For release: Thursday, March 13, 2008
A new study shows that leptin, a hormone normally associated with eating and metabolism, can inhibit seizures in animal models of epilepsy. The finding may lead to new ways of treating epilepsy. It also may help explain how the ketogenic diet, which is sometimes used to treat epilepsy, reduces seizures.
The ketogenic diet is extremely high in fats and low in carbohydrates. The diet reduces seizures in many people, but researchers are not certain how it works. Recent studies have shown that the diet increases blood levels of leptin in rodents. Other studies in cell cultures have shown that leptin can alter seizure-like brain signals.
In the new study, investigators led by Liu Lin Thio M.D., Ph.D. and Kelvin Yamada, M.D., of Washington University in St. Louis, tested whether leptin might contribute to the anti-convulsant effect of the ketogenic diet. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the January 2008 issue of The Journal of Clinical Investigation.
"We are looking for a new treatment for epilepsy, something different from the standard approach," Dr. Yamada explains.
Most anticonvulsant drugs are chemical compounds that act on neurotransmitters (nerve signaling chemicals) and pore-like structures called ion channels throughout the brain. In contrast, leptin is made up of a short sequence of amino acids called a peptide. Leptin acts on proteins called receptors that may trigger changes which reduce brain excitability. It also may work in other ways that are not yet determined. Therefore it might be able to treat seizures in different ways and with fewer side effects than current anticonvulsant drugs.
In the new study, the researchers tested leptin's effect on focal seizures (seizures restricted to one part of the brain) by injecting leptin along with a seizure-inducing drug called 4-aminopyridine into the brains of rats. They found that rats which received leptin had shorter and less frequent seizures than rats that received 4-aminopyridine alone.
The researchers also tested leptin's effect on generalized convulsive seizures induced by a chemical called pentylenetetrazole. Generalized seizures affect both sides of the brain. The researchers gave mice leptin as a nose spray 30 minutes prior to the seizure-inducing drug. The intranasal leptin rapidly entered the brain and bloodstream and delayed the onset of seizures. Additional studies showed that leptin made cultured hippocampal neurons less likely to fire out of control under seizure-promoting conditions.
Dr. Yamada and his colleagues also showed that leptin activated two signaling proteins called JAK2 (Janus kinase 2) and P13K (phosphatidylinositol 3-kinase). These proteins blocked nerve signals triggered by the neurotransmitter glutamate. This provides a possible explanation for leptin's anticonvulsant effect.
Because the brain's leptin levels increased rapidly after leptin was sprayed into the nose, the researchers suspect that it entered the brain directly rather than first going into the bloodstream. If so, leptin might be very useful in emergency situations where seizures need to be halted very quickly, Dr. Yamada says. Most anticonvulsants must go into the bloodstream before they can reach the brain, which slows their effect.
While the study shows that leptin can reduce seizures in an acute setting, leptin may not be useful as a chronic treatment because it has a short half-life of 15-30 minutes, Dr. Yamada says. People would have to take it approximately every half hour or use a continuous infusion to maintain stable levels of the drug in the brain. However, researchers might be able to find a drug with similar effects that will last longer in the body. Doctors might also be able to use gene therapy to trigger leptin production in brain regions where seizures begin, the researchers said.
Although these studies suggest that the ketogenic diet may work by increasing production of leptin, more studies are needed to confirm this. The diet may have other anticonvulsant effects that are not yet defined. In addition, the chronically elevated leptin caused by the ketogenic diet might affect the brain differently than a single dose of leptin given near the time of a seizure, Dr. Yamada says.
The researchers are now planning additional studies to determine how leptin reaches the brain and how it influences neuronal signaling. They are also studying JAK2 and P13K to try to verify that those proteins are important to leptin's anti-seizure activity. If so, drugs that increase the levels of JAK2 and P13K might be useful for treating epilepsy.
The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services. The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
-By Natalie Frazin
]Xu L, Rensing N, Yang X-F, Zhang HX, Thio LL, Rothman SM, Weisenfeld AE, Wong M, Yamada KA. Leptin inhibits 4-aminopyridine– and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents. The Journal of Clinical Investigation, January 2008, Vol. 118, No. 1, pp. 272-280.
Last Modified March 13, 2008