Thymoquinone Potentiates the Effect of Phenytoin against Electroshock-Induced Convulsions in Rats by Reducing the Hyperactivation of m-TOR Pathway and Neuroinflammation: Evidence from In Vivo, In Vitro and Computational Studies

Pottoo, Faheem Hyder; Salahuddin, M.; Khan, Firdos Alam; Alomar, Fadhel A.; Dhamen, Marwa Abdullah Al; Alhashim, Abrar Fouad; Alqattan, Hawra Hussain; Gomaa, Mohamed S.; Alomary, Mohammad N.

doi:10.3390/ph14111132

Cited by 10 publications

(12 citation statements)

References 66 publications

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“…Phenytoin (PHT), also known as 5,5-diphenylhydantoin, was first synthesized as a barbiturate derivative in 1908 by German chemist Heinrich Biltz. Two decades later, animal model studies showed that PHT had the property of electroshock convulsion suppression[ 1 ]. In 1938, Tracy Putnam and H. Houston Merritt found out that PHT was useful as an antiepileptic.…”

Section: Introductionmentioning

confidence: 99%

Phenytoin-associated movement disorder

Rissardo

Caprara

2022

Tzu Chi Medical Journal

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Phenytoin (PHT) was first synthesized as a barbiturate derivative and was approved in 1953 by the Food and Drug Administration. This work aimed to review the pathophysiology, epidemiology, clinical presentation, and treatment of PHT-associated movement disorders (MDs). Studies were searched in relevant databases (ScienceDirect, Google Scholar, Excerpta Medica, Latin American and Caribbean Health Sciences Literature, Medline, and Scientific Electronic Library Online) and were selected by two reviewers irrespective of language between 1963 and 2021. Papers of PHT-induced ataxia alone or tremor were excluded. In total, 127 reports with 219 individuals who developed MDs associated with PHT were encountered. MDs found: 126 dyskinesias, 49 myoclonus, 19 dystonia, 14 parkinsonism, 6 tics, 3 stuttering, and 2 restless legs syndrome. The mean age was 35 years (standard deviation [SD]: 23.5) and the predominant sex was male (53.4%). The mean PHT dose when the MD took place was 370.4 mg (SD: 117.5). A serum PHT concentration was reported in 103 cases, ranging from 4 to 110 μg/mL (median: 27.7 μg/mL). No significant relationship was found between PHT dose and age or PHT level. The mean onset time of PHT-associated MD was 23.4 months (SD: 4.4). The mean recovery time after MD management was 3.7 weeks (SD: 1.1). Regarding management, the most common form was PHT withdrawal in 90.4%. 86.3% of the individuals recovered fully. PHT-induced MD was extensively reported in the literature. Only general terms were used in the majority of the reports. The mechanisms underlying the adverse events caused by PHT probably depend on the presence of predisposing factors.

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Section: Introductionmentioning

confidence: 99%

Phenytoin-associated movement disorder

Rissardo

Caprara

2022

Tzu Chi Medical Journal

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“…The animal studies as well have confirmed the anti-ictal effect of THQ. Beyazcicek et al, 2016 reported that THQ reduces the incidence of spike waves and epileptic activity and frequency in penicillin-induced seizures [ 29 ], Hosseinzadeh et al, 2005 reported reduction in time to onset of seizures and seizure duration in the PTZ model [ 56 ] and Pottoo et al, 2021 reported reduction in THLE following MES induced seizures in THQ treated rats [ 57 ]. The duo-drug combinatorial therapy of SVP (150 mg/kg) with BFN (5 mg/kg) exhibited anticonvulsant effect, but the efficacy was no better than monotherapy with individual drugs.…”

Section: Discussionmentioning

confidence: 99%

Trio-Drug Combination of Sodium Valproate, Baclofen and Thymoquinone Exhibits Synergistic Anticonvulsant Effects in Rats and Neuro-Protective Effects in HEK-293 Cells

Pottoo

Salahuddin

Khan

et al. 2022

CIMB

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Epilepsy is a chronic brain disorder, with anti-epileptic drugs (AEDs) providing relief from hyper-excitability of neurons, but largely failing to restrain neurodegeneration. We investigated a progressive preclinical trial in rats, whereby the test drugs; sodium valproate (SVP; 150 and 300 mg/kg), baclofen (BFN; 5 and 10 mg/kg), and thymoquinone (THQ; 40 and 80 mg/kg) were administered (i.p, once/day for 15 days) alone, and as low dose combinations, and subsequently tested for antiseizure and neuroprotective potential using electrical stimulation of neurons by Maximal electroshock (MES). The seizure stages were monitored, and hippocampal levels of m-TOR, IL-1β, IL-6 were measured. Hippocampal histopathology was also performed. Invitro and Insilco studies were run to counter-confirm the results from rodent studies. We report the synergistic effect of trio-drug combination; SVP (150 mg/kg), BFN (5 mg/kg) and THQ (40 mg/kg) against generalized seizures. The Insilco results revealed that trio-drug combination binds the Akt active site as a supramolecular complex, which could have served as a delivery system that affects the penetration and the binding to the new target. The potential energy of the ternary complex in the Akt active site after dynamics simulation was found to be −370.426 Kcal/mol, while the supramolecular ternary complex alone was −38.732 Kcal/mol, with a potential energy difference of −331.694 Kcal/mol, which favors the supramolecular ternary complex at Akt active site binding. In addition, the said combination increased cell viability by 267% and reduced morphological changes induced by Pentylenetetrazol (PTZ) in HEK-293 cells, which indicates the neuroprotective property of said combination. To conclude, we are the first to report the anti-convulsant and neuroprotective potential of the trio-drug combination.

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“…Epilepsy is one of the most heterogeneous neurological disorders, which is characterized by persistent neural activity and recurrent spontaneous seizures. This neurological disorder can occur for a number of reasons, including as a result of traumatic brain injury and genetic factors [70,71]. Violation of the inhibitory-excitatory balance in the brain is considered as an important mechanism of the pathogenesis of epilepsy.…”

Section: Neuroprotective Properties Of Thymoquinone In Modeling Epilepsymentioning

confidence: 99%

Antioxidant Thymoquinone and Its Potential in the Treatment of Neurological Diseases

2023

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Oxidative stress is one of the main pathogenic factors of neuron damage in neurodegenerative processes; this makes it an important therapeutic target to which the action of neuroprotectors should be directed. One of these drugs is thymoquinone. According to modern data, this substance has a wide range of pharmacological activity, including neuroprotective, which was demonstrated in experimental modeling of various neurodegenerative diseases and pathological conditions of the brain. The neuroprotective effect of thymoquinone is largely due to its antioxidant ability. Currently available data show that thymoquinone is an effective means to reduce the negative consequences of acute and chronic forms of cerebral pathology, leading to the normalization of the content of antioxidant enzymes and preventing an increase in the level of lipid peroxidation products. Antioxidant properties make this substance a promising basis for the development of prototypes of therapeutic agents aimed at the treatment of a number of degenerative diseases of the central nervous system.

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Thymoquinone Potentiates the Effect of Phenytoin against Electroshock-Induced Convulsions in Rats by Reducing the Hyperactivation of m-TOR Pathway and Neuroinflammation: Evidence from In Vivo, In Vitro and Computational Studies

Cited by 10 publications

References 66 publications

Phenytoin-associated movement disorder

Phenytoin-associated movement disorder

Trio-Drug Combination of Sodium Valproate, Baclofen and Thymoquinone Exhibits Synergistic Anticonvulsant Effects in Rats and Neuro-Protective Effects in HEK-293 Cells

Antioxidant Thymoquinone and Its Potential in the Treatment of Neurological Diseases

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