Product

Resources

About