Embelin Protects Against Acute Pentylenetetrazole-Induced Seizures and Positively Modulates Cognitive Function in Adult Zebrafish

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.

Anti-High Mobility Group Box-1 Monoclonal Antibody Attenuates Seizure-Induced Cognitive Decline by Suppressing Neuroinflammation in an Adult Zebrafish Model

“…The reduced inflection ratio in the second hit PTZ group at 3 and 24 h when compared to the VC group reflect the memory impairment in the second hit PTZ group. This finding is in agreement with earlier finding reporting PTZ induced cognitive impairment in adult zebrafish ( Kundap et al, 2019a ). These impairment in memory induced by second hit PTZ was ameliorated upon treatment with mAbs as evidenced by increased inflection ratio at 3 h and 24 h. Worth mentioning here is that, the significant upregulation of inflection ratio was only observed with mAb 5 at 24 h T-maze test.…”

“…Several lines of investigation have earlier reported that epileptic zebrafish exhibited memory impairment ( Kundap et al, 2017 ; Kundap et al, 2019a ) which is in agreement with the fact that memory impairment is associated with epilepsy ( Kesselmayer et al, 2019 ; Laurent et al, 2020 ). This reflects that the future therapeutic strategies against epileptic seizures should not only exert the disease supression but also ameliorate the related memory impairment.…”

“…However, difference in the modulation of Glutamate by extracellular HMGB1 in difference type of seizure models and study types ( in vitro and in vivo ) is not yet known. The modulation of GABA by different dose of mAb is in different line from the current understanding where amelioration of seizure leads to the upregulated level of GABA in seizure model in adult zebrafish ( Kundap et al, 2019a ). Hence, further studies are warranted to confirm our finding, that could explore on the modulation of GABA by mAb HMGB1 and GABA.…”

“…Rodent model of epilepsy has demonstrated that memory impairment is correlated with neuronal injuries in TLE ( Kotloski et al, 2002 ; Do Val-da Silva et al, 2016 ). Memory impairment has been reported in Pentylenetetrazol (PTZ) induced seizure model in adult zebrafish ( Kundap et al, 2019a ). T-Maze test has been used to assess the memory impairment in the zebrafish were the time needed for the zebrafish to reach the deeper chamber is termed as the transfer latency (TL), which is also expressed as inflection ratio ( Kundap et al, 2019a ).…”

Naturally Occurring HMGB1 Inhibitor, Glycyrrhizin, Modulates Chronic Seizures-Induced Memory Dysfunction in Zebrafish Model

“…76−78 Reduced level of NPY in our second hit PTZ group depicts the occurrence of seizure and impairment in learning and memory, which corroborates the reduced mRNA expression of NPY in PTZ and second hit PTZ induced seizure in adult zebrafish. 79,80 However, pretreatment with GL 25, GL 50, and GL 100 does not exert any significant effect in modulating the mRNA expression of NPY when compared to the second hit PTZ group.…”