Researchers speculated that reductions in a protein modification called O-GlcNAcylation in the brain cells of rats and mice might lead to neural excitability, which is a known trigger of seizures.
In the new study, increasing levels of this protein with glucosamine — which is a supplement used to help reduce pain in osteoarthritis, among other conditions — was found to reduce neural excitability in rodents.
The findings not only help to shed light on the processes behind neural excitability, but they may also have identified a new treatment target for epilepsy.
Study co-author Prof. John Chatham, of the Department of Pathology at the University of Alabama at Birmingham, and colleagues recently reported their findings in The Journal of Neuroscience.
Epilepsy is a neurological disorder that is estimated to affect around 3 million adults and 470,000 children in the United States.
The condition is characterized by unpredictable, recurrent seizures, which can occur when brain cells become hyperactive. This may cause surges of electrical activity that disrupt signaling between brain cells.
In a previous study, Prof. Chatham and team found that increases in protein O-GlcNAcylation are associated with a reduction in the strength of synapses in the hippocampus of the brain. Synapses are structures that allow neurons to transmit signals to each other.
The team notes that neural excitability in the hippocampus — or the learning and memory region of the brain — is often implicated in people with epilepsy.
Given their previous findings, the researchers hypothesized that increasing O-GlcNAcylation levels could help to reduce neural excitability, thereby preventing seizures.
O-GlcNAcylation levels and neural activity
The researchers tested their theory with their latest research, by monitoring the effects of the dietary supplement glucosamine against neural excitability.
The team explains that glucosamine blocks an enzyme that clears O-GlcNAcylation from the brain, which leads to a rapid increase in levels of the protein.
For their study, Prof. Chatham and colleagues first applied glucosamine — alongside another compound that inhibits the O-GlcNAcylation-clearing enzyme — to hippocampal brain slices derived from rats and mice. Neural excitability in the brain slices was induced by drugs.
Treatment with the two compounds prompted an increase in O-GlcNAcylation levels, which led to a reduction in surges of electrical activity in a hippocampal region called CA1.
What is more, the researchers found that treatment with glucosamine alone for just 10 minutes was enough to reduce drug-induced neural excitability.
Interictal spikes reduced in mice
The scientists also identified a decrease in spontaneous firing of pyramidal brain cells in the CA3 region of the hippocampus in response to an increase in O-GlcNAcylation levels.
Since the CA3 region regulates neural firing in the CA1 region, the team speculates that reduced spontaneous firing in the CA3 region is likely what reduces neural excitability in CA1.
In mouse models, the researchers found that increasing O-GlcNAcylation levels also led to a reduction in brain activity spikes related to epilepsy, which are known as interictal spikes.
Taken together, the researchers believe that their findings may point to a novel target for the treatment of epilepsy. The team concludes:
"Our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics."