Leptin-regulated autophagy plays a role in long-term neurobehavioral injury after neonatal seizures and the regulation of zinc/cPLA2 and CaMK II signaling in cerebral cortex

Abstract

Metabolic disorders play an important role in the pathogenesis of many neurological diseases. Recent evidence suggests that leptin levels in peripheral blood and brain are lower in patients with epilepsy. Leptin is an energy-regulating hormone that plays a neuroprotective role in neurodegenerative diseases and brain trauma. However, little is known about the effects and molecular mechanisms of leptin treatment on long-term neurobehavioral impairment caused by developmental seizures. The present study evaluated whether chronic leptin treatment protected against neurobehavioral impairments induced by recurrent seizures in newborns treated with flurothyl. We also examined the effect of leptin on the expression of zinc/cPLA2-related autophagy signaling molecules and CaMKII in the cerebral cortex. Twenty Sprague-Dawley rats (6 days after birth, P6) were randomly divided into two groups, a neonatal seizure group and control group. Rats were subdivided on P13 into control, control + leptin (leptin, 2 mg/kg/day, continuous 10 days), seizure (RS), and seizure + leptin group (RS + leptin, 2 mg/kg/day for 10 consecutive days). Neurological behavioral parameters (negative geotaxis reaction reflex, righting reflex, cliff avoidance reflex, forelimb suspension reflex and open field test) were observed from P23 to P30. mRNA and protein levels in the cerebral cortex were detected using real-time RT-PCR and Western blotting, respectively. Flurothyl-induced seizures (RS group) produced long-term abnormal neurobehavior, which was improved with leptin treatment. Chronic leptin treatment restored several expression parameters affected by neonatal seizures, including seizure-induced up-regulated zinc transporter ZnT1/ZIP7, lipid membrane injury-related cPLA2, autophagy marker beclin-1/bcl2, LC3II/LC3I, and its execution molecule cathepsin-E, and down-regulated memory marker CaMK II alpha. Our results suggest that the early use of leptin after neonatal recurrent seizures may exert neuroprotective effects and antagonize the long-term neurobehavioral impairment caused by seizures. Autophagy-mediated Zn/cPLA2 and CaMK II signaling in the cerebral cortex may be involved in the neuroprotective effect of leptin. Our results provide new clues for anti-epileptogenetic treatment.