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

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 pentylenetetrazoleinduced 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.

Leptin regulation of hippocampal synaptic function in health and disease

“…Indeed, our laboratory was the first to report that application of leptin to juvenile hippocampal slices (P11-18) induces a rapid depression of excitatory synaptic transmission that readily reverses on leptin washout [14]. In accordance with this, transient synaptic depressions have been reported in response to leptin in both mouse and rat hippocampus at similar stages of postnatal development [28,29]. However, the leptindriven synaptic depression observed during early postnatal development is in marked contrast to the effects of this hormone in adult tissue.…”

Leptin Is Induced in the Ischemic Cerebral Cortex and Exerts Neuroprotection Through NF-κB/c-Rel–Dependent Transcription

“…A similar pattern of U-shaped dose-response to leptin has been reported in other experimental settings. 19 At 100 ng/mL, even delayed application of leptin provided neuroprotection (Figure 1B). Leptin significantly reduced the rate of OGDinduced neuronal apoptosis measured by means of TUNEL/ Hoechst 33258 nuclear staining ( Figure 1C).…”

Anticonvulsant effects of leptin in epilepsy

“…This study reveals that, in agreement with previous findings on leptin's effect on the hippocampus and seizures (11), it is the JAK2/PI3K pathway (leptin is known to signal through its receptor by activating JAK/STAT and JAK2/PI3K pathways) that is likely to be involved, as Xu et al show that JAK2 and PI3K antagonists prevented leptin inhibition of AMPA receptor-regulated synaptic transmission (Figure 1). In light of the results of Xu et al (8) and earlier observations that leptin levels may be increased during consumption of a ketogenic diet (12), it is plausible that leptintriggered signaling may play a role in the known beneficial effects of a ketogenic diet on suppression of seizures (13).…”

“…First, the rodent models tested by Xu et al (8) are acute models of seizure generation, and seizures were generated in the face of elevated leptin levels either via cortical or nasal application of the hormone. In almost all cases of epilepsy, patients are identified and treated after the first episode of a seizure has occurred.…”

“…While new avenues of research in this area are being pursued by many, the study by Xu et al reported in this issue of the JCI (8) reveals that the leptin signaling pathway has important functions that go beyond its role in the regulation of food intake and metabolism. In their study, these authors describe the mechanisms of action of leptin in the hippocampus and show that leptin opposes the propagation of seizures in two rodent seizure models.…”