Zebrafish larvae exposed to ginkgotoxin exhibit seizure-like behavior that is relieved by pyridoxal-5'-phosphate, GABA and anti-epileptic drugs.
The etiology of epilepsy is a very complicated, multifactorial process that is not completely understood. Therefore, the availability of epilepsy animal models induced by different mechanisms is crucial in advancing our knowledge and developing new therapeutic regimens for this disorder. Considering the advantages of zebrafish, we have developed a seizure model in zebrafish larvae using ginkgotoxin, a neurotoxin naturally occurring in Ginkgo biloba and hypothesized to inhibit the formation of the neurotransmitter γ-aminobutyric acid (GABA). We found that a 2-hour exposure to ginkgotoxin induced a seizure-like behavior in zebrafish larvae. This seizure-like swimming pattern was alleviated by the addition of either pyridoxal-5'-phosphate (PLP) or GABA and responded quickly to the anti-convulsing activity of gabapentin and phenytoin, two commonly prescribed anti-epileptic drugs (AEDs). Unexpectedly, the ginkgotoxin-induced PLP depletion in our experimental setting did not affect the homeostasis of folate-mediated one-carbon metabolism, another metabolic pathway playing a crucial role in neural function that also relies on the availability of PLP. This ginkgotoxin-induced seizure behavior was also relieved by primidone, which had been tested on a pentylenetetrazole-induced zebrafish seizure model but failed to rescue the seizure phenotype, highlighting the potential use and complementarity of this ginkgotoxin-induced seizure model for AED development. Structural and morphological characterization showed that a 2-hour ginkgotoxin exposure did not cause appreciable changes in larval morphology and tissues development. In conclusion, our data suggests that this ginkgotoxin-induced seizure in zebrafish larvae could serve as an in vivo model for epileptic seizure research and potential AED screening.
Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, 701 Taiwan.
Gang-Hui
GH
Lee
Shian-Ying
SY
Sung
Wen-Ni
WN
Chang
Tseng-Ting
TT
Kao
Hung-Chi
HC
Du
Tsun-Hsien
TH
Hsiao
Martin K
MK
Safo
Tzu-Fun
TF
Fu
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002244:Carbon / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism; D007814:Larva / Q000033:anatomy & histology / Q000187:drug effects; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010433:Pentylenetetrazole; D011324:Primidone / Q000494:pharmacology / Q000627:therapeutic use; D011732:Pyridoxal Phosphate / Q000494:pharmacology / Q000627:therapeutic use*; D011736:Pyridoxine / Q000031:analogs & derivatives* / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D013550:Swimming; D015027:Zebrafish / Q000254:growth & development / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000627:therapeutic use*
C406624:4'-O-methylpyridoxine; D000927:Anticonvulsants; D009498:Neurotoxins; D011324:Primidone; D005680:gamma-Aminobutyric Acid; D011732:Pyridoxal Phosphate; D002244:Carbon; D005492:Folic Acid; D011736:Pyridoxine; D010433:Pentylenetetrazole