Abstract
Purpose of the research: Epilepsy is a continuous process of neurodegeneration categorized by an enduring tendency to generate uncontrolled electrical firing known as seizures causing involuntary movement all over the body. Cognitive impairment and behavioral disturbances are among the more alarming co-morbidities of epilepsy. Anti-epileptic drugs (AEDs) were found to be successful in controlling epilepsy but are reported to worsen cognitive status in patients. Embelin (EMB) is a benzoquinone derived from the plant Embelia ribes and is reported to have central nervous system (CNS) activity. This study aims to evaluate the effectiveness of EMB against pentylenetetrazole (PTZ) induced acute seizures and its associated cognitive dysfunction. This was done via docking studies as well as evaluating neurotransmitter and gene expression in the zebrafish brain. The principal results: Behavioral observations showed that EMB reduced epileptic seizures and the T-maze study revealed that EMB improved the cognitive function of the fish. The docking study of EMB showed a higher affinity toward gamma-aminobutyric acid (GABAA) receptor as compared to the standard diazepam, raising the possibility of EMB working via the alpha subunit of the GABA receptor. EMB was found to modulate several genes, neurotransmitters, and also neuronal growth, all of which play an important role in improving cognitive status after epileptic seizures. Healthy zebrafish treated with EMB alone were found to have no behavioral and biochemical interference or side effects. The immunohistochemistry data suggested that EMB also promotes neuronal protection and neuronal migration in zebrafish brains. Major Conclusions: It was perceived that EMB suppresses seizure-like behavior via GABAA receptor pathway and has a positive impact on cognitive functions. The observed effect was supported by docking study, T-maze behavior, neurotransmitter and gene expression levels, and immunohistology study. The apparatus such as the T-maze and seizure scoring behavior tank were found to be a straightforward technique to score seizure and test learning ability after acute epileptic seizures. These research findings suggest that EMB could be a promising molecule for epilepsy induced learning and memory dysfunction.
Highlights
Epilepsy is a neurological condition with complications associated with diverse neurobiological and behavioral alterations characterized by recurrent, spontaneous epileptic seizures (Galanopoulou et al, 2012)
The sections were incubated with mouse anti-BrdU antibody (1:500; Roche Diagnostics, IN, USA) in 10% horse serum with 0.5% bovine serum albumin (BSA) (Sigma Life Science, USA) in phosphate buffered saline (PBS) containing 0.1% Triton-X-100 for 18 h at 4°C
It was observed that animals treated with EMB-2.5 mg/kg to EMB-10 mg/kg (+PTZ) display seizure scores that are similar to the PTZ treated group
Summary
Epilepsy is a neurological condition with complications associated with diverse neurobiological and behavioral alterations characterized by recurrent, spontaneous epileptic seizures (Galanopoulou et al, 2012). It is the fourth most common neurological disorder (Newton and Garcia, 2012), affecting over 70 million people of all ages around the world (Copmans et al, 2017). A notion exists that the rate/effects of seizures and the dose of AEDs play a key role in the cognitive decline of epileptic patients (Lagae, 2006; Park and Kwon, 2008). Adverse effects due to cognitive impairment are a major problem associated with AEDs as they alter the role of different genes that are associated with epileptogenesis and memory function (Gupta et al, 2017) (Gayatri and Livingston, 2006)
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