Protective effect of N-acetyl cysteine on the mitochondrial dynamic imbalance in temporal lobe epilepsy: Possible role of mTOR

Mohammadi, Ekram; Nikbakht, Farnaz; Barati, Mahmoud; Roghani, Mehrdad; Vazifekhah, Somayeh; Khanizadeh, Ali Mohammad; heidari, zahra

doi:10.1016/j.npep.2022.102294

Cited by 5 publications

(5 citation statements)

References 59 publications

(26 reference statements)

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“…This shows that 1400W not only acted directly to inhibit iNOS but also exerted modulatory effect on the endogenous antioxidant system. Other exogenous antioxidants such as N-acetylcysteine and sulforaphane has been previously shown to potentiate the glutathione antioxidant system which controlled the oxidative stress in animal and modified epileptogenesis (Liang and Patel, 2006;Carrasco-Pozo et al, 2015;Pauletti et al, 2019;Mohammadi et al, 2022). A seizure initiates, when a sufficient number of neurons depolarize and produce action potentials (Holmes and Ben-Ari, 2001).…”

Section: Discussionmentioning

confidence: 99%

1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model

Massey

Vasanthi

Samidurai

et al. 2023

Front. Mol. Neurosci.

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Organophosphate nerve agent (OPNA) exposure induces acute and long-term neurological deficits. OPNA exposure at sub-lethal concentrations induces irreversible inhibition of acetylcholinesterase and cholinergic toxidrome and develops status epilepticus (SE). Persistent seizures have been associated with increased production of ROS/RNS, neuroinflammation, and neurodegeneration. A total of 1400W is a novel small molecule, which irreversibly inhibits inducible nitric oxide synthase (iNOS) and has been shown to effectively reduce ROS/RNS generation. In this study, we investigated the effects of 1400W treatment for a week or two weeks at 10 mg/kg or 15 mg/kg per day in the rat diisopropylfluorophosphate (DFP) model. 1400W significantly reduced the number of microglia, astroglia, and NeuN+FJB positive cells compared to the vehicle in different regions of the brain. 1400W also significantly reduced nitrooxidative stress markers and proinflammatory cytokines in the serum. However, neither of the two concentrations of 1400W for two weeks of treatment had any significant effect on epileptiform spike rate and spontaneous seizures during the treatment period in mixed sex cohorts, males, or females. No significant sex differences were found in response to DFP exposure or 1400W treatment. In conclusion, 1400W treatment at 15 mg/kg per day for two weeks was more effective in significantly reducing DFP-induced nitrooxidative stress, neuroinflammatory and neurodegenerative changes.

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Section: Discussionmentioning

confidence: 99%

1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model

Massey

Vasanthi

Samidurai

et al. 2023

Front. Mol. Neurosci.

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“…Although it has been observed for many years that mTOR inhibition contributes to antiepileptogenic therapy, the regulatory mechanism of mTOR in seizure‐induced neurological changes is not well known. Interestingly, emerging studies have demonstrated that overactivated mTOR induces the pathogenesis of epilepsy by disrupting the formation of neural circuits and altering existing neural networks (Mohammadi et al., 2022; Nguyen et al., 2022). Thus, whether epilepsy is a direct consequence of mTORC1 overactivation or an inevitable result of disrupted neural networks caused by abnormal cortical structures has become the focus of many discussions.…”

Section: The Role Of the Mtor Signaling Pathway In Epilepsymentioning

confidence: 99%

Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy

et al. 2023

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Introduction: Epilepsy is one of the most common and serious brain syndromes and has adverse consequences on a patient's neurobiological, cognitive, psychological, and social wellbeing, thereby threatening their quality of life. Some patients with epilepsy experience poor treatment effects due to the unclear pathophysiological mechanisms of the syndrome. Dysregulation of the mammalian target of the rapamycin (mTOR) pathway is thought to play an important role in the onset and progression of some epilepsies.Methods: This review summarizes the role of the mTOR signaling pathway in the pathogenesis of epilepsy and the prospects for the use of mTOR inhibitors. Results:The mTOR pathway functions as a vital mediator in epilepsy development through diverse mechanisms, indicating that the it has great potential as an effective target for epilepsy therapy. The excessive activation of mTOR signaling pathway leads to structural changes in neurons, inhibits autophagy, exacerbates neuron damage, affects mossy fiber sprouting, enhances neuronal excitability, increases neuroinflammation, and is closely associated with tau upregulation in epilepsy. A growing number of studies have demonstrated that mTOR inhibitors exhibit significant antiepileptic effects in both clinical applications and animal models. Specifically, rapamycin, a specific inhibitor of TOR, reduces the intensity and frequency of seizures. Clinical studies in patients with tuberous sclerosis complex have shown that rapamycin has the function of reducing seizures and improving this disease. Everolimus, a chemically modified derivative of rapamycin, has been approved as an added treatment to other antiepileptic medicines. Further explorations are needed to evaluate the therapeutic efficacy andThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…The hypermodulation of the mTOR pathway is connected to seizure development, yet, the pathway in normal condition is responsible for axonal growth and regeneration [38]. Leu was also shown to enhance mTOR signalling and promoted neurodegeneration [39][40][41]. Since neutral essential AA including BCAA are transported across cell membranes by SLC7 transporters such as LAT1 (SLC7A5), and leucine (Leu) and histidine (His) levels inversely correlated (Figure 5), we speculated that PTX may modulate and act on LAT1.…”

Section: Pharmacometabolic Changes On Amino Acid and Neurotransmitter...mentioning

confidence: 99%

Pharmacometabolic Effects of Pteryxin and Valproate on Pentylenetetrazole-Induced Seizures in Zebrafish Reveal Vagus Nerve Stimulation

Skiba

Pellegata

Morozova

et al. 2023

Cells

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Zebrafish (Danio rerio) assays provide a versatile pharmacological platform to test compounds on a wide range of behaviors in a whole organism. A major challenge lies in the lack of knowledge about the bioavailability and pharmacodynamic effects of bioactive compounds in this model organism. Here, we employed a combined methodology of LC-ESI-MS/MS analytics and targeted metabolomics with behavioral experiments to evaluate the anticonvulsant and potentially toxic effects of the angular dihydropyranocoumarin pteryxin (PTX) in comparison to the antiepileptic drug sodium valproate (VPN) in zebrafish larvae. PTX occurs in different Apiaceae plants traditionally used in Europe to treat epilepsy but has not been investigated so far. To compare potency and efficacy, the uptake of PTX and VPN into zebrafish larvae was quantified as larvae whole-body concentrations together with amino acids and neurotransmitters as proxy pharmacodynamic readout. The convulsant agent pentylenetetrazole (PTZ) acutely reduced the levels of most metabolites, including acetylcholine and serotonin. Conversely, PTX strongly reduced neutral essential amino acids in a LAT1 (SLCA5)-independent manner, but, similarly to VPN specifically increased the levels of serotonin, acetylcholine, and choline, but also ethanolamine. PTX dose and time-dependent manner inhibited PTZ-induced seizure-like movements resulting in a ~70% efficacy after 1 h at 20 µM (the equivalent of 4.28 ± 0.28 µg/g in larvae whole-body). VPN treated for 1 h with 5 mM (the equivalent of 18.17 ± 0.40 µg/g in larvae whole-body) showed a ~80% efficacy. Unexpectedly, PTX (1–20 µM) showed significantly higher bioavailability than VPN (0.1–5 mM) in immersed zebrafish larvae, possibly because VPN in the medium dissociated partially to the readily bioavailable valproic acid. The anticonvulsive effect of PTX was confirmed by local field potential (LFP) recordings. Noteworthy, both substances specifically increased and restored whole-body acetylcholine, choline, and serotonin levels in control and PTZ-treated zebrafish larvae, indicative of vagus nerve stimulation (VNS), which is an adjunctive therapeutic strategy to treat refractory epilepsy in humans. Our study demonstrates the utility of targeted metabolomics in zebrafish assays and shows that VPN and PTX pharmacologically act on the autonomous nervous system by activating parasympathetic neurotransmitters.

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Protective effect of N-acetyl cysteine on the mitochondrial dynamic imbalance in temporal lobe epilepsy: Possible role of mTOR

Cited by 5 publications

References 59 publications

1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model

1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model

Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy

Pharmacometabolic Effects of Pteryxin and Valproate on Pentylenetetrazole-Induced Seizures in Zebrafish Reveal Vagus Nerve Stimulation

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