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.
Summary:Purpose: The antiepileptic drug levetiracetam (LEV) is an enigma. Despite the fact that it specifically binds to the presynaptic vesicle protein, SV2A, no satisfactory mechanism of action has yet been identified. Using a combination of electrophysiological and cellular imaging techniques, we carefully tested the hypothesis that LEV directly interferes with neurotransmitter release.Methods: We measured extracellular evoked responses in the CA1 region of rat hippocampal slices after paired pulse stimulation and after application of up to 10 pulses applied at 5-80 Hz. In parallel experiments, we used quantitative 2-photon microscopy and the fluorescent vesicular marker FM1-43 to measure the effect of repetitive stimulation on presynaptic vesicle release.Results: Acute exposure to LEV (100 µM) had no effect on paired pulse synaptic responses. However, when slices were exposed to LEV for 3 h, there was a significant alteration in paired pulse responses and a more striking reduction in late synaptic potentials delivered in an 80 Hz train. LEV significantly reduced the rate of vesicle release assessed by FM1-43 destaining during 1 Hz stimulation.Conclusion: LEV is unique among currently available antiepileptics, because it directly inhibits presynaptic neurotransmitter release in a use-dependent fashion. While there are alternate explanations for this observation, it is plausible that LEV exerts its effect by binding to a protein selectively expressed in presynaptic nerve terminals.
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