Abstracts

Leptin is a neurohormone that helps regulate body weight and also has complex effects on neuronal excitability. Because its predominant effect on neuronal excitability in vivo is unclear, we examined the susceptibility of leptin deficient ob/ob mice to pentylenetetrazol (PTZ) induced seizures., We studied PTZ induced seizures in 31 wild type (C57BL/6J) and 30 ob/ob (B6.V-Lep^ob/J) male mice at 44-58 days of age using continuous video EEG recordings. After 15 minutes of baseline recording, a 25, 50, 75 or 100 mg/kg dose of PTZ was injected intraperitoneally. The recording continued for 30 minutes after the injection or until death, whichever came first. PTZ induced generalized absence, myoclonic, clonic and clonic-tonic seizures. Maximal clinical seizure severity, latency to clinical seizure onset, latency to the first epileptiform abnormality and the normalized cumulative epileptiform duration were determined. Clinical seizure severity was rated as: 0= no seizures, 1= absence seizures with normal clinical behavior and EEG interictally, 2= myoclonic seizures with normal clinical behavior and EEG interictally, 3= generalized clonic or clonic-tonic seizures with normal clinical behavior and EEG interictally, 4= repetitive absence or myoclonic seizures without normal interictal behavior or EEG throughout the 30 minute recording, 5= death. The normalized cumulative epileptiform duration was the sum of the duration of all epileptiform abnormalities divided by the total time of the recording after PTZ injection. Comparisons were made using a t-test with statistical significance set at p [lt] 0.05., The background EEG for both wild type and ob/ob mice showed 6-7 Hz theta activity without any epileptiform abnormalities. In both groups, PTZ induced the same types of clinical and electrographic seizures in a dose-dependent manner. The latency to the first clinical seizure and to the first epileptiform abnormality was the same in wild type and ob/ob mice at all PTZ doses. The maximal clinical severity at 25 mg/kg and 100 mg/kg PTZ were the same in wild type and ob/ob mice. However, at 75 mg/kg PTZ the clinical severity was 5.0 [plusmn] 0.0 for the ob/ob mice because all mice died whereas it was 3.5 [plusmn] 0.8 (p [lt] 0.05) for wild type mice. At 75 mg/kg PTZ, the normalized cumulative epileptiform duration was 9 [plusmn] 3% for ob/ob mice and 5 [plusmn] 1% for wild type mice (p [lt] 0.05). ob/ob mice also showed a higher maximal clinical severity and normalized cumulative epileptiform duration at 50 mg/kg PTZ. A greater number of generalized clonic and clonic-tonic seizures accounts for the greater severity of seizures in the ob/ob mice., These results indicate that PTZ induces more severe seizures in ob/ob mice. These results are consistent with leptin acting as an endogenous anticonvulsant and support a role for leptin in the treatment of epilepsy., (Supported by Washington University McDonnell Center for Cellular and Molecular Neurobiology, NS 42744 and JDRF 1-2004-594.)