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Thyroid hormones: Possible roles in epilepsy pathology

Tamijani SM, Karimi B, Amini E, Golpich M, Dargahi L, Ali RA, et al.

Seizure, 2015 Sep;31:155-64.
PMID: 26362394 DOI: 10.1016/j.seizure.2015.07.021

Thyroid hormones (THs) L-thyroxine and L-triiodothyronine, primarily known as metabolism regulators, are tyrosine-derived hormones produced by the thyroid gland. They play an essential role in normal central nervous system development and physiological function. By binding to nuclear receptors and modulating gene expression, THs influence neuronal migration, differentiation, myelination, synaptogenesis and neurogenesis in developing and adult brains. Any uncorrected THs supply deficiency in early life may result in irreversible neurological and motor deficits. The development and function of GABAergic neurons as well as glutamatergic transmission are also affected by THs. Though the underlying molecular mechanisms still remain unknown, the effects of THs on inhibitory and excitatory neurons may affect brain seizure activity. The enduring predisposition of the brain to generate epileptic seizures leads to a complex chronic brain disorder known as epilepsy. Pathologically, epilepsy may be accompanied by mitochondrial dysfunction, oxidative stress and eventually dysregulation of excitatory glutamatergic and inhibitory GABAergic neurotransmission. Based on the latest evidence on the association between THs and epilepsy, we hypothesize that THs abnormalities may contribute to the pathogenesis of epilepsy. We also review gender differences and the presumed underlying mechanisms through which TH abnormalities may affect epilepsy here.

Matched MeSH terms: Epilepsy/metabolism*
Tau Related Pathways as a Connecting Link between Epilepsy and Alzheimer's Disease

Paudel YN, Angelopoulou E, Jones NC, O'Brien TJ, Kwan P, Piperi C, et al.

ACS Chem Neurosci, 2019 10 16;10(10):4199-4212.
PMID: 31532186 DOI: 10.1021/acschemneuro.9b00460

Emerging findings point toward an important interconnection between epilepsy and Alzheimer's disease (AD) pathogenesis. Patients with epilepsy (PWE) commonly exhibit cognitive impairment similar to AD patients, who in turn are at a higher risk of developing epilepsy compared to age-matched controls. To date, no disease-modifying treatment strategy is available for either epilepsy or AD, reflecting an immediate need for exploring common molecular targets, which can delineate a possible mechanistic link between epilepsy and AD. This review attempts to disentangle the interconnectivity between epilepsy and AD pathogenesis via the crucial contribution of Tau protein. Tau protein is a microtubule-associated protein (MAP) that has been implicated in the pathophysiology of both epilepsy and AD. Hyperphosphorylation of Tau contributes to the different forms of human epilepsy and inhibition of the same exerted seizure inhibitions and altered disease progression in a range of animal models. Moreover, Tau-protein-mediated therapy has demonstrated promising outcomes in experimental models of AD. In this review, we discuss how Tau-related mechanisms might present a link between the cause of seizures in epilepsy and cognitive disruption in AD. Untangling this interconnection might be instrumental in designing novel therapies that can minimize epileptic seizures and cognitive deficits in patients with epilepsy and AD.

Matched MeSH terms: Epilepsy/metabolism*
Pharmacokinetics of phenytoin in routine clinic patients in Malaysia

Ismail R, Rahman AF, Chand P

J Clin Pharm Ther, 1994 Aug;19(4):245-8.
PMID: 7989403

We estimated individual and population Michaelis-Menten pharmacokinetic parameters for phenytoin (DPH) in epileptic patients attending our neurology clinic using the computer programme. OPT. Our results agreed well with literature values but were lower than those we obtained earlier in a smaller number of patients. The Km was independent of age, weight and sex but there was a weak, correlation between Vm and body weight. We conclude that the use of population Vm and Km in normograms could lead to errors in DPH dose estimations as they correlated very poorly with patient characteristics. OPT was easy to use and sufficiently accurate for deriving dose estimates in routine patients. Its use would enable practitioners to generate their patients' own parameters for use in individual dosage adjustments. The estimates can subsequently be updated as more data become available.

Matched MeSH terms: Epilepsy/metabolism*
Potential anti-epileptic phytoconstituents: An updated review

Kaur J, Famta P, Famta M, Mehta M, Satija S, Sharma N, et al.

J Ethnopharmacol, 2021 Mar 25;268:113565.
PMID: 33166627 DOI: 10.1016/j.jep.2020.113565

ETHNOPHARMACOLOGICAL RELEVANCE: Epilepsy is one of the most commonly occurring non-communicable neurological disorder that affects people of all age groups. Around 50 million people globally are epileptic, with 80% cases in developing countries due to lack of access to treatments determined by high cost and poor availability or it can be defined by the fraction of active epileptic patients who are not appropriately being treated. The availability of antiepileptic drugs and their adjuvant therapy in such countries is less than 50% and these are highly susceptible to drug interactions and severe adverse effects. As a result, the use of herbal medicine is increasingly becoming popular.
AIM OF THE STUDY: To provide pharmacological information on the active constituents evaluated in the preclinical study to treat epilepsy with potential to be used as an alternative therapeutic option in future. It also provides affirmation for the development of novel antiepileptic drugs derived from medicinal plants.
MATERIALS AND METHODS: Relevant information on the antiepileptic potential of phytoconstituents in the preclinical study (in-vitro, in-vivo) is provided based on their effect on screening parameters. Besides, relevant information on pharmacology of phytoconstituents, the traditional use of their medicinal plants related to epilepsy and status of phytoconstituents in the clinical study were derived from online databases, including PubMed, Clinicaltrial. gov, The Plant List (TPL, www.theplantlist.org), Science Direct. Articles identified using preset searching syntax and inclusion criteria are presented.
RESULTS: More than 70% of the phytoconstituents reviewed in this paper justified the traditional use of their medicinal plant related to epilepsy by primarily acting on the GABAergic system. Amongst the phytoconstituents, only cannabidiol and tetrahydrocannabinol have been explored for clinical application in epilepsy.
CONCLUSION: The preclinical and clinical data of the phytoconstituents to treat epilepsy and its associated comorbidities provides evidence for the discovery and development of novel antiepileptic drugs from medicinal plants. In terms of efficacy and safety, further randomized and controlled clinical studies are required to understand the complete pharmacodynamic and pharmacokinetic picture of phytoconstituents. Also, specific botanical source evaluation is needed.

Matched MeSH terms: Epilepsy/metabolism
Decreased glutamine synthetase, increased citrulline-nitric oxide cycle activities, and oxidative stress in different regions of brain in epilepsy rat model

Swamy M, Yusof WR, Sirajudeen KN, Mustapha Z, Govindasamy C

J Physiol Biochem, 2011 Mar;67(1):105-13.
PMID: 20960085 DOI: 10.1007/s13105-010-0054-2

To understand their role in epilepsy, the nitric oxide synthetase (NOS), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), glutamine synthetase (GS), and arginase activities, along with the concentration of nitrate/nitrite (NOx), thiobarbituric acid reactive substances (TBARS), and total antioxidant status (TAS), were estimated in different regions of brain in rats subjected to experimental epilepsy induced by subcutaneous administration of kainic acid (KA). The short-term (acute) group animals were killed after 2 h and the long term (chronic) group animals were killed after 5 days of single injection of KA (15 mg/kg body weight). After decapitation of rats, the brain regions were separated and in their homogenates, the concentration of NOx, TBARS and TAS and the activities of NOS, AS, AL, arginase and glutamine synthetase were assayed by colorimetric methods. The results of the study demonstrated the increased activity of NOS and formation of NO in acute and chronic groups epilepsy. The activities of AS and AL were increased and indicate the effective recycling of citrulline to arginine. The activity of glutamine synthetase was decreased in acute and chronic groups of epilepsy compared to control group and indicate the modulation of its activity by NO in epilepsy. The activity of arginase was not changed in acute group; however it was decreased in chronic group and may favor increased production of NO in this condition. The concentration TBARS were increased and TAS decreased in acute and chronic groups of epilepsy and supports the oxidative stress in epilepsy.

Matched MeSH terms: Epilepsy/metabolism*