Researchers begin to map neuroprotective pathway after epileptic seizure.

In the brain, patterns of neural activity are perfectly balanced. The interplay between activating and inhibitory neurotransmitters ensures that the level of activity stays within the physiological range. Neuronal degeneration represents a pathogenetic hallmark after different brain insults, such as ischemia and epilepsy.  During an epileptic attack excitation gains the upper hand resulting in the death of neurons.

Excessive release of glutamate triggered by pathophysiologic synaptic activity has been put forward as key mechanism in this context.  However, the downstream targets mediating neuroprotection remained so far unknown.  Now, a study from researchers at Bonn University has identified a key player in a signal transduction cascade, which protects neurons from hyperexcitation-induced cell death, like those seen in brain insults. The team state that their results open a new direction for the development of novel therapy options.

Previous studies show that in response to pathophysiologic synaptic activity, multiple signaling cascades are activated that initiate expression of specific genes, which decide between neuronal survival versus death. This can be observed after an epileptic insult where this hyperexcitation is caused by excessive release of the signaling molecule glutamate.  This neurotransmitter can switch on signaling cascades that act neurotoxic; neurons try to protect themselves and prevent the damaging hyperexcitation.  Accumulating evidence shows transcription factors to play an essential role in the processes by which neurons protect themselves. These factors switch on certain genes, which then result in the production of neuroprotective substances via ‘signal transduction cascades’. However, the molecular nature of these ‘body guards’ is so far unresolved.  The current study shows that the protein Synaptotagmin 10 (Syt10) is an integral part of this protective shield.

The current study utilised neurons from mice, in which the Syt10 gene had been ablated, and stimulated them with a glutamate like substance. Results show that when the rats experience an epileptic seizure, the amount of Syt10 in the hippocampal formation of the brain strongly increases.  Data findings show that this treatment resulted in substantial neuronal death.

Results identified the transcription factor, namely NPAS4, which activates the gene for Syt10 in response to pathophysiological neuronal activity. The lab then cultured rodent neurons and added several transcription factors. Data findings show that NPAS4 activated the Syt10 gene and required Syt10 to exert its neuroprotective function.  The group conclude that NPAS4 triggers a signaling cascade that results in the production of neuroprotective factors.

The team surmise that the molecular identity of the neuroprotective substances is still unknown, therefore, the next step is to test other substances. For the future, the researchers state that once the identities of the neuroprotective body guards are revealed, novel avenues for therapy development open up, for example for stroke and epilepsy patients.  They go on to add that the goal would be to administer these protective substances in order to prevent neuronal cell death in the brain.

Source: Bonn University Medical School


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