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Leptin inhibits 4-aminopyridine– and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents
Lin Xu, … , Michael Wong, Kelvin A. Yamada
Lin Xu, … , Michael Wong, Kelvin A. Yamada
Published December 20, 2007
Citation Information: J Clin Invest. 2008;118(1):272-280. https://doi.org/10.1172/JCI33009.
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Research Article

Leptin inhibits 4-aminopyridine– and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents

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Abstract

Leptin is a hormone that reduces excitability in some hypothalamic neurons via leptin receptor activation of the JAK2 and PI3K intracellular signaling pathways. We hypothesized that leptin receptor activation in other neuronal subtypes would have anticonvulsant activity and that intranasal leptin delivery would be an effective route of administration. We tested leptin’s anticonvulsant action in 2 rodent seizure models by directly injecting it into the cortex or by administering it intranasally. Focal seizures in rats were induced by neocortical injections of 4-aminopyridine, an inhibitor of voltage-gated K+ channels. These seizures were briefer and less frequent upon coinjection of 4-aminopyridine and leptin. In mice, intranasal administration of leptin produced elevated brain and serum leptin levels and delayed the onset of chemical convulsant pentylenetetrazole-induced generalized convulsive seizures. Leptin also reduced neuronal spiking in an in vitro seizure model. Leptin inhibited α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor–mediated synaptic transmission in mouse hippocampal slices but failed to inhibit synaptic responses in slices from leptin receptor–deficient db/db mice. JAK2 and PI3K antagonists prevented leptin inhibition of AMPAergic synaptic transmission. We conclude that leptin receptor activation and JAK2/PI3K signaling may be novel targets for anticonvulsant treatments. Intranasal leptin administration may have potential as an acute abortive treatment for convulsive seizures in emergency situations.

Authors

Lin Xu, Nicholas Rensing, Xiao-Feng Yang, Hai Xia Zhang, Liu Lin Thio, Steven M. Rothman, Aryan E. Weisenfeld, Michael Wong, Kelvin A. Yamada

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Figure 1

Leptin inhibits in vivo focal neocortical seizures in rats induced by 4AP injections into the left motor cortex.

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Leptin inhibits in vivo focal neocortical seizures in rats induced by 4A...
(A) Top trace: 15-minute EEG segment recorded from the frontal area ipsilateral to the injection site 45 minutes after the injection of 12.5 nmol 4AP. Asterisks indicate 4 individual seizures. Bottom trace: a 1-minute seizure at an expanded time base to illustrate the electrographic details of the seizure (underlined). (B) Top trace: 15-minute EEG segment recorded 45 minutes after the injection of 12.5 nmol 4AP plus 39 pmol leptin shows 2 shorter, lower-amplitude seizures (asterisks). Bottom trace: a 10-second seizure shown at an expanded time base (underlined). Note the different time calibration compared with A. (C) Location of the burr hole, injection site, and EEG electrodes relative to standard landmarks. (D) Leptin reduced the frequency and duration of 4AP-induced seizures. Seizure frequency (left) and duration (right) in rats injected with 12.5 nmol 4AP alone (white bars; n = 5) or 12.5 nmol plus 39 pmol leptin (black bars; n = 5). Seizure frequency and duration for each rat were determined from the 60 minutes of EEG recordings collected between 30 and 90 minutes after 4AP injection. *P < 0.02 for frequency vs. 4AP alone and *P < 0.001 for duration vs. 4AP alone (unpaired t test).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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