title: Protective role of astrocytic leptin signaling against excitotoxicity.
abstract: Both proconvulsive and anticonvulsive roles of leptin have been reported, suggesting cell-specific actions of leptin in different models of seizure and epilepsy. The goal of our study was to determine the regulation and function of astrocytic leptin receptors in a mouse model of epilepsy and glutamate-induced cytotoxicity. We show that in pilocarpine-challenged mice developing epilepsy with recurrent seizures after a latent period of 2 weeks, hippocampal leptin receptor (ObR) immunofluorescence was increased at 6 weeks. This was more pronounced in astrocytes than in neurons. In cultured astrocytes, glutamate increased ObRa and ObRb expression, whereas leptin pretreatment attenuated glial cytotoxicity by excess glutamate, reflected by better preserved adenosine triphosphate production. The protective role of astrocytic leptin signaling is further supported by the higher lethality of the astrocyte-specific leptin receptor knockout mice in the initial phase of seizure production. Thus, leptin signaling in astrocytes plays a protective role against seizure, and the effects are at least partially mediated by attenuation of glutamate toxicity. Astrocytic leptin signaling, therefore, may be a novel therapeutic target.
authors.affiliation: Blood-Brain Barrier Group, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: Bhavaani
authors.initials: B
authors.lastname: Jayaram
authors.forename: Reas S
authors.initials: RS
authors.lastname: Khan
authors.forename: Abba J
authors.initials: AJ
authors.lastname: Kastin
authors.forename: Hung
authors.initials: H
authors.lastname: Hsuchou
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wu
authors.forename: Weihong
authors.initials: W
authors.lastname: Pan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001254:Astrocytoma / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000633:toxicity; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D005911:Gliosis / Q000209:etiology / Q000473:pathology; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity*; D010862:Pilocarpine / Q000633:toxicity; D054411:Receptors, Leptin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D012008:Recurrence; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D003292:Convulsants; D005904:Glial Fibrillary Acidic Protein; D020738:Leptin; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D010862:Pilocarpine; D018698:Glutamic Acid