<p>Myelin regeneration has been shown in previous studies to ameliorate varying degrees of cognitive impairment in patients with neurodegenerative disorders such as epilepsy. The problem of myelin regeneration in adults with drug-resistant status epilepticus is a major key to the difficulty of treating cognitive impairment in adults with drug-resistant epilepsy (DRE). The purpose of this study is to provide a molecular map of myelin-related molecules under the cognitive deficits seen in DRE. We used a lamotrigine-pentylenetetrazol-resistant epilepsy mouse model and verified the cognitive problems and myelin changes using a water maze and conventional molecular biology techniques. We then analyzed the OLs in the hippocampus of the mice and the effect on myelin using sn RNA-seq technology. We found that the problem of cognitive impairment in drug-resistant epileptic mice is due to altered myelin plasticity. OL maturation induces pathological myelin regeneration which ultimately leads to cognitive impairment. The three glial cell types are closely related to the occurrence of myelin regeneration and jointly promote pathological myelin regeneration. Our study revealed the presence of myelin regeneration in DRE. All of this evidence suggests that normal myelin regeneration contributes to cognitive impairment improvement, but pathological myelin regeneration impairs cognition.</p> Graphical Abstract <p>Schematic representation of myelin regeneration in cognitive impairment in adult drug-resistant epilepsy. Boxed are pathways or molecules related to the promotion of myelin regeneration in which a subpopulation is involved. Red font indicates promotion, blue font indicates inhibition, and gray font indicates unknown but relevant.</p>