Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy.

Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated ß-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.

Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy.

OBJECTIVE: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP. METHODS: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5c/- ), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures. RESULTS: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic-ECG records on Depdc5c/- mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia. INTERPRETATION: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies. ANN NEUROL 2022;91:101-116.

Adsorption of estrone, 17ß-estradiol, and 17α-ethinylestradiol from water onto modified multi-walled carbon nanotubes, carbon cryogel, and carbonized hydrothermal carbon.

Carbon materials of different structural and textural properties (multi-walled carbon nanotubes, carbon cryogel, and carbonized hydrothermal carbon) were used as adsorbents for the removal of estrone, 17ß-estradiol, and 17α-ethinylestradiol from aqueous solutions. Chemical modification and/or activation were applied to alter surface characteristics and to increase the adsorption and desorption efficiency of carbon materials. Surfaces of treated and untreated carbon materials were characterized through the examination of the textural properties, the nature of surface functional groups, and surface acidity. It was found that the adsorption capacity of tested carbon materials is not directly proportional to the specific surface area and the content of surface oxygen groups. However, a high ratio of surface mesoporosity affected the adsorption process most prominently, by increasing adsorption capacity and the rate of the adsorption process. Adsorption of estrone, 17ß-estradiol, and 17α-ethinylestradiol followed pseudo-second-order kinetic model, while the equilibrium adsorption data were best fitted with the Langmuir isotherm model. Calculated mean adsorption energy values, along with the thermodynamic parameters, indicated that removal of selected hormones was dominated by the physisorption mechanism. High values of adsorption efficiency (88-100 %) and Langmuir adsorption capacities (29.45-194.7 mg/g) imply that examined materials, especially mesoporous carbon cryogel and multi-walled carbon nanotubes, can be used as powerful adsorbents for relatively fast removal of estrogen hormones from water.