Childhood absence epilepsy (CAE), a subtype of idiopathic generalized epilepsy, is characterized by frequent ‘absent‘ seizures, during these seizures the patient‘s consciousness is briefly impaired. The child will stare blankly ahead and can be unaware or unresponsive for between 5 and 20 s. Theses seizures are typically not accompanied by convulsions. Absent seizures emerge between 3 and 12 years of age and can occur from 20 to several hundred times each day. Absent seizures are slightly more common in girls than in boys and account for 10–12% of epilepsy cases in children under 16 years of age. “Childhood absence epilepsy strikes at a critical developmental age that can result in scholastic and learning disabilities as well as problems in social adaptation and family interactions”, explains Antonio V Delgado-Escueta (David Geffen School of Medicine, CA, USA).
A total of 20 mutations in the CACNA1H gene have been associated with CAE. Now researchers at UCLA (CA, USA) have identified a mutation in the gene encoding the GABA receptor (GABAR) that is responsible for the development of CAE. This finding may also provide an explanation for why the disease disappears in adulthood. Drugs such as valproate, ethosuximide and clonazepam are currently used to control absent seizures, but it is hoped that this discovery will aid the development of new treatments for CAE, as well as other kinds of epilepsy.
The DNA of 48 CAE patients was analyzed and a mutation in the GABAR gene was discovered in four patients. “We identified this genetic mutation in 8% of study patients with CAE, which is significant”, commented study author Richard W Olsen. The neurotransmitter GABA binds to GABAR, which inhibits the excitation of nerve cells in the brain. When this mechanism is lost or reduced seizures develop. It was also found that the mutation was inherited, with the mutant gene affecting several generations of families. By contrast, the variation was not observed in the 630 healthy individuals who were not suffering from CAE.
The location of the mutation was pinpointed to the GABRB3 gene, which encodes the GABAR β3 subunit. The researchers found that the mutations were located in a signal peptide, rather than in the main body of the GABAR β3 subunit. Signal peptides are short sequences that guide the transport of proteins. GABAR β3 has an alternative signal peptide termed exon 1A. Exon 1A is highly expressed in the developing brain, but expression is reduced as the brain matures and children reach adulthood. “This may help explain why CAE disappears during adolescence and adulthood since exon 1a is not expressed at an adult age in the critical region responsible for absence seizures”, said Miyabi Tanaka.
The mutation in the signal peptide resulted in excessive post-translational modification of the protein. The developing protein was modified with sugars and this hyperglycosylation led to a reduction in the number of GABARs at the nerve cell surface. As a result, the total GABA currents (which are important for regulating the cell) were reduced, which resulted in absent seizures.
The researchers hope that new treatment approaches for epilepsy may result from these findings, with suppression of the expression of the mutated signal peptide being a possibility. The next step will be a larger population study of children with CAE that have no family history of epilepsy. This will allow the researchers to determine how common the mutations are.
Source: Tanaka M, Olsen RW, Medina TM et al.: Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am. J. Hum. Genet. 82(6), 1249–1261.
Study links air pollution to risk of stroke
Researchers from the University of Michigan (MI, USA) have conducted a study to investigate the association between ambient air pollution and the risk of ischemic stroke and transient ischemic attack (TIA). The results are published in Annals of Neurology.
Lynda Lisabeth and colleagues conducted the research into the effects of air pollution in a community with a large petroleum and petrochemical industry. The Brain Attack Surveillance in Corpus Christi (BASIC) project is a population-based stroke surveillance project designed to record all the strokes occurring in Nueces County, TX, USA. The researchers obtained daily counts of ischemic strokes and TIAs from the BASIC project between 2001 and 2005. These cases were identified by trained staff, with later verification by neurologists. Daily particulate matter less than 2.5 µm (PM2.5) in diameter and ozone meteorological data were also obtained for the same time period.
Lisabeth and colleagues found borderline significant associations between ischemic stroke/TIA risk and same day and previous day exposure to fine particulate matter. They also observed similar associations between ozone exposure and stroke/TIA risk. The researchers noted that, compared with other regions in the USA, PM2.5 exposures were relatively low, possibly as a result of prevailing wind patterns and the proximity to the coast. “Although the magnitude of elevated risk of stroke/TIA due to PM2.5 exposure was relatively small, the vast majority of the public is exposed to ambient air pollution at the levels observed in this community or greater every day, suggesting a potentially large public health impact”, warn the authors.
Data suggest that particulate air pollution is associated with acute vasoconstriction of arteries and increased plasma viscosity. These changes may enhance blood clot formation, although further studies will be required to confirm this. Nevertheless, the current study supports the hypothesis that recent exposure to fine particulate matter may increase the risk of ischemic cerebrovascular events. “While our observed association between PM2.5 and stroke/TIA risk requires further study in additional regions in the USA with varying types of climates and possibly with alternative study designs, it does call into question current standards for fine particulate matter and whether these standards are sufficient to protect the public with regard to stroke, our nation‘s third leading cause of death”, said the authors. Furthermore, while the focus of the study was on PM2.5, the observed association between ozone levels and stroke/TIA risk suggest that ambient air pollution in general may be a risk factor.
Source: Lisabeth LD, Escobar JD, Dvonch JT et al.: Ambient air pollution and risk for ischemic stroke and transient ischemic attack. Ann. Neurol. DOI: 10.1002/ana.21403 (2008) (Epub ahead of print).
Seizure drug may be used to treat alcohol dependence
Gabapentin has mainly been used in the treatment of seizures due to its anticonvulsant properties. Recent research conducted at The Scripps Research Institute, CA, USA, suggests that gabapentin could be used to treat alcohol-dependence. Cellular and behavioral studies were conducted in order to analyze the effect of gabapentin on the central amygdala, a region of the brain involved in fear- and stress-related behaviors as well as regulating ethanol consumption. Previous studies have shown that gabapentin can significantly reduce alcohol intake and cravings following detoxification in alcoholics. However, the mechanism of action oF gabapentin in the brain remains to be fully elucidated. This new study provides some insight into the neural signaling mechanism of gabapentin in combating alcohol dependence.
The effects of gabapentin on the behavior of alcohol-dependent and nondependent rats were analyzed. It was found that alcohol-dependent rats that received gabapentin drank significantly less alcohol and exhibited less anxiety when faced with alcohol abstinence in comparison to rats that did not receive gabapentin. No change in behavior was seen in nondependent rats receiving the drug. Effects of gabapentin were blocked in the presence of a GABAB-receptor antagonist, indicating that gabapentin‘s cellular mechanisms are likely due to changes in the release of the transmitter GABA at inhibitory synapses.
“The results are exciting”, said Marisa Roberto, a Research Assistant Professor at Scripps. “Our research shows that gabapentin not only changes the alcohol-consumption patterns of addicted rats (and not of the control group), but also may reverse some of the effects of addiction on a specific neurotransmitter in the brain”. George Koob, chair of the Scripps Research Committee on the Neurobiology of Addictive Disorders and co-director of the Pearson Center for Alcoholism and Addiction Research at Scripps Research Institute added, “Cellular and behavioral studies converged to suggest that indeed gabapentin could normalize GABAergic tone in a specific brain region known to be dysregulated in dependent animals. Such results provide a strong rationale for translating these observations back to the clinical setting for the treatment of alcoholism”.
The researchers will further investigate the mechanism of action of gabapentin. Clinical trials will also be conducted to assess the efficacy of gabapentin as a potential treatment for alcohol dependence.
Source: www.sciencedaily.com/releases/2008/05/080528121256.htm and, Roberto M, Gilpin NW, O‘Dell LE et al.: Cellular and behavioral interactions of gabapentin with alcohol dependence. J. Neurosci. 28(22), 5762–5771 (2008).
New drug candidate discovered for the treatment of Alzheimer‘s disease
A novel drug candidate has been shown to offer nerve cell protection in patients suffering from Alzheimer‘s disease.
AL-108, discovered by Illana Gozes from Tel Aviv University, Israel, was seen to protect patients with mild cognitive damage against memory loss. Gozes emphasized the fact that drugs should be developed that maintain the survival of healthy cells rather than attempt to save dying cells, “My logic is that if you try to protect a dead cell, it won‘t work. We need to protect the living cell between the death sentence of having Alzheimer‘s and actual cell death”, states Gozes.
The discovery of AL-108 came about from the hypothesis that proteins produced by glial cells may be able to repair cell damage brought on by neurodegenerative disorders, since glial cells provide support and protection for neurons and are involved in neuronal repair.
Investigation by Gozes and her team of researchers led to the identification of activity-dependent neuroprotective protein (ADNP), a protein involved in brain repair. However, development of this protein into a drug would mean that it would be unable to cross the BBB. This led the researchers to undertake a systematic deletion of the protein. One fragment of the protein (NAP) was seen to display significant neuroprotection as it was able to protect nerve cells against severe oxidative stress. “What happens in the nerve cells of Alzheimer‘s brains can be likened to a derailed train”, says Gozes. “The nerve cell skeleton – the microtubules – are like the rails, and a protein called tau functions like the ties between the rails. In Alzheimer‘s, the ties fall off, the tracks fall apart and nerve cells die. AL-108 however, seems to prevent this process from accelerating”.
Results show that AL-108 is able to protect against the formation of amyloid plaques, which is a feature associated with Alzheimer‘s disease. In addition, AL-108 appears to protect against a decline in cognitive function.
AL-108 has recently passed a Phase II study in a US FDA approved clinical trial. It is currently being developed by Allon Therapeutics, Canada, and is thought to be ready in approximately 5 years time.
Source: www.sciencedaily.com/releases/2008/05/080529162711.htm