Epilepsy is a chronic neurological disorder characterized by irregular, excessive neuronal excitability,
and recurrent seizures that affect millions of patients worldwide. Currently, accessible antiepileptic drugs (AEDs)
do not adequately support all epilepsy patients, with around 30% patients not responding to the existing therapies.
As lifelong epilepsy treatment is essential, the search for new and more effective AEDs with an enhanced safety
profile is a significant therapeutic goal. Seizures are a combination of electrical and behavioral events that can
induce biochemical, molecular, and anatomic changes. Therefore, appropriate animal models are required to
evaluate novel potential AEDs. Among the large number of available animal models of seizures, the acute pentylenetetrazole
(PTZ)-induced myoclonic seizure model is the most widely used model assessing the anticonvulsant
effect of prospective AEDs, whereas chronic PTZ-kindled seizure models represent chronic models in which the
repeated administration of PTZ at subconvulsive doses leads to the intensification of seizure activity or enhanced
seizure susceptibility similar to that in human epilepsy. In this review, we summarized the memory deficits accompanying
acute or chronic PTZ seizure models and how these deficits were evaluated applying several behavioral
animal models. Furthermore, major advantages and limitations of the PTZ seizure models in the discovery of
new AEDs were highlighted. With a focus on PTZ seizures, the major biochemicals, as well as morphological
alterations and the modulated brain neurotransmitter levels associated with memory deficits have been illustrated.
Moreover, numerous medicinal compounds with concurrent anticonvulsant, procognitive, antioxidant effects,
modulating effects on several brain neurotransmitters in rodents, and several newly developed classes of compounds
applying computer-aided drug design (CADD) have been under development as potential AEDs. The
article details the in-silico approach following CADD, which can be utilized for generating libraries of novel
compounds for AED discovery. Additionally, in vivo studies could be useful in demonstrating efficacy, safety,
and novel mode of action of AEDs for further clinical development.