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Link between infant seizures and adult epilepsy unravelled
Newsdesk Viral vehicle advances ALS therapy Researchers in the USA are hoping for a breakthrough in the treatment of amyotrophic lateral sclerosis (ALS) after they successfully used a virus to transport insulin-like growth factor 1 (IGF-1) genes into diseased motor neurons (Science 2003; 301: 839–42). In ALS, the motor neurons of the brainstem and spinal cord gradually degenerate, leading to atrophy of limb, axial, and respiratory muscles, and eventually to death. “There is no treatment for ALS”, explains Fred Gage (Salk Institute for Biological Studies, La Jolla, CA, USA), “but this may be because it is hard to continuously deliver drugs into the CNS. After our recent discovery that adeno-associated virus [AAV] is transported retrogradely from presynaptic terminals back to the nuclei of motor neurons, we decided to test whether it could deliver genes for neurotrophic factors that might improve the course of the disease.”
Gage’s team injected AAV containing the IGF-1 gene into the respiratory and limb motor muscles of transgenic mice that overexpress superoxide dismutase 1. By use of histochemical techniques, the researchers showed that the injected AAV reached viral receptors on local motor-neuron projections and then travelled up the axons back to the nuclei, where the IGF-1 gene was expressed. In these mice, disease symptoms typically appear on postnatal day 90, followed by death 30 days later. Injection of AAV carrying the IGF-1 gene at postnatal day 60 delayed disease onset by 31 days. The treatment also increased median lifespan from 123 days to 160 days. Even when disease symptoms were already visible, the treatment significantly improved the course of the disease. When injected on day 90, the median lifespan of the animals was 22 days longer than that of
controls. Furthermore, control animals showed substantial muscular disability at 100–110 days, whereas similar symptoms were delayed by 20 days in treated animals. Treated animals also maintained their muscular mass and total bodyweight for much longer than controls. “IGF-1 appears to be able to both delay disease onset and retard its progression”, Gage told The Lancet Neurology. “Our data suggest this may be due to the prevention of apoptosis in affected neurons.” “The main issue in this devastating disease has been getting presumed therapeutic molecules to the site of the pathology (ie, the motor neuron)”, remarked Douglas Mitchell (Royal Preston Hospital, Preston, UK). “This is a way of doing it, and it could have exciting implications for diseasemodifying treatments.” Plans for a clinical trial are being drawn up. Adrian Burton
Link between infant seizures and adult epilepsy unravelled A newly discovered form of cortical long-term plasticity that occurs after fever-induced seizures in infants provides a possible explanation for the increase in susceptibility to adult epilepsy that follows these childhood seizures. Ivan Soltesz and colleagues (University of California, Irvine, CA, USA) first found a link between infant febrile seizures and adult epilepsy in 1999, and have now identified a likely explanation for the connection. The researchers investigated changes in inhibitory GABAergic transmission in the hippocampus of neonatal rats (postnatal day 10) after hyperthermia-induced seizures (Neuron 2003; 39: 599–611). Under normal conditions in the hippocampus, postsynaptically released endocannabinnoids bind to CB1 cannabinnoid receptors on presynaptic neurons, which causes a decrease in presynaptic GABA release in a negative feedback manner. The end result is a decrease in inhibition
THE LANCET Neurology Vol 2 October 2003
of firing in the postsynaptic cell, a mechanism termed depolarisationinduced suppression of inhibition (DSI). “The endocannabinoid-mediated system becomes much more effective after a single episode of prolonged febrile seizures in infancy”, says Soltesz. “After the seizures, the same amount of excitation will lead to an even larger decrease in inhibition”. DSI after seizures shows a more prolonged decay compared with DSI in control animals; Soltesz and colleagues suggest that these effects occur as a result of an increase in the number of CB1 receptors in a subpopulation of GABA-releasing axon terminals in the hippocampus. “This is certainly a mechanism that could promote hyperexcitability and recurrent seizures”, explains Soltesz. As such, “endocannabinoids could prove to be extremely promising, versatile, novel targets for future anti-seizure drug development”, he adds.
The pathophysiological relevance of this mechanism has, however, yet to be confirmed. “It still remains to be determined whether the increased cannabinoid signalling plays a role in the lowering of the epileptic threshold that follows a febrile seizure”, Giovanni Diana (Istituto Superiore di Sanita’, Rome, Italy) told The Lancet Neurology. Stephen Davies (University of Aberdeen, UK) notes: “This paper is not directly addressing the mechanisms of epilepsy. Instead it is looking at the consequences of a seizure event on the activity of the endocannabinoid system . . . and we have next to no idea what the physiological role of this system might be.” Irrespective of the medical implications of this study, Diana thinks that “this paper should represent the dawn of a series of new studies on the role of the endocannabinoid system in neurological and psychiatric disease”. Keri Page
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
589
Gage’s team injected AAV containing the IGF-1 gene into the respiratory and limb motor muscles of transgenic mice that overexpress superoxide dismutase 1. By use of histochemical techniques, the researchers showed that the injected AAV reached viral receptors on local motor-neuron projections and then travelled up the axons back to the nuclei, where the IGF-1 gene was expressed. In these mice, disease symptoms typically appear on postnatal day 90, followed by death 30 days later. Injection of AAV carrying the IGF-1 gene at postnatal day 60 delayed disease onset by 31 days. The treatment also increased median lifespan from 123 days to 160 days. Even when disease symptoms were already visible, the treatment significantly improved the course of the disease. When injected on day 90, the median lifespan of the animals was 22 days longer than that of
controls. Furthermore, control animals showed substantial muscular disability at 100–110 days, whereas similar symptoms were delayed by 20 days in treated animals. Treated animals also maintained their muscular mass and total bodyweight for much longer than controls. “IGF-1 appears to be able to both delay disease onset and retard its progression”, Gage told The Lancet Neurology. “Our data suggest this may be due to the prevention of apoptosis in affected neurons.” “The main issue in this devastating disease has been getting presumed therapeutic molecules to the site of the pathology (ie, the motor neuron)”, remarked Douglas Mitchell (Royal Preston Hospital, Preston, UK). “This is a way of doing it, and it could have exciting implications for diseasemodifying treatments.” Plans for a clinical trial are being drawn up. Adrian Burton
Link between infant seizures and adult epilepsy unravelled A newly discovered form of cortical long-term plasticity that occurs after fever-induced seizures in infants provides a possible explanation for the increase in susceptibility to adult epilepsy that follows these childhood seizures. Ivan Soltesz and colleagues (University of California, Irvine, CA, USA) first found a link between infant febrile seizures and adult epilepsy in 1999, and have now identified a likely explanation for the connection. The researchers investigated changes in inhibitory GABAergic transmission in the hippocampus of neonatal rats (postnatal day 10) after hyperthermia-induced seizures (Neuron 2003; 39: 599–611). Under normal conditions in the hippocampus, postsynaptically released endocannabinnoids bind to CB1 cannabinnoid receptors on presynaptic neurons, which causes a decrease in presynaptic GABA release in a negative feedback manner. The end result is a decrease in inhibition
THE LANCET Neurology Vol 2 October 2003
of firing in the postsynaptic cell, a mechanism termed depolarisationinduced suppression of inhibition (DSI). “The endocannabinoid-mediated system becomes much more effective after a single episode of prolonged febrile seizures in infancy”, says Soltesz. “After the seizures, the same amount of excitation will lead to an even larger decrease in inhibition”. DSI after seizures shows a more prolonged decay compared with DSI in control animals; Soltesz and colleagues suggest that these effects occur as a result of an increase in the number of CB1 receptors in a subpopulation of GABA-releasing axon terminals in the hippocampus. “This is certainly a mechanism that could promote hyperexcitability and recurrent seizures”, explains Soltesz. As such, “endocannabinoids could prove to be extremely promising, versatile, novel targets for future anti-seizure drug development”, he adds.
The pathophysiological relevance of this mechanism has, however, yet to be confirmed. “It still remains to be determined whether the increased cannabinoid signalling plays a role in the lowering of the epileptic threshold that follows a febrile seizure”, Giovanni Diana (Istituto Superiore di Sanita’, Rome, Italy) told The Lancet Neurology. Stephen Davies (University of Aberdeen, UK) notes: “This paper is not directly addressing the mechanisms of epilepsy. Instead it is looking at the consequences of a seizure event on the activity of the endocannabinoid system . . . and we have next to no idea what the physiological role of this system might be.” Irrespective of the medical implications of this study, Diana thinks that “this paper should represent the dawn of a series of new studies on the role of the endocannabinoid system in neurological and psychiatric disease”. Keri Page
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
589